| 1. |
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| 2. |
- Parnetti, L, et al.
(författare)
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Changes in CSF acetyl- and butyrylcholinesterase activity after long-term treatment with AChE inhibitors in Alzheimer's disease.
- 2011
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Ingår i: Acta neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314. ; 124:2, s. 122-129
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Tidskriftsartikel (refereegranskat)abstract
- Objectives - To measure cerebrospinal fluid (CSF) activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in patients with Alzheimer's disease (AD) participating in randomized clinical trials from three European centers, before and after long-term treatment with different AChE inhibitors (AChEIs). Materials and methods - Of the 144 patients included in the study, 104 were treated with donepezil, 15 with galantamine, 16 with rivastigmine, and nine with placebo. CSF AChE and BChE activities were measured at baseline and after 1-year treatment. Results - Donepezil and galantamine groups showed a significant increase in CSF AChE activity at follow-up, while no changes for BChE activity were observed; in donepezil group, a positive correlation between plasma concentration and AChE activity was documented. Conversely, in rivastigmine group, a decrease in CSF activity of both enzymes was observed. CSF AChE and BChE activities were not correlated with the clinical outcome in any group considered. CSF biomarkers did not show any change after treatment. Conclusions - AChEIs differently influence the activity of target enzymes in CSF independent of their pharmacodynamic effects.
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| 3. |
- Abdulridha-Aboud, Wissam, et al.
(författare)
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Characterization of macular structure and function in two swedish families with genetically identified autosomal dominant retinitis pigmentosa
- 2016
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Ingår i: Molecular Vision. - 1090-0535. ; 22, s. 362-373
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To study the phenotype in two families with genetically identified autosomal dominant retinitis pigmentosa (adRP) focusing on macular structure and function. Methods: Clinical data were collected at the Department of Ophthalmology, Lund University, Sweden, for affected and unaffected family members from two pedigrees with adRP. Examinations included optical coherence tomography (OCT), full-field electroretinography (ffERG), and multifocal electroretinography (mfERG). Molecular genetic screening was performed for known mutations associated with adRP. Results: The mode of inheritance was autosomal dominant in both families. The members of the family with a mutation in the PRPF31 (p.IVS6+1G>T) gene had clinical features characteristic of RP, with severely reduced retinal rod and cone function. The degree of deterioration correlated well with increasing age. The mfERG showed only centrally preserved macular function that correlated well with retinal thinning on OCT. The family with a mutation in the RHO (p.R135W) gene had an extreme intrafamilial variability of the phenotype, with more severe disease in the younger generations. OCT showed pathology, but the degree of morphological changes was not correlated with age or with the mfERG results. The mother, with a de novo mutation in the RHO (p.R135W) gene, had a normal ffERG, and her retinal degeneration was detected merely with the reduced mfERG. Conclusions: These two families demonstrate the extreme inter-and intrafamilial variability in the clinical phenotype of adRP. This is the first Swedish report of the clinical phenotype associated with a mutation in the PRPF31 (p.IVS6+1G>T) gene. Our results indicate that methods for assessment of the central retinal structure and function may improve the detection and characterization of the RP phenotype.
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| 4. |
- Ali, Ashfaq, et al.
(författare)
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Paranoid potato : phytophthora-resistant genotype shows constitutively activated defense
- 2012
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Ingår i: Plant Signaling and Behavior. - : Informa UK Limited. - 1559-2316 .- 1559-2324. ; 7:3, s. 400-408
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Tidskriftsartikel (refereegranskat)abstract
- Phytophthora is the most devastating pathogen of dicot plants. There is a need for resistance sources with different modes of action to counteract the fast evolution of this pathogen. In order to better understand mechanisms of defense against P. infestans, we analyzed several clones of potato. Two of the genotypes tested, Sarpo Mira and SW93-1015, exhibited strong resistance against P. infestans in field trials, whole plant assays and detached leaf assays. The resistant genotypes developed different sizes of hypersensitive response (HR)-related lesions. HR lesions in SW93-1015 were restricted to very small areas, whereas those in Sarpo Mira were similar to those in Solanum demissum, the main source of classical resistance genes. SW93-1015 can be characterized as a cpr (constitutive expressor of PR genes) genotype without spontaneous microscopic or macroscopic HR lesions. This is indicated by constitutive hydrogen peroxide (H₂O₂) production and PR1 (pathogenesis-related protein 1) secretion. SW93-1015 is one of the first plants identified as having classical protein-based induced defense expressed constitutively without any obvious metabolic costs or spontaneous cell death lesions.
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| 5. |
- Andreasson, Ingela, 1953, et al.
(författare)
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Assessments and intervention for pupils with reading difficulties in Sweden - A text analyses of individual education plans
- 2015
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Ingår i: International Journal of Special Education. - 0827-3383. ; 30:1, s. 15-24
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Tidskriftsartikel (refereegranskat)abstract
- Since 1995 all Swedish compulsory schools have been required to establish Individual Educational Plans (IEPs) for pupils with special educational needs. According to the Swedish Education Act such a plan should be drawn up if pupils do not achieve the goals in the curriculum or the syllabus. The process of IEPs covers a prior investigation to identify and assess what kind of problems or difficulties a pupil has. These investigations should be the basis for decision to ensure that the pupils get adequate support for their needs. In the current study we examine the use of IEPs for pupils with reading difficulties. Data in the study comprised 150 IEPs. One important part of the analysis of the IEPs included quality aspects of investigations and interventions. The results show a large variation of the quality for both. In many cases there is a lack of prior investigation in the IEPs and in other cases a limited connection between the assessments of the investigations and the interventions. Furthermore, the results indicate interventions based on assessments of the investigations, generally show a higher quality level. Therefore, the key conclusion is that investigations are crucial in designing interventions and establishing IEPs.
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| 6. |
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| 7. |
- Andreasson, Ulrika, et al.
(författare)
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B cell lymphomas express CX(3)CR1 a non-B cell lineage adhesion molecule
- 2008
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Ingår i: Cancer Letters. - : Elsevier BV. - 0304-3835 .- 1872-7980. ; 259:2, s. 138-145
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Tidskriftsartikel (refereegranskat)abstract
- To study the differential expression of cell membrane-bound receptors and their potential role in growth and/or survival of the tumor cells, highly purified follicular lymphoma cells were analyzed, using gene expression analysis, and compared to non-malignant B cell populations. Filtering the genome for overexpressed genes coding for cell membrane-bound proteins/receptors resulted in a hit list of 27 identified genes. Among these, we have focused on the aberrant over expression of CX3CR1, in different types of B cell lymphoma, as compared to non-malignant B cells. We show that CX3CR1, which normally is not expressed on B cells, is expressed both at the mRNA and protein level in several subtypes of lymphoma. CX3CR1 has also shown to be involved in the homing to specific tissues that express the ligand, CX3CL1, in breast and prostate cancer and may thus be involved in dissemination of lymphoma.
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| 8. |
- Andreasson, Ulrika, et al.
(författare)
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Identification of molecular targets associated with transformed diffuse large B cell lymphoma using highly purified tumor cells
- 2009
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Ingår i: American Journal of Hematology. - : Wiley. - 0361-8609 .- 1096-8652. ; 84:12, s. 803-808
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Tidskriftsartikel (refereegranskat)abstract
- Follicular lymphoma (FL) frequently transforms into the more aggressive diffuse large B cell lymphoma (DLBCL-tr), but no protein biomarkers have been identified for predictive or early diagnosis. Gene expression analyses have identified genes changing on transformation but have failed to be reproducible in different studies, reflecting the heterogeneity within the tumor tissue and between tumor samples. Gene expression analyses on Affymetrix Human Genome U133 Plus 2.0 arrays were performed, using flow cytometry sorted tumor cells derived from FL and transformed DLBCL. To identify molecular targets associated with the transformation, subsequent immunohistochemistry (IHC) analyses of the corresponding proteins were performed. Using highly purified cells, this study identified 163 genes, which were significantly deregulated during the transformation in a majority of cases. Among the upregulated transcripts, 13 genes were selected for validation using IHC, based on the availability of commercial antibodies, and galectin-3 and NEK2 proteins specifically identify DLBCL-tr, when compared with FL. We demonstrate that by purifying tumor cells through cell sorting, thereby reducing the heterogeneity due to infiltrating cells, it was possible to identify distinct differences between tumor entities rather than variations due to cellular composition. Galectin-3 and NEK2 both identified a subgroup of DLBCL-tr, and the function of these protein markers also suggests a biological role in the transformation process.
