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  • 1.
    Alanentalo, Tomas
    et al.
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Asayesh, Amir
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Morrison, Harris
    Lorén, Christina E
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Holmberg, Dan
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM). Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Sharpe, James
    Ahlgren, Ulf
    Umeå universitet, Medicinsk fakultet, Umeå centrum för molekylär medicin (UCMM).
    Tomographic molecular imaging and 3D quantification within adult mouse organs.2007Inngår i: Nature Methods, ISSN 1548-7091, Vol. 4, nr 1, 31-33 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 2.
    Alanentalo, Tomas
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Hörnblad, Andreas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Mayans, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Nilsson, Anna Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sharpe, James
    Larefalk, Åsa
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Quantification and 3-D imaging of the insulitis-induced destruction of β-cells in murine type 1 diabetes2010Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, nr 7, 1756-1764 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: The aim of this study was to refine the information regarding the quantitative and spatial dynamics of infiltrating lymphocytes and remaining beta-cell volume during the progression of type 1 diabetes in the NOD mouse model of the disease.

    Research design and methods: Using an ex vivo technique, optical projection tomography (OPT), we quantified and assessed the 3D spatial development and progression of insulitis and beta-cell destruction in pancreas from diabetes prone NOD and non-diabetes prone congenic NOD.H-2b mice between 3 and 16 weeks of age.

    Results: Together with results showing the spatial dynamics of the insulitis process we provide data of beta-cell volume distributions down to the level of the individual islets and throughout the pancreas during the development and progression of type 1 diabetes. Our data provide evidence for a compensatory growth potential of the larger insulin(+) islets during the later stages of the disease around the time point for development of clinical diabetes. This is in contrast to smaller islets, which appear less resistant to the autoimmune attack. We also provide new information on the spatial dynamics of the insulitis process itself, including its apparently random distribution at onset, the local variations during its further development, and the formation of structures resembling tertiary lymphoid organs at later phases of insulitis progression.

    Conclusions: Our data provides a powerful tool for phenotypic analysis of genetic and environmental effects on type 1 diabetes etiology as well as for evaluating the potential effect of therapeutic regimes.

  • 3.
    Alanentalo, Tomas
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Lorén, Christina E
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Larefalk, Asa
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Sharpe, James
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    High-resolution three-dimensional imaging of islet-infiltrate interactions based on optical projection tomography assessments of the intact adult mouse pancreas2008Inngår i: Journal of Biomedical Optics, ISSN 1083-3668, Vol. 13, nr 5, 054070- s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A predicament when assessing the mechanisms underlying the pathogenesis of type-1 diabetes (T1D) has been to maintain simultaneous global and regional information on the loss of insulin-cell mass and the progression of insulitis. We present a procedure for high-resolution 3-D analyses of regions of interest (ROIs), defined on the basis of global assessments of the 3-D distribution, size, and shape of molecularly labeled structures within the full volume of the intact mouse pancreas. We apply a refined protocol for optical projection tomography (OPT)-aided whole pancreas imaging in combination with confocal laser scanning microscopy of site-directed pancreatic microbiopsies. As such, the methodology provides a useful tool for detailed cellular and molecular assessments of the autoimmune insulitis in T1D. It is anticipated that the same approach could be applied to other areas of research where 3-D molecular distributions of both global and regional character is required.