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| 9. |
- Andreasson, Ulrika, et al.
(författare)
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Identification of uniquely expressed transcription factors in highly purified B-cell lymphoma samples.
- 2010
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Ingår i: American Journal of Hematology. - : Wiley. - 0361-8609 .- 1096-8652. ; 85:6, s. 418-425
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Tidskriftsartikel (refereegranskat)abstract
- Transcription factors (TFs) are critical for B-cell differentiation, affecting gene expression both by repression and transcriptional activation. Still, this information is not used for classification of B-cell lymphomas (BCLs). Traditionally, BCLs are diagnosed based on a phenotypic resemblance to normal B-cells; assessed by immunohistochemistry or flow cytometry, by using a handful of phenotypic markers. In the last decade, diagnostic and prognostic evaluation has been facilitated by global gene expression profiling (GEP), providing a new powerful means for the classification, prediction of survival, and response to treatment of lymphomas. However, most GEP studies have typically been performed on whole tissue samples, containing varying degrees of tumor cell content, which results in uncertainties in data analysis. In this study, global GEP analyses were performed on highly purified, flow-cytometry sorted tumor-cells from eight subgroups of BCLs. This enabled identification of TFs that can be uniquely associated to the tumor cells of chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), hairy cell leukemia (HCL), and mantle cell lymphoma (MCL). The identified transcription factors influence both the global and specific gene expression of the BCLs and have possible implications for diagnosis and treatment.
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| 10. |
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| 11. |
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| 12. |
- Andreasson, Ulrika, et al.
(författare)
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The human IgE-encoding transcriptome to assess antibody repertoires and repertoire evolution
- 2006
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 1089-8638 .- 0022-2836. ; 362:2, s. 212-227
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Tidskriftsartikel (refereegranskat)abstract
- Upon encounter with antigen, the B lymphocyte population responds by producing a diverse set of antigen-specific antibodies of various isotypes. The vast size of the responding populations makes it very difficult to study clonal evolution and repertoire composition occurring during these processes in humans. Here, we have explored an approach utilizing the H-EPSILON-encoding transcriptome to investigate aspects of repertoire diversity during the season of antigen exposure. We show through sequencing of randomly picked transcripts that the sizes of patients' repertoires are relatively small. This specific aspect of the transcriptome allows us to construct evolutionary trees pinpointing features of somatic hypermutation as it occurs in humans. Despite the small size of the repertoires, they are highly diverse with respect to VDJ gene usage, suggesting that the H-EPSILON-encoding transcriptome is a faithful mimic of other class-switched isotypes. Importantly, it is possible to use antibody library and selection technologies to define the specificity of clonotypes identified by random sequencing. The small size of the H-EPSILON-encoding transcriptome of peripheral blood B cells, the simple identification of clonally related sets of genes in this population, and the power of library and selection technologies ensure that this approach will allow us to investigate antibody evolution in human B lymphocytes of known specificity. As H-EPSILON repertoires show many of the hallmarks of repertoires encoding other isotypes, we suggest that studies of this type will have an impact on our understanding of human antibody evolution even beyond that occurring in the IgE-producing B cell population.
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| 13. |
- Andreasson, Ulrika
(författare)
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Transcriptional Analysis of Cell-Sorted B-cell Lymphomas From High-throughput to Focused Identification of Molecular Targets
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- B cell lymphomas (BCLs) are a group of severe cancers, afflicting both men and women at different ages. Gene expression profiling (GEP), have during the latest decades fundamentally contributed to a better classification and biological understanding of the different BCLs. Most studies using GEP have analyzed mRNA from tumor tissue constituted of both tumor cells and non-malignant bystander cells. This thesis is based on four original papers where pure, cell-sorted BCL cells are analyzed by GEP. This procedure allows identification of differences in tumor cells rather than variations due to cellular composition. These studies focus on identifying new prognostic, diagnostic and/or functional markers for BCLs, using four different approaches. In the first study, GEP of pure mantle cell lymphoma (MCL) cells were used to identify MCL-associated targets genes. Subsequent immunohistochemistry (IHC) using antibodies raised against a unique protein epitope signature (PrEST) was performed. Using this high-throughput strategy we were able to identify proteins either uniquely or highly expressed in MCL compared to normal lymphoid tissue. This study confirmed the usage of transcriptional screening to identify molecular tumor-associated targets, as well as suggest the PrEST-approach as a novel efficient technique to identify molecular targets with both a known and unknown identity. The indolent growing follicular lymphoma (FL) cells are dependent on interplay with cells in the microenvironment for survival. We analyzed, in a second study, pure FL cells for highly expressed genes encoding surface bound proteins. An aberrant expression of CX3CR1 on the surface, not only on FL cells but also on tumor cells in several other BCLs was identified. CX3CR1 is suggested to be involved in site-specific dissemination, the possibility to use CX3CR1 as a target for antibody-mediated intervention needs however further investigations. The indolent FL often transforms to diffuse large B-cell lymphoma (DLBCL-tr). Previous studies analyzing tumor tissue for markers involved in this high-grade transformation have revealed results with low concordance. In a, we analyzed purified FL and DLBCL-tr tumor cells and found that large inter-tumor heterogeneity still was observed. Despite the heterogenous gene expression, this third study identified distinct differences between tumor entities rather than differences due to various composition of bystander cell and two proteins, galectin-3 and NEK2 pinpointing a subgroup of DLBCL-tr over FL were identified. In the last study, we used a unique material of eight different B cell lymphomas and identified for the first time unique transcription factors for each of these highly purified entities. The identified TFs are not only potential new molecular targets but are also partly responsible for the differences in global gene expression in the different BCLs as demonstrated by unsupervised clustering. In conclusion, analyzing pure lymphoma cells, dramatically enhance the resolution of analyses and allowed for identification of tumor-cell related genes using different approaches. Downstream analyzes of these genes allow for identification of proteins with a major biological importance for BCLs and potentially of new biomarkers.
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| 14. |
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| 15. |
- Areblom, Maria, et al.
(författare)
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A Description of the Yield of Genetic Reinvestigation in Patients with Inherited Retinal Dystrophies and Previous Inconclusive Genetic Testing
- 2023
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Ingår i: Genes. - 2073-4425. ; 14:7
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Tidskriftsartikel (refereegranskat)abstract
- In the present era of evolving gene-based therapies for inherited retinal dystrophies (IRDs), it has become increasingly important to verify the genotype in every case, to identify all subjects eligible for treatment. Moreover, combined insight concerning phenotypes and genotypes is crucial for improved understanding of thevisual impairment, prognosis, and inheritance. The objective of this study was to investigate to what extent renewed comprehensive genetic testing of patients diagnosed with IRD but with previously inconclusive DNA test results can verify the genotype, if confirmation of the genotype has an impact on the understanding of the clinical picture, and, to describe the genetic spectrum encountered in a Swedish IRD cohort. The study included 279 patients from the retinitis pigmentosa research registry (comprising diagnosis within the whole IRD spectrum), hosted at the Department of Ophthalmology, Skåne University hospital, Sweden. The phenotypes had already been evaluated with electrophysiology and other clinical tests, e.g., visual acuity, Goldmann perimetry, and fundus imaging at the first visit, sometime between 1988–2015 and the previous—in many cases, multiple—genetic testing, performed between 1995 and 2020 had been inconclusive. All patients were aged 0–25 years at the time of their first visit. Renewed genetic testing was performed using a next generation sequencing (NGS) IRD panel including 322 genes (Blueprint Genetics). Class 5 and 4 variants, according to ACMG guidelines, were considered pathogenic. Of the 279 samples tested, a confirmed genotype was determined in 182 (65%). The cohort was genetically heterogenous, including 65 different genes. The most prevailing were ABCA4 (16.5%), RPGR (6%), CEP290 (6%), and RS1 (5.5%). Other prevalent genes were CACNA1F (3%), PROM1 (3%), CHM (3%), and NYX (3%). In 7% of the patients there was a discrepancy between the diagnosis made based on phenotypical or genotypical findings alone. To conclude, repeated DNA-analysis was beneficial also in previously tested patients and improved our ability to verify the genotype–phenotype association increasing the understanding of how visual impairment manifests, prognosis, and the inheritance pattern. Moreover, repeated testing using a widely available method could identify additional patients eligible for future gene-based therapies.
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| 16. |
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| 17. |
- Conrotto, Paolo, et al.
(författare)
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Knock-down of SOX11 induces autotaxin-dependent increase in proliferation in vitro and more aggressive tumors in vivo
- 2011
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Ingår i: Molecular Oncology. - : Wiley. - 1574-7891. ; 5, s. 527-537
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Tidskriftsartikel (refereegranskat)abstract
- Abstract in UndeterminedThe transcription factor SOX11 is a novel diagnostic marker for mantle cell lymphoma (MCL), distinguishing this aggressive tumor from potential simulators. Recent data also show that the level of SOX11 correlates to in vitro growth properties in MCL, as well as the clinical progression. We have previously shown that MCL-associated pathways, such as Rb-E2F, are dysregulated leading to decreased proliferation upon overexpression of SOX11, emphasizing the impact of SOX11 on MCL-specific gene expression and growth control. However, it remains to be determined which growth regulatory pathways that are induced upon SOX11 knock-down, leading to an increased cellular growth. Consequently, we established a model cell line with constitutive down-regulation of SOX11. The highly proliferative features of this cell line were investigated by gene expression analysis, proliferation assay, cell cycle distribution and potential to induce tumors in NOD-SCID mice. Our in vitro studies demonstrated a SOX11-dependent regulation of MCL-specific gene expression. In addition, we identified autotaxin (ATX) to be regulated by SOX11. Our results clearly showed a correlation between SOX11 level and cellular growth rate, which was dependent on ATX, as well as a direct relation between the level of SOX11 in tumorigenic cells and the growth rate of these tumors in NOD-SCID mice.
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| 18. |
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| 19. |
- Eriksson, Dennis, et al.
(författare)
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Overview and Breeding Strategies of Table Potato Production in Sweden and the Fennoscandian Region
- 2016
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Ingår i: Potato Research. - : Springer Science and Business Media LLC. - 0014-3065 .- 1871-4528. ; 59, s. 279-294
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Tidskriftsartikel (refereegranskat)abstract
- Recent reductions in the public commitment to potato breeding in Sweden, Norway and Finland call for an evaluation of the current situation regarding the commercial basis for, and structure of, potato breeding in these countries. We here review the extent of cultivation, processing and consumption of table potato in Sweden, as well as provide an overview of the potato breeding tools and programmes in the three countries. We then discuss various strategies to provide long-term stability and increase the impact of public potato breeding, based on the similar overall conditions for potato cultivation across the Fennoscandian region. The conclusions are twofold; first, an increased long-term funding of the public potato breeding programmes is necessary to maintain a minimum level of material, and second, a coordination of the breeding activities in the Fennoscandian region would be of great benefit to all involved stakeholders and allow an enhancement of the current national breeding programmes. In addition, we propose a minimum first field year population size for potato breeding.
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| 20. |
- Forsman, Huamei, et al.
(författare)
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Galectin 3 Aggravates Joint Inflammation and Destruction in Antigen-Induced Arthritis
- 2011
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Ingår i: ARTHRITIS AND RHEUMATISM. - : John Wiley and Sons, Ltd. - 0004-3591 .- 1529-0131. ; 63:2, s. 445-454
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Galectin 3, an endogenous beta galactoside-binding lectin, plays an important role in the modulation of immune responses. The finding that galectin 3 is present in the inflamed synovium in patients with rheumatoid arthritis suggests that the protein is associated with the pathogenesis of this disease. We undertook this study to investigate the influence of galectin 3 deficiency in a murine model of arthritis. Methods. Wild-type (WT) and galectin 3-deficient (galectin 3(-/-)) mice were subjected to antigen-induced arthritis (AIA) through immunization with methylated bovine serum albumin. The concentration of serum cytokines (interleukin-6 [IL-6] and tumor necrosis factor alpha [TNF alpha]) and antigen-specific antibodies was evaluated using a cytometric bead array platform and enzyme-linked immunosorbent assay (ELISA). Cellular IL-17 responses were examined by flow cytometry, ELISA, and enzyme-linked immunospot assay. Results. The joint inflammation and bone erosion of AIA were markedly suppressed in galectin 3(-/-) mice as compared with WT mice. The reduced arthritis in galectin 3(-/-) mice was accompanied by decreased levels of antigen-specific IgG and proinflammatory cytokines. The frequency of IL-17-producing cells in the spleen was reduced in galectin 3(-/-) mice as compared with WT mice. Exogenously added recombinant galectin 3 could partially restore the reduced arthritis and cytokines in galectin 3(-/-) mice. Conclusion. Our findings show that galectin 3 plays a pathogenic role in the development and progression of AIA and that the disease severity is accompanied by alterations of antigen-specific IgG levels, systemic levels of TNF alpha and IL-6, and frequency of IL-17-producing T cells. To our knowledge, this is the first report of in vivo evidence that galectin 3 plays a crucial role in the development of arthritis.
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| 21. |
- Galli, Joakim, et al.
(författare)
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The Biobanking Analysis Resource Catalogue (BARCdb): a new research tool for the analysis of biobank samples.
- 2015
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 1362-4962 .- 0305-1048. ; 43:D1, s. 1158-1162
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Tidskriftsartikel (refereegranskat)abstract
- We report the development of a new database of technology services and products for analysis of biobank samples in biomedical research. BARCdb, the Biobanking Analysis Resource Catalogue (http://www.barcdb.org), is a freely available web resource, listing expertise and molecular resource capabilities of research centres and biotechnology companies. The database is designed for researchers who require information on how to make best use of valuable biospecimens from biobanks and other sample collections, focusing on the choice of analytical techniques and the demands they make on the type of samples, pre-analytical sample preparation and amounts needed. BARCdb has been developed as part of the Swedish biobanking infrastructure (BBMRI.se), but now welcomes submissions from service providers throughout Europe. BARCdb can help match resource providers with potential users, stimulating transnational collaborations and ensuring compatibility of results from different labs. It can promote a more optimal use of European resources in general, both with respect to standard and more experimental technologies, as well as for valuable biobank samples. This article describes how information on service and reagent providers of relevant technologies is made available on BARCdb, and how this resource may contribute to strengthening biomedical research in academia and in the biotechnology and pharmaceutical industries.
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| 22. |
- Gorcenco, Sorina, et al.
(författare)
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Ataxia-pancytopenia syndrome with SAMD9L mutations
- 2017
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Ingår i: Neurology: Genetics. - 2376-7839. ; 3:5
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We describe the neurologic, neuroradiologic, and ophthalmologic phenotype of 1 Swedish and 1 Finnish family with autosomal dominant ataxia-pancytopenia (ATXPC) syndrome and SAMD9L mutations.METHODS: Members of these families with germline SAMD9L c.2956C>T, p.Arg986Cys, or c.2672T>C, p.Ile891Thr mutations underwent structured interviews and neurologic and ophthalmologic examinations. Neuroimaging was performed, and medical records were reviewed. Previous publications on SAMD9L-ATXPC were reviewed.RESULTS: Twelve individuals in both families were affected clinically. All mutation carriers examined had balance impairment, although severity was very variable. All but 1 had nystagmus, and all but 1 had pyramidal tract signs. Neurologic features were generally present from childhood on and progressed slowly. Two adult patients, who experienced increasing clumsiness, glare, and difficulties with gaze fixation, had paracentral retinal dysfunction verified by multifocal electroretinography. Brain MRI showed early, marked cerebellar atrophy in most carriers and variable cerebral periventricular white matter T2 hyperintensities. Two children were treated with hematopoietic stem cell transplantation for hematologic malignancies, and the neurologic symptoms of one of these worsened after treatment. Three affected individuals had attention deficit hyperactivity disorder or cognitive problems. Retinal dysfunction was not previously reported in individuals with ATXPC.CONCLUSIONS: The neurologic phenotype of this syndrome is defined by balance or gait impairment, nystagmus, hyperreflexia in the lower limbs and, frequently, marked cerebellar atrophy. Paracentral retinal dysfunction may contribute to glare, reading problems, and clumsiness. Timely diagnosis of ATXPC is important to address the risk for severe hemorrhage, infection, and hematologic malignancies inherent in this syndrome; regular hematologic follow-up might be beneficial.