  • 4.
    Alexeyev, Oleg A
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lundskog, Bertil
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Ganceviciene, Ruta
    Palmer, Ruth H
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    McDowell, Andrew
    Patrick, Sheila
    Zouboulis, Christos
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Pattern of tissue invasion by Propionibacterium acnes in acne vulgaris2012Inngår i: Journal of dermatological science (Amsterdam), ISSN 0923-1811, E-ISSN 1873-569X, Vol. 67, nr 1, 63-66 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 5. Alonso, Andres
    et al.
    Narisawa, Sonoko
    Bogetz, Jori
    Tautz, Lutz
    Hadzic, Radinka
    Huynh, Huong
    Williams, Scott
    Gjörloff-Wingren, Anette
    Bremer, Meire C D
    Holsinger, Leslie J
    Millán, José L
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Mustelin, Tomas
    VHY, a novel myristoylated testis-restricted dual specificity protein phosphatase related to VHX.2004Inngår i: J Biol Chem, ISSN 0021-9258, Vol. 279, nr 31, 32586-91 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 6. Anderson, H Clarke
    et al.
    Harmey, Dympna
    Camacho, Nancy P
    Garimella, Rama
    Sipe, Joseph B
    Tague, Sarah
    Bi, Xiaohong
    Johnson, Kristen
    Terkeltaub, Robert
    Millán, José Luis
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Sustained osteomalacia of long bones despite major improvement in other hypophosphatasia-related mineral deficits in tissue nonspecific alkaline phosphatase/nucleotide pyrophosphatase phosphodiesterase 1 double-deficient mice.2005Inngår i: The American journal of pathology, ISSN 0002-9440, Vol. 166, nr 6, 1711-20 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 7. Anderson, H Clarke
    et al.
    Sipe, Joseph B
    Hessle, Lovisa
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Dhanyamraju, Rama
    Atti, Elisa
    Camacho, Nancy P
    Millán, José Luis
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Dhamyamraju, Rama
    Impaired calcification around matrix vesicles of growth plate and bone in alkaline phosphatase-deficient mice.2004Inngår i: Am J Pathol, ISSN 0002-9440, Vol. 164, nr 3, 841-7 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 8.
    Andersson, Charlotta
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Li, Xingru
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Lorenz, Fryderyk
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Wahlin, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Li, Aihong
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Reduction in WT1 Gene Expression During Early Treatment Predicts the Outcome in Patients With Acute Myeloid Leukemia2012Inngår i: Diagnostic molecular pathology (Print), ISSN 1052-9551, E-ISSN 1533-4066, Vol. 21, nr 4, 225-233 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Wilms tumor gene 1 (WT1) expression has been suggested as an applicable minimal residual disease marker in acute myeloid leukemia (AML). We evaluated the use of this marker in 43 adult AML patients. Quantitative assessment of WT1 gene transcripts was performed using real-time quantitative-polymerase chain reaction assay. Samples from both the peripheral blood and the bone marrow were analyzed at diagnosis and during follow-up. A strong correlation was observed between WT1 normalized with 2 different control genes (beta-actin and ABL1, P < 0.001). WT1 mRNA level at diagnosis was of no prognostic relevance (P > 0.05). A >= 1-log reduction in WT1 expression in bone marrow samples taken < 1 month after diagnosis significantly correlated with an improved overall survival (P = 0.004) and freedom from relapse (P = 0.010) when beta-actin was used as control gene. Furthermore, a reduction in WT1 expression by >= 2 logs in peripheral blood samples taken at a later time point significantly correlated with a better outcome for overall survival (P = 0.004) and freedom from relapse (P = 0.012). This result was achieved when normalizing against both b-actin and ABL1. These results therefore suggest that WT1 gene expression can provide useful information for minimal residual disease detection in adult AML patients and that combined use of control genes can give more informative results.

  • 9. Barbany, Gisela
    et al.
    Andersen, Mette K
    Autio, Kirsti
    Borgström, Georg
    Franco, Lucia Cavalier
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Heim, Sverre
    Heinonen, Kristina
    Hovland, Randi
    Johansson, Bertil
    Johannsson, Johann H
    Kjeldsen, Eigil
    Nordgren, Ann
    Palmqvist, Lars
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Additional aberrations of the ETV6 and RUNX1 genes have no prognostic impact in 229 t(12;21)(p13;q22)-positive B-cell precursor acute lymphoblastic leukaemias treated according to the NOPHO-ALL-2000 protocol2012Inngår i: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 36, nr 7, 936-938 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 10. Berglund, Eva C.
    et al.
    Lindqvist, Carl Mårten
    Hayat, Shahina
    Övernäs, Elin
    Henriksson, Niklas
    Nordlund, Jessica
    Wahlberg, Per
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Lönnerholm, Gudmar
    Syvänen, Ann-Christine
    Accurate detection of subclonal single nucleotide variants in whole genome amplified and pooled cancer samples using HaloPlex target enrichment2013Inngår i: BMC Genomics, ISSN 1471-2164, Vol. 14, 856- s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Target enrichment and resequencing is a widely used approach for identification of cancer genes and genetic variants associated with diseases. Although cost effective compared to whole genome sequencing, analysis of many samples constitutes a significant cost, which could be reduced by pooling samples before capture. Another limitation to the number of cancer samples that can be analyzed is often the amount of available tumor DNA. We evaluated the performance of whole genome amplified DNA and the power to detect subclonal somatic single nucleotide variants in non-indexed pools of cancer samples using the HaloPlex technology for target enrichment and next generation sequencing. Results: We captured a set of 1528 putative somatic single nucleotide variants and germline SNPs, which were identified by whole genome sequencing, with the HaloPlex technology and sequenced to a depth of 792-1752. We found that the allele fractions of the analyzed variants are well preserved during whole genome amplification and that capture specificity or variant calling is not affected. We detected a large majority of the known single nucleotide variants present uniquely in one sample with allele fractions as low as 0.1 in non-indexed pools of up to ten samples. We also identified and experimentally validated six novel variants in the samples included in the pools. Conclusion: Our work demonstrates that whole genome amplified DNA can be used for target enrichment equally well as genomic DNA and that accurate variant detection is possible in non-indexed pools of cancer samples. These findings show that analysis of a large number of samples is feasible at low cost, even when only small amounts of DNA is available, and thereby significantly increases the chances of indentifying recurrent mutations in cancer samples.