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| 23. |
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| 24. |
- Gustavsson, Carolina, et al.
(författare)
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Cerebrospinal fluid levels of insulin, leptin, and agouti-related protein in relation to BMI in pregnant women
- 2016
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Ingår i: Obesity. - : Wiley. - 1930-7381. ; 24:6, s. 1299-1304
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveDuring pregnancy, metabolic interactions must be adapted, though neuroendocrine mechanisms for increased food intake are poorly understood. The objective of this study was to characterize differences in insulin, leptin, and agouti-related protein (AgRP) levels in serum and cerebrospinal fluid (CSF) in pregnant women with normal weight (NW) and pregnant women with overweight (OW) or obesity (OB). Placenta as a source for increased peripheral AgRP levels during pregnancy was also investigated. MethodsWomen were recruited at admission for elective cesarean section. Insulin, AgRP, and leptin were measured in serum and CSF from 30 NW, 25 OW, and 21 OB at term. Serum during pregnancy and placenta at term were collected for further AgRP analysis. ResultsImmunohistology showed placental production of AgRP and serum AgRP levels increased throughout pregnancy. CSF AgRP, leptin, and insulin levels were higher in OW and OB than NW. Serum leptin and insulin levels were higher and AgRP lower in OB than NW. ConclusionsHigh serum AgRP levels might protect from the suppressive effects of leptin during pregnancy. Pregnant women with OB and OW might further be protected from the suppressive effect of leptin by high CSF AgRP levels. Evidence was found, for the first time, of human placental AgRP production mirrored by levels in the circulation.
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| 25. |
- Hall, Ulrika Andersson, et al.
(författare)
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Central and Peripheral Leptin and Agouti-Related Protein during and after Pregnancy in Relation to Weight Change.
- 2018
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Ingår i: Clinical endocrinology. - : Wiley. - 1365-2265 .- 0300-0664. ; 88:2, s. 263-271
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Tidskriftsartikel (refereegranskat)abstract
- To study changes of neuropeptides and adipokines in cerebrospinal fluid (CSF) and serum from pregnancy to post-pregnancy in relation to weight changes, fat mass and glucose metabolism.With high postpartum weight retention being a risk factor in future pregnancies and of life-long obesity we evaluated neuropeptide and adipokine changes in women who either gained weight or were weight stable.Women were followed for 5±1 years after pregnancy and divided into two groups, Weight-Stable and Weight-Gain, by weight change from start of pregnancy.Twenty-five women (BMI 27±5kg/m2 ) recruited at admission for elective caesarean section.CSF and serum levels of agouti-related protein (AgRP), leptin, and insulin, and serum levels of adiponectin and soluble leptin receptor were measured during and after pregnancy. These measurements were further related to fat mass and insulin sensitivity (HOMA-IR).S-AgRP levels during pregnancy were lower in the Weight-Stable group and a 1 unit increase in s-AgRP was associated with 24% higher odds of pertaining to the Weight-Gain group. After pregnancy, s-AgRP increased in the Weight-Stable group but decreased in the Weight-Gain group. Decreased transport of leptin into CSF during pregnancy was reversed by an increased CSF:serum leptin ratio after pregnancy. In women who returned to their pre-pregnancy weight, serum adiponectin increased after pregnancy and correlated negatively with HOMA-IR.S-AgRP concentration in late pregnancy may be one factor predicting weight change after pregnancy, and circulating AgRP may be physiologically important in the long-term regulation of body weight. This article is protected by copyright. All rights reserved.
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| 26. |
- Kjellström, Ulrika, et al.
(författare)
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A five-year follow-up of ABCA4 carriers showing deterioration of retinal function and increased structural changes
- 2022
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Ingår i: Molecular Vision. - 1090-0535. ; 28, s. 300-316
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To investigate whether the reduced retinal function and morphological retinal changes previously demonstrated in ABCA4 carriers had remained stationary or had deteriorated over time at 5-year follow-up to further explore if carriers of an autosomal recessive trait also express a weak phenotype, although this is not expected for an autosomal recessive disorder. Methods: Thirteen ABCA4 carriers from a previous study that included parents to patients with well known genetically verified ABCA4-associated retinal degenerations were reexamined 5 years after the initial examination. As novel genes and new variants in already established genes are continuously reported, all subjects underwent renewed genetic testing with a next-generation sequencing (NGS) panel that included 288 genes associated with retinal dystrophies and an analysis of deep intronic mutations and copy number variations in the ABCA4 gene. Moreover, to evaluate any changes in retinal function and/or structure over time, clinical reassessment with Goldmann perimetry, visual acuity testing, fundus photography, fundus autofluorescence (FAF) imaging, optical coherence tomography (OCT), full-field electro-retinography (ffERG), and multifocal ERG (mf ERG) were performed 5 years after the initial investigation. The values of the ffERG parameters were compared between the two time points (the measurements obtained in the initial study versus the measurements at 5-year follow-up) and with the controls. The mf ERG results of the carriers were compared with those of the controls. Results: The renewed genetic testing confirmed the previously established ABCA4 mutations but also revealed the hypomorph ABCA4 variant c.5603A>T in five ABCA4 carriers. In three of them, the variant was found to be associated with known disease-causing alleles that always carry the c.5603A>T in cis. According to recent publications, the subjects could still be considered ABCA4 carriers because both variants are on the same allele. In the remaining two subjects, c.5603A>T could be in trans with the previously known ABCA4 variant, and the subjects were therefore excluded from the study since they could no longer be considered as carriers only. Statistical comparison of ffERG parameters showed significant reduction of the isolated rod,-as well as the combined rod-cone amplitudes over the five years of follow-up, but not compared with the controls. Concerning macular function, mf ERG amplitudes were reduced for all rings in the carriers compared with the controls. Fundus photographs demonstrated morphological changes in 64% of the carriers, and 36% of them had further changes at follow-up. FAF images showed alterations in 55% of the carriers, with increased changes in 36% of them. Abnormalities on OCT were observed in 82% of the carriers, of whom 9% had newly found abnormalities at follow-up. Conclusions: At 5-year follow-up, the ABCA4 carriers, who previously demonstrated reduced macular function, presented with deterioration of general retinal function, including reduced isolated rod and mixed rod-cone ffERG responses combined with a slight increase in morphological changes in some subjects. This indicates that carriership of at least some ABCA4 variants may cause a condition similar to a subgroup of dry age-related macular degeneration (AMD). In the long run, this might be of importance concerning the possibilities to also treat this subgroup of AMD patients with future gene-based and pharmacological drugs targeting ABCA4-associated disorders.
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| 27. |
- Kjellström, Ulrika, et al.
(författare)
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Attenuation of the retinal nerve fibre layer and reduced retinal function assessed by optical coherence tomography and full-field electroretinography in patients exposed to vigabatrin medication.