  • 11. Blaydon, Diana C
    et al.
    Lind, Lisbet K
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Plagnol, Vincent
    Linton, Kenneth J
    Smith, Francis JD
    Wilson, Neil J
    McLean, WH Irwin
    Munro, Colin S
    South, Andrew P
    Leigh, Irene M
    O'Toole, Edel A
    Lundström, Anita
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Dermatologi och venereologi.
    Kelsell, David P
    Mutations in AQP5, encoding a water-channel protein, cause autosomal-dominant diffuse nonepidermolytic palmoplantar keratoderma2013Inngår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 93, nr 2, 330-335 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 12. Blink, Marjolein
    et al.
    Zimmermann, Martin
    von Neuhoff, Christine
    Reinhardt, Dirk
    de Haas, Valerie
    Hasle, Henrik
    O'Brien, Maureen M
    Stark, Batia
    Tandonnet, Julie
    Pession, Andrea
    Tousovska, Katerina
    Cheuk, Daniel K L
    Kudo, Kazuko
    Taga, Takashi
    Rubnitz, Jeffrey E
    Haltrich, Iren
    Balwierz, Walentyna
    Pieters, Rob
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Johansson, Bertil
    van den Heuvel-Eibrink, Marry M
    Zwaan, C Michel
    Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome: a retrospective, international study2014Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, nr 2, 299-307 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Myeloid leukemia of Down syndrome has a better prognosis than sporadic pediatric acute myeloid leukemia. Most cases of myeloid leukemia of Down syndrome are characterized by additional cytogenetic changes besides the constitutional trisomy 21, but their potential prognostic impact is not known. We, therefore, conducted an international retrospective study of clinical characteristics, cytogenetics, treatment, and outcome of 451 children with myeloid leukemia of Down syndrome. All karyotypes were centrally reviewed before assigning patients to subgroups. The overall 7-year event-free survival for the entire cohort was 78% (± 2%), with the overall survival rate being 79% (± 2%), the cumulative incidence of relapse 12% (± 2%), and the cumulative incidence of toxic death 7% (± 1%). Outcome estimates showed large differences across the different cytogenetic subgroups. Based on the cumulative incidence of relapse, we could risk-stratify patients into two groups: cases with a normal karyotype (n=103) with a higher cumulative incidence of relapse (21%± 4%) than cases with an aberrant karyotype (n=255) with a cumulative incidence of relapse of 9% (± 2%) (P=0.004). Multivariate analyses revealed that white blood cell count ≥ 20 × 10(9)/L and age >3 years were independent predictors for poor event-free survival, while normal karyotype independently predicted inferior overall survival, event-free survival, and relapse-free survival. In conclusion, this study showed large differences in outcome within patients with myeloid leukemia of Down syndrome and identified novel prognostic groups that predicted clinical outcome and hence may be used for stratification in future treatment protocols.

  • 13.
    Blomstedt, Patric
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Hariz, Marwan I
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Tisch, Stephen
    Holmberg, Monica
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Bergenheim, Tommy A
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    A family with a hereditary form of torsion dystonia from northern Sweden treated with bilateral pallidal deep brain stimulation2009Inngår i: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 24, nr 16, 2415-2419 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To evaluate pallidal DBS in a non-DYT1 form of hereditary dystonia. We present the results of pallidal DBS in a family with non-DYT1 dystonia where DYT5 to 17 was excluded. The dystonia is following an autosomal dominant pattern. Ten members had definite dystonia and five had dystonia with minor symptoms. Four patients received bilateral pallidal DBS. Mean age was 47 years. The patients were evaluated before surgery, and "on" stimulation after a mean of 2.5 years (range 1-3) using the Burke-Fahn-Marsden scale (BFM). Mean BFM score decreased by 79 % on stimulation, from 42.5 +/- 24 to 9 +/- 6.5 at the last evaluation. Cervical involvement improved by 89%. The 2 patients with oromandibular dystonia and blepharospasm demonstrated a reduction of 95% regarding these symptoms. The present study confirms the effectiveness of pallidal DBS in a new family with hereditary primary segmental and generalized dystonia.