- 2014
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Ingår i: Acta Ophthalmologica. - : Wiley. - 1755-3768 .- 1755-375X. ; 92:2, s. 149-157
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To investigate the clinical value of assessment of peripapillary retinal nerve fibre layer (RNFL) thickness with OCT in addition to the evaluation of retinal function measured by full-field electroretinography (ff-ERG) in patients with suspected vigabatrin (VGB)-attributed visual field defects. Methods: Visual fields from adult patients in our clinical follow-up program for VGB medication were analysed. Twelve patients with suspected VGB-attributed visual field defects were selected for the study. They were re-examined with computerized kinetic perimetry, ff-ERG and OCT (2D circle scan). Results: Constricted visual fields were found in all patients. Comparative analysis of ff-ERG parameters showed reduced b-wave amplitudes for the isolated and the combined rod and cone responses (p < 0.0001). The a-wave, reflecting photoreceptor activity, was reduced (p = 0.001), as well as the summed amplitude of oscillatory potentials (p = 0.029), corresponding to inner retinal function. OCT measurements demonstrated attenuation of the RNFL in nine of 12 patients, most frequently superiorly and/or inferiorly. No temporal attenuation was found. Significant positive correlations were found between the total averaged RNFL thickness, superior and inferior RNFL thickness and reduced ff-ERG parameters. Positive correlations were also found between RNFL thickness and isopter areas. Conclusion: OCT measurements can detect attenuation of the RNFL in patients exposed to VGB medication. RNFL thickness correlates with reduced ff-ERG parameters and isopter areas of constricted visual fields, indicating that VGB is retino-toxic on several levels, from photoreceptors to ganglion cells. The study also supports previous studies, suggesting that OCT measurement of the RNFL thickness may be of clinical value in monitoring patients on vigabatrin therapy.
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| 28. |
- Kjellström, Ulrika, et al.
(författare)
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Autosomal recessive Stickler syndrome associated with homozygous mutations in the COL9A2 gene
- 2021
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Ingår i: Ophthalmic Genetics. - : Informa UK Limited. - 1381-6810 .- 1744-5094. ; 42:2, s. 161-169
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Tidskriftsartikel (refereegranskat)abstract
- Background: Stickler syndrome is a hereditary disorder of collagen tissues causing ocular, auditory, orofacial, and joint manifestations. Ocular findings typically include vitreous degeneration, high myopia, retinal detachment, and cataract. Many subjects demonstrate sensorineural or conductive hearing loss. The inheritance is autosomal dominant with mutations in COL2A1, COL11A1, or COL11A2 or autosomal recessive due to mutations in COL9A1, COL9A2, or COL9A3. We describe a family with Stickler syndrome caused by homozygous loss-of-function mutations in COL9A2. Methods: Two brothers from a consanguineous family were examined with genetic testing, visual acuity, Goldmann perimetry, full-field and multifocal electroretinography (ffERG, mERG), optical coherence tomography (OCT), fundus autofluorescence (FAF), fundus photography, and pure-tone audiograms. Results: Both subjects were homozygous for the mutation c.1332del in COL9A2. Their parents were heterozygous for the same mutation. The boys demonstrated reduced visual acuity, vitreous changes and myopia. The proband was operated for retinal detachment and cataract in one eye. FfERG revealed reduced function of both rods and cones and mERG showed reduced macular function. No morphological macular changes were found by OCT or FAF. Both brothers have severe sensorineural hearing loss with down-sloping audiograms but only subtle midface hypoplasia and no, or mild joint problems. Conclusion: Only a few families with Stickler syndrome caused by COL9A2 mutations have been reported. We confirm previous descriptions with a severe ocular and auditory phenotype but mild orofacial and joint manifestations. Moreover, we demonstrate reduced macular and overall retinal function explaining the reduced visual acuity in patients with Stickler syndrome also without retinal complications.
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| 29. |
- Kjellström, Ulrika, et al.
(författare)
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Dose-related changes in retinal function and PKC-alpha expression in rabbits on vigabatrin medication : Effect of vigabatrin in the rabbit eye.
- 2009
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Ingår i: Graefe's Archive for Clinical and Experimental Ophthalmology. - : Springer Science and Business Media LLC. - 1435-702X .- 0721-832X. ; 247:8, s. 1057-1067
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: To investigate, in a rabbit model, the effect of two different doses of vigabatrin (VGB) on retinal function and morphology. METHODS: Twenty-nine rabbits of mixed strain were divided into two groups, receiving either high-dose (n = 15) or low-dose (n = 14) oral VGB treatment (cumulative dose 29.8 +/- 2.9 g and 14.2 +/- 0.6 g respectively). Ten rabbits receiving water served as control animals. The rabbits underwent three baseline ff-ERG measurements before initiation of VGB medication and two ff-ERG registrations during treatment, after 8 and 12-14 weeks respectively. At the end of the study, the expression of protein kinase C-alpha (PKC-alpha), gamma amino butyric acid (GABA) A receptors, vimentin, glial fibrillary acidic protein (GFAP) and peanut agglutinin (PNA) was examined in retinal sections from all rabbits. RESULTS: In animals of the high-dose group, the ff-ERG measurements revealed a significant decrease of isolated rod b-wave amplitudes, combined rod-cone b-wave amplitudes and amplitudes of oscillatory potentials (OPs); OP1, OP2 and OP3. In the low-dose group, the b-wave amplitudes of combined rod-cone responses as well as OP2 and OP3 were significantly reduced. PKC-alpha labeling demonstrated a dose-related translocation of the enzyme in rod bipolar cells, also revealing a significant decline of the number of PKC-alpha labeled rod bipolar cells in treated animals. Vimentin labeling showed a dose-related deviant labeling pattern of Müller cells, with strikingly low labeling intensity in the outer parts of the cells; in the outer limiting membrane (OLM) as well as the outer nuclear layer (ONL). Labeling with antibodies against GABA A receptors and GFAP, as well as PNA staining, revealed no differences between treated animals and controls. CONCLUSIONS: In this study, VGB medication was associated, in a dose-related manner, with a decrease of ff-ERG amplitudes as well as with altered protein expression in rod bipolar cells and Müller cells, suggesting alterations of inner retinal function. The dose-related morphological and electrophysiological changes indicate a retinal pathology that may explain the constricted visual fields seen in some patients treated with VGB.
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| 30. |
- Kjellström, Ulrika, et al.
(författare)
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Electrophysiological evaluation of retinal function in children receiving vigabatrin medication
- 2011
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Ingår i: Journal of Pediatric Ophthalmology and Strabismus. - : SLACK, Inc.. - 0191-3913 .- 1938-2405. ; 48:6, s. 65-357
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To evaluate retinal function in children taking vigabatrin and to explore the influence of age and dose parameters on the results of full-field electroretinography (ff-ERG).METHODS: The ff-ERGs from 14 children receiving vigabatrin were compared with ff-ERGs from healthy controls. Treated children were further grouped according to age (pre-school = 12-71 months; older = 72-228 months). Parameters of drug dosage were compared.RESULTS: Treated children showed rod and cone dysfunction reflected by reduced b-wave amplitudes for the isolated rod response, the combined rod-cone response, and the 30-Hz flicker response. The a-wave amplitude and implicit time for the combined rod-cone response, reflecting photoreceptor function, were also altered. Further evaluation of age groups revealed similar findings in the pre-school group but not in the older group. Alterations in ff-ERG were seen in 57% of the treated children. Pre-school children had received significantly higher daily drug doses with start of medication at younger age. No differences were found concerning cumulative doses or duration of medication.CONCLUSION: Alterations in ff-ERG are as frequent in children as in adults and the results indicate that exposure to high daily doses of vigabatrin may be associated with increased risk of retinal dysfunction, including photoreceptor damage, not previously shown in children. Thus, recommendations of careful follow-up for children receiving vigabatrin are supported.
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| 31. |
- Kjellström, Ulrika, et al.
(författare)
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Full-field ERG and visual fields in patients 5 years after discontinuing vigabatrin therapy.
- 2008
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Ingår i: Documenta Ophthalmologica. - : Springer Science and Business Media LLC. - 1573-2622 .- 0012-4486. ; 117, s. 93-101
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Tidskriftsartikel (refereegranskat)abstract
- Purpose In numerous studies vigabatrin medication has been associated with visual field constriction and alterations in the full-field electroretinogram (ff-ERG), but it is not clear whether these changes are reversible or not. The purpose of this study was to examine patients with visual field loss and reduced ff-ERG several years after discontinuing vigabatrin therapy, in order to investigate reversibility. Methods Eight patients with visual field constriction and reduced cone responses measured by 30 Hz flicker ERG were examined with Goldmann perimetry and ff-ERG 4-6 years after discontinuing medication. The results were compared with investigations conducted during medication, 4-6 years previously. Statistical analysis was also used to compare the ff-ERG results of the patients, during treatment and at follow-up, with a group of 70 healthy subjects. Results Visual field constriction remained 4-6 years after discontinuing vigabatrin therapy. The amplitude of the 30 Hz flicker response also remained reduced on follow-up both compared with the results during treatment and with the control group. Moreover, the amplitude of the isolated rod response and the combined rod-cone response were decreased in the patients compared with the control group, during vigabatrin treatment as well as on follow-up. On follow-up, oscillatory potentials (OPs) also were registered, showing reduced amplitudes in patients compared with controls. The within subject comparison showed no significant changes. Conclusion Vigabatrin attributed visual field constriction and reduced ff-ERG responses remain several years after discontinuing vigabatrin therapy, indicating drug-induced permanent retinal damage.
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| 32. |
- Kjellström, Ulrika, et al.
(författare)
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Increased Plasma cGMP in a Family With Autosomal Recessive Retinitis Pigmentosa Due to Homozygous Mutations in the PDE6A Gene
- 2016
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Ingår i: Investigative Ophthalmology and Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 1552-5783. ; 57:14, s. 6048-6057
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To describe genotype and phenotype in a family with autosomal recessive retinitis pigmentosa (arRP) carrying homozygous mutations in the gene for the α-subunit of cyclic guanosine monophosphate (cGMP)-hydrolyzing phosphodiesterase 6 (PDE6A). Moreover, to compare their plasma cGMP levels to controls, exploring the possible role for cGMP in RP diagnostics.Methods: Seven siblings and their parents were recruited. Microarray, verified by Sanger sequencing, was used for genotyping. Investigations included slit lamp and fundus examination, Goldmann perimetry, full-field and multifocal electroretinography (ERG), and optical coherence tomography (OCT). Cyclic GMP was measured with an immunoassay kit.Results: All siblings and their father were homozygous, and the mother heterozygous, for IVS6+1G>A in PDE6A. Seven family members also carried c1532G>A in ABCA4. Visual fields were constricted with mere central remnants in older subjects and additional temporal crescents in younger subjects. Visual acuity ranged from 0.8 to amaurosis. Full-field ERGs showed extinguished rod responses and minimal cone responses. Multifocal ERGs were severely reduced. Optical coherence tomography revealed either general attenuation or central macular edema. Mean plasma cGMP in patients was approximately twice that in controls.Conclusions: To our knowledge, this is the first phenotypic description of arRP due to homozygous IVS6+1G>A mutations in PDE6A and these seem here to be associated with severe RP leading to early extinction of rod responses as well as reduced macular function. Additionally, patients showed increased plasma levels of cGMP, indicating a possible role for cGMP measurements as part of the clinical tests for this and, after further investigations, maybe other forms of RP.
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| 33. |
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| 34. |
- Lenman, Marit, et al.
(författare)
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Effector-driven marker development and cloning of resistance genes against Phytophthora infestans in potato breeding clone SW93-1015
- 2016
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Ingår i: TAG Theoretical and Applied Genetics. - : Springer Science and Business Media LLC. - 0040-5752 .- 1432-2242. ; 129, s. 105-115
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Tidskriftsartikel (refereegranskat)abstract
- Phytophthora infestans is one of the most devastating plant pathogens worldwide. We have earlier found that the SW93-1015 potato breeding clone has an efficient resistance against P. infestans under field conditions in Sweden, which has an unusually high local diversity of the pathogen. This potato clone has characteristics that are different from classical R-gene-mediated resistance such as elevated levels of hydrogen peroxide (H2O2) under controlled conditions. Analysis of 76 F1 potato progenies from two individual crosses resulted in nearly 50 % resistant clones, from both crosses. This result suggests that the SW93-1015 clone has a simplex genotype for this trait. Screening with over 50 different P. infestans effectors, containing the conserved motif RXLR (for Arg, any amino acid, Leu, Arg), revealed a specific response to Avr2, which suggests that SW93-1015 might contain a functional homolog of the R2 resistance gene. We cloned eight R2 gene homologs from SW93-1015, whereof seven have not been described before and one gene encoded a protein identical to Rpi-ABPT. Expression of this gene in potato cultivar D,sir,e provided R2-specific resistance, whereas other homologues did not. Using RNAseq analyses we designed a new DNA marker for the R2 resistance in SW93-1015. In summary, we have demonstrated the use of effector screening in practical breeding material and revealed the key resistance mechanism for SW93-1015.
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| 35. |
- Ljung Faxén, Ulrika, et al.
(författare)
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HFpEF and HFrEF Display Different Phenotypes as Assessed by IGF-1 and IGFBP-1
- 2017
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Ingår i: Journal of Cardiac Failure. - : Elsevier BV. - 1071-9164 .- 1532-8414. ; 23:4, s. 293-303
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAnabolic drive is impaired in heart failure with reduced ejection fraction (HFrEF) but insufficiently studied in heart failure with preserved ejection fraction (HFpEF). Insulin-like growth factor 1 (IGF-1) mediates growth hormone effects and IGF binding protein 1 (IGFBP-1) regulates IGF-1 activity. We tested the hypothesis that HFpEF and HFrEF are similar with regard to IGF-1 and IGFBP-1.Methods and ResultsIn patients with HFpEF (n = 79), HFrEF (n = 85), and controls (n = 136), we analyzed serum IGF-1 and IGFBP-1 concentrations, correlations, and associations with outcome. Age-standardized scores of IGF-1 were higher in HFpEF, median arbitrary units (interquartile range); 1.21 (0.57–1.96) vs HFrEF, 0.09 (-1.40–1.62), and controls, 0.22 (-0.47-0.96), P overall <.001. IGFBP-1 was increased in HFpEF, 48 (28–79), and HFrEF, 65 (29–101), vs controls, 27(14–35) µg/L, P overall <.001. These patterns persisted after adjusting for metabolic and HF severity confounders. IGF-1 was associated with outcomes in HFrEF, hazard ratio per natural logarithmic increase in IGF-1 SD score 0.51 (95% confidence interval 0.32–0.82, P = .005), but not significantly in HFpEF. IGFBP-1 was not associated with outcomes in either HFpEF nor HFrEF.ConclusionHFpEF and HFrEF phenotypes were similar with regard to increased IGFBP-1 concentrations but differed regarding IGF-1 levels and prognostic role. HFrEF and HFpEF may display different impairment in anabolic drive.
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| 36. |
- Ljung Faxen, Ulrika, et al.
(författare)
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HFpEF and HFrEF exhibit different phenotypes as assessed by leptin and adiponectin
- 2017
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 228, s. 709-716
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Tidskriftsartikel (refereegranskat)abstract
- Background: Heart failure with reduced ejection fraction (HFrEF) exhibits a reverse metabolic profile. Whether this profile exists in HF with preserved ejection fraction (HFpEF) is unknown. We tested the hypothesis that HFpEF and HFrEF are similar regarding concentrations of and prognostic impact of leptin and adiponectin.Methods: In patients with HFpEF(n = 79), HFrEF(n = 84), and controls(n = 71), we analyzed serum leptin and adiponectin concentrations, their correlations, and associations with outcome.Results: Leptin levels in HFpEF and HFrEF were increased (p < 0.05) compared to controls; with the highest levels in HFpEF, median (IQR), 23.1 (10.2-51.0), vs. HFrEF 15.0 (6.2-33.2), and vs. controls 10.8 (5.4-18.9) ng/mL. There was no difference between HFpEF and HFrEF p=0.125 (adjusted for gender, BMI and age). Leptin was inversely associated with NT-proBNP (r = -0.364 p = 0.001) and associated with better outcome in HFrEF (HR per ln increase of leptin 0.76, 95% CI 0.58-0.99, p = 0.044) but not in HFpEF.Crude levels of adiponectin were similar in HFpEF: 11.8 (7.9-20.1), HFrEF: 13.7 (7.0-21.1), and controls: 10.5 (7.4-15.1) mu g/L. In men, adjusted similarly as leptin, there was no difference between HFpEF and HFrEF, p = 0.310 but, compared to controls, higher levels in HFpEF (p - 0.044) and HFrEF (p - 0.001). Adiponectin correlated positively with NT-proBNP; r = 0.396 p < 0.001 and higher levels were associated with adverse outcome only in HFrEF (HR per ln increase 2.88 (95% CI 1.02-8.14, p = 0.045).Conclusion: HFpEF and HFrEF share elevated levels of leptin and adiponectin. However, the concept of reverse metabolic profile could not be confirmed in HFpEF, suggesting that HFpEF might have a conventional metabolic profile, rather than a distinct HF syndrome.
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| 37. |
- Ndegwa, Nelson, et al.
(författare)
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Gastric Microbiota in a Low-Helicobacter pylori Prevalence General Population and Their Associations With Gastric Lesions
- 2020
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Ingår i: Clinical and Translational Gastroenterology. - : LIPPINCOTT WILLIAMS & WILKINS. - 2155-384X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION:Non-Helicobacter pylori microbiota might account for some cases with unexplained chronic gastritis that may in a minority eventually progress to gastric cancer through the Correa cascade. We characterized gastric microbiota by describing the normal stomach, compared it with early precancerous lesions and other disease states, and assessed whether H. pylori status affects bacterial diversity.METHODS:In a population-based study of those with and without gastrointestinal symptoms, cytology brush samples were collected during endoscopy from 316 individuals. Mucosal status was classified as normal mucosa (171), nonatrophic H. pylori gastritis (33), atrophic gastritis (12), or antral chemical gastritis (61). The 16S rRNA gene sequencing and analysis were performed to characterize the microbiota.RESULTS:Microbiota in atrophic gastritis and nonatrophic H. pylori gastritis stomachs were dysbiotic and differed from those in the normal stomach (P = 0.001). The normal stomach had the highest microbial diversity, followed by antral chemical gastritis. The atrophic gastritis and chronic H. pylori gastritis groups had the lowest diversity, a difference that was statistically significant (P = 0.01). Besides H. pylori, non-H. pylori bacteria accounted for group differences. Microbial network analysis showed that the normal group network was most highly connected, whereas the H. pylori gastritis group had the lowest connection. We found an increasing positive co-occurrence of oral bacteria in the stomach because samples deviated from the normal network, some of which were pathogens. The H. pylori-negative group had the highest microbial diversity (Shannon index) compared with the H. pylori-positive group (P = 0.001).DISCUSSION:In this low-H. pylori prevalence general population, the gastric mucosal microbiota of the normal stomach differed significantly from those with nonatrophic or atrophic gastritis. There was an increasing abundance of pathogenic bacteria from the normal state to early precancerous states.
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| 38. |
- Nikopoulos, Konstantinos, et al.
(författare)
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Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects
- 2016
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 99:3, s. 770-776
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Tidskriftsartikel (refereegranskat)abstract
- Cone-rod degeneration (CRD) belongs to the disease spectrum of retinal degenerations, a group of hereditary disorders characterized by an extreme clinical and genetic heterogeneity. It mainly differentiates from other retinal dystrophies, and in particular from the more frequent disease retinitis pigmentosa, because cone photoreceptors degenerate at a higher rate than rod photoreceptors, causing severe deficiency of central vision. After exome analysis of a cohort of individuals with CRD, we identified biallelic mutations in the orphan gene CEP78 in three subjects from two families: one from Greece and another from Sweden. The Greek subject, from the island of Crete, was homozygous for the c.499+1G>T (IVS3+1G>T) mutation in intron 3. The Swedish subjects, two siblings, were compound heterozygotes for the nearby mutation c.499+5G>A (IVS3+5G>A) and for the frameshift-causing variant c.633delC (p.Trp212Glyfs(∗)18). In addition to CRD, these three individuals had hearing loss or hearing deficit. Immunostaining highlighted the presence of CEP78 in the inner segments of retinal photoreceptors, predominantly of cones, and at the base of the primary cilium of fibroblasts. Interaction studies also showed that CEP78 binds to FAM161A, another ciliary protein associated with retinal degeneration. Finally, analysis of skin fibroblasts derived from affected individuals revealed abnormal ciliary morphology, as compared to that of control cells. Altogether, our data strongly suggest that mutations in CEP78 cause a previously undescribed clinical entity of a ciliary nature characterized by blindness and deafness but clearly distinct from Usher syndrome, a condition for which visual impairment is due to retinitis pigmentosa.
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| 39. |
- Nordström, Lena, et al.
(författare)
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Expanded clinical and experimental use of SOX11-using a monoclonal antibody
- 2012
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 12:269
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Tidskriftsartikel (refereegranskat)abstract
- Background: The transcription factor SOX11 is of diagnostic and prognostic importance in mantle cell lymphoma (MCL) and epithelial ovarian cancer (EOC), respectively. Thus, there is an unmet clinical and experimental need for SOX11-targeting assays with low background, high specificity and robust performance in multiple applications, including immunohistochemistry (IHC-P) and flow cytometry, which until now has been lacking. Methods: We have developed SOX11-C1, a monoclonal mouse antibody targeting SOX11, and successfully evaluated its performance in western blots (WB), IHC-P, fluorescence microscopy and flow cytometry. Results: We confirm the importance of SOX11 as a diagnostic antigen in MCL as 100% of tissue micro array (TMA) cases show bright nuclear staining, using the SOX11-C1 antibody in IHC-P. We also show that previous reports of weak SOX11 immunostaining in a fraction of hairy cell leukemias (HCL) are not confirmed using SOX11-C1, which is consistent with the lack of transcription. Thus, high sensitivity and improved specificity are demonstrated using the monoclonal SOX11-C1 antibody. Furthermore, we show for the first time that flow cytometry can be used to separate SOX11 positive and negative cell lines and primary tumors. Of note, SOX11-C1 shows no nonspecific binding to primary B or T cells in blood and thus, can be used for analysis of B and T cell lymphomas from complex clinical samples. Dilution experiments showed that low frequencies of malignant cells (similar to 1%) are detectable above background using SOX11 as a discriminant antigen in flow cytometry. Conclusions: The novel monoclonal SOX11-specific antibody offers high sensitivity and improved specificity in IHC-P based detection of MCL and its expanded use in flow cytometry analysis of blood and tissue samples may allow a convenient approach to early diagnosis and follow-up of MCL patients.
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| 40. |
- Panneman, Daan M., et al.
(författare)
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Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis
- 2023
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Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media SA. - 2296-634X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (WES) is commonly used by diagnostic facilities, the costs and required infrastructure prevent its global applicability. Previous studies have shown the cost-effectiveness of sequence analysis using single molecule Molecular Inversion Probes (smMIPs) in a cohort of patients diagnosed with Stargardt disease and other maculopathies. Methods: Here, we introduce a smMIPs panel that targets the exons and splice sites of all currently known genes associated with RP and LCA, the entire RPE65 gene, known causative deep-intronic variants leading to pseudo-exons, and part of the RP17 region associated with autosomal dominant RP, by using a total of 16,812 smMIPs. The RP-LCA smMIPs panel was used to screen 1,192 probands from an international cohort of predominantly RP and LCA cases. Results and discussion: After genetic analysis, a diagnostic yield of 56% was obtained which is on par with results from WES analysis. The effectiveness and the reduced costs compared to WES renders the RP-LCA smMIPs panel a competitive approach to provide IRD patients with a genetic diagnosis, especially in countries with restricted access to genetic testing.
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| 41. |
- Persson, Helena, et al.
(författare)
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Delineating diversity and specificity of an IgE-encoding transcriptome
- 2008
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Konferensbidrag (refereegranskat)abstract
- IgE is a minor component of the humoral immune response but one that is of extensive medical importance as it is a major mediator of type 1 hypersensitivity or allergy. Allergy affects up to 30% of the population in the industrialized countries, consequently affecting the quality of life of millions of people. In this study we sought to investigate the IgE repertoire and its evolution as it occurs in grass pollen allergic subjects. For this purpose, a human IgE library was constructed by combining the IgE heavy chain genes with kappa and lambda light chain genes, which were isolated from peripheral blood B-cells of an individual with timothy allergy. The library was screened, using phage display, against a panel of six different timothy allergens. This procedure allowed us to delineate the specificity of more than 25% of the IgE-producing transcripts in this allergic individual. Apart from providing valuable insights into the diversity and specificity of allergy-inducing repertoires, we have established a range of antibodies that can aid us in the quest to define ways how human IgE antibodies recognize grass pollen allergens, which in turn can provide important clues in the design of new allergy vaccines.
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| 42. |
- Portelius, Erik, 1977, et al.
(författare)
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Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer's disease.
- 2015
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 138, s. 3373-3385
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Tidskriftsartikel (refereegranskat)abstract
- Synaptic dysfunction is linked to cognitive symptoms in Alzheimer's disease. Thus, measurement of synapse proteins in cerebrospinal fluid may be useful biomarkers to monitor synaptic degeneration. Cerebrospinal fluid levels of the postsynaptic protein neurogranin are increased in Alzheimer's disease, including in the predementia stage of the disease. Here, we tested the performance of cerebrospinal fluid neurogranin to predict cognitive decline and brain injury in the Alzheimer's Disease Neuroimaging Initiative study. An in-house immunoassay was used to analyse neurogranin in cerebrospinal fluid samples from a cohort of patients who at recruitment were diagnosed as having Alzheimer's disease with dementia (n = 95) or mild cognitive impairment (n = 173), as well as in cognitively normal subjects (n = 110). Patients with mild cognitive impairment were grouped into those that remained cognitively stable for at least 2 years (stable mild cognitive impairment) and those who progressed to Alzheimer's disease dementia during follow-up (progressive mild cognitive impairment). Correlations were tested between baseline cerebrospinal fluid neurogranin levels and baseline and longitudinal cognitive impairment, brain atrophy and glucose metabolism within each diagnostic group. Cerebrospinal fluid neurogranin was increased in patients with Alzheimer's disease dementia (P < 0.001), progressive mild cognitive impairment (P < 0.001) and stable mild cognitive impairment (P < 0.05) compared with controls, and in Alzheimer's disease dementia (P < 0.01) and progressive mild cognitive impairment (P < 0.05) compared with stable mild cognitive impairment. In the mild cognitive impairment group, high baseline cerebrospinal fluid neurogranin levels predicted cognitive decline as reflected by decreased Mini-Mental State Examination (P < 0.001) and increased Alzheimer's Disease Assessment Scale-cognitive subscale (P < 0.001) scores at clinical follow-up. In addition, high baseline cerebrospinal fluid neurogranin levels in the mild cognitive impairment group correlated with longitudinal reductions in cortical glucose metabolism (P < 0.001) and hippocampal volume (P < 0.001) at clinical follow-up. Furthermore, within the progressive mild cognitive impairment group, elevated cerebrospinal fluid neurogranin levels were associated with accelerated deterioration in Alzheimer's Disease Assessment Scale-cognitive subscale (β = 0.0017, P = 0.01). These data demonstrate that cerebrospinal fluid neurogranin is increased already at the early clinical stage of Alzheimer's disease and predicts cognitive deterioration and disease-associated changes in metabolic and structural biomarkers over time.
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| 43. |
- Schroeder, Marion, et al.
(författare)
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A novel phenotype associated with the R162W variant in the KCNJ13 gene
- 2022
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Ingår i: Ophthalmic Genetics. - : Informa UK Limited. - 1381-6810 .- 1744-5094. ; 43:4, s. 500-507
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pathogenic variants in KCNJ13 have been associated with both autosomal dominant Snowflake vitreoretinal degeneration (SVD) and autosomal recessive Leber congenital amaurosis. SVD is characterized by aberrant vitreoretinal interface leading to increased risk of retinal detachment, crystalline retinal snowflake deposits, optic disc abnormalities, early-onset cataract, and cornea guttae. Reduced dark adaptation and reduced scotopic rod b-waves have also been described. We report a novel phenotype associated with the R162W variant in KCNJ13. Methods: Four affected members of a Swedish family were included. Three of them were examined with best corrected visual acuity, Goldmann perimetry, full-field—and multifocal electroretinography, optical coherence tomography, fundus color photographs, fundus autofluorescence images, slit lamp inspection, and genetic testing. The fourth subject only managed genetic testing. Results: All subjects carry the pathogenic missense variant; c.484C>T (NM_002242.4), R162W, in KCNJ13. ERG measurements revealed reduced macular—as well as general retinal function. Two of the subjects had a history of retinal detachment and the two younger subjects demonstrated early onset cataract. They all had structural macular changes and slightly gliotic optic discs. Conclusion: In this family, the R162W variant in KCNJ13, previously described in association with SVD, causes a somewhat novel phenotype including macular dystrophy and moderate reduction of general retinal function as the main features combined with disc abnormalities, retinal detachment, and presenile cataract that has been described before. In times of up-coming gene-based therapies, it is important to report new genotype—phenotype associations to improve the possibilities to identify future treatment candidates.
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| 44. |
- Stubelius, Alexandra, 1983, et al.
(författare)
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Role of 2-methoxyestradiol as inhibitor of arthritis and osteoporosis in a model of postmenopausal rheumatoid arthritis
- 2011
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Ingår i: Clinical Immunology. - : Elsevier BV. - 1521-6616. ; 140:1, s. 37-46
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Tidskriftsartikel (refereegranskat)abstract
- In postmenopausal rheumatoid arthritis, both the inflammatory disease and estrogen deficiency contribute to the development of osteoporosis. As hormone replacement therapy is no longer an option, we hypothesized that 2-methoxyestradiol (2me2) could be beneficial, and asked if such therapy was associated with effects on reproductive organs. Mice were ovariectomized and arthritis was induced, whereafter mice were administered 2me2, estradiol, or placebo. Clinical and histological scores of arthritis, together with bone mineral density were evaluated. Uteri weight, reactive oxygen species (ROS) from spleen cells, and characterization of cells from joints and lymph nodes were analyzed. In addition, in vivo activation of estrogen response elements (ERE) by 2me2 was evaluated. Treatment with 2me2 and estradiol decreased the frequency and severity of arthritis and preserved bone. Joint destruction was reduced, neutrophils diminished and ROS production decreased. The uterine weight increased upon long-term 2me2 exposure, however short-term exposure did not activate ERE in vivo.
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| 45. |
- Tracewska-Siemiątkowska, Anna, et al.
(författare)
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An Expanded Multi-Organ Disease Phenotype Associated with Mutations in YARS
- 2017
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Ingår i: Genes. - Basel, Switzerland : MDPI AG. - 2073-4425. ; 8:12
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Tidskriftsartikel (refereegranskat)abstract
- Whole exome sequence analysis was performed in a Swedish mother-father-affected proband trio with a phenotype characterized by progressive retinal degeneration with congenital nystagmus, profound congenital hearing impairment, primary amenorrhea, agenesis of the corpus callosum, and liver disease. A homozygous variant c.806T > C, p.(F269S) in the tyrosyl-tRNA synthetase gene (YARS) was the only identified candidate variant consistent with autosomal recessive inheritance. Mutations in YARS have previously been associated with both autosomal dominant Charcot-Marie-Tooth syndrome and a recently reported autosomal recessive multiorgan disease. Herein, we propose that mutations in YARS underlie another clinical phenotype adding a second variant of the disease, including retinitis pigmentosa and deafness, to the spectrum of YARS-associated disorders.
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| 46. |
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