  • 14. Brauner, Hanna
    et al.
    Elemans, Marjet
    Lemos, Sara
    Broberger, Christian
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Flodström-Tullberg, Malin
    Kärre, Klas
    Höglund, Petter
    Distinct phenotype and function of NK cells in the pancreas of nonobese diabetic mice.2010Inngår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 184, nr 5, 2272-2280 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Little is known about target organ-infiltrating NK cells in type 1 diabetes and other autoimmune diseases. In this study, we identified NK cells with a unique phenotype in the pancreas of NOD mice. Pancreatic NK cells, localized to the endocrine and exocrine parts, were present before T cells during disease development and did not require T cells for their infiltration. Furthermore, NK cells, or NK cell precursors, from the spleen could traffic to the pancreas, where they displayed the pancreatic phenotype. Pancreatic NK cells from other mouse strains shared phenotypic characteristics with pancreatic NK cells from NOD mice, but displayed less surface killer cell lectin-like receptor G1, a marker for mature NK cells that have undergone proliferation, and also did not proliferate to the same extent. A subset of NOD mouse pancreatic NK cells produced IFN-gamma spontaneously, suggesting ongoing effector responses. However, most NOD mouse pancreatic NK cells were hyporesponsive compared with spleen NK cells, as reflected by diminished cytokine secretion and a lower capacity to degranulate. Interestingly, such hyporesponsiveness was not seen in pancreatic NK cells from the nonautoimmune strain C57BL/6, suggesting that this feature is not a general property of pancreatic NK cells. Based on our data, we propose that NK cells are sentinel cells in a normal pancreas. We further speculate that during inflammation, pancreatic NK cells initially mediate proinflammatory effector functions, potentially contributing to organ-specific autoimmunity, but later become hyporesponsive because of exhaustion or regulation.

  • 15.
    Brönnestam, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Polymorphism of the human complement component C3- genetic and immunological aspects1973Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Genetic polymorphism is by definition the occurrence in the same population of two or more alleles at one locus,each with a frequency high enough not to be maintained by recurrent mutation only (1). Among the human plasmaproteins two major categories of polymorphism have been described, allotypic and electrophoretic heterogeneity. Allotypy is defined by Oudin as individual antigenic differences among proteins within a species (2). The first discovered polymorphism of this category was the Gm system of immunoglobulin G by Grubb (3). The first described electrophoretic heterogeneity in plasma proteins was theHp (haptoglobin) system discovered by Smithies (4). Sincethen genetic variants of several other human plasma proteins have been found. This dissertation is concerned with thegenetic and immunological aspects of the polymorphism of the third component of human complement, C3.

  • 16. Buitenkamp, Trudy D.
    et al.
    Izraeli, Shai
    Zimmermann, Martin
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Heerema, Nyla A.
    van den Heuvel-Eibrink, Marry M.
    Pieters, Rob
    Korbijn, Carin M.
    Silverman, Lewis B.
    Schmiegelow, Kjeld
    Liang, Der-Cheng
    Horibe, Keizo
    Arico, Maurizio
    Biondi, Andrea
    Basso, Giuseppe
    Rabin, Karin R.
    Schrappe, Martin
    Cario, Gunnar
    Mann, Georg
    Morak, Maria
    Panzer-Grumayer, Renate
    Mondelaers, Veerle
    Lammens, Tim
    Cave, Helene
    Stark, Batia
    Ganmore, Ithamar
    Moorman, Anthony V.
    Vora, Ajay
    Hunger, Stephen P.
    Pui, Ching-Hon
    Mullighan, Charles G.
    Manabe, Atsushi
    Escherich, Gabriele
    Kowalczyk, Jerzy R.
    Whitlock, James A.
    Zwaan, C. Michel
    Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group2014Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 123, nr 1, 70-77 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Children with Down syndrome (DS) have an increased risk of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The prognostic factors and outcome of DS-ALL patients treated in contemporary protocols are uncertain. We studied 653 DS-ALL patients enrolled in 16 international trials from 1995 to 2004. Non-DS BCP-ALL patients from the Dutch Child Oncology Group and Berlin-Frankfurt-Munster were reference cohorts. DS-ALL patients had a higher 8-year cumulative incidence of relapse (26% +/- 2% vs 15% +/- 1%, P < .001) and 2-year treatment-related mortality (TRM) (7% +/- 1% vs 2.0% +/- < 1%, P < .0001) than non-DS patients, resulting in lower 8-year event-free survival (EFS) (64% +/- 2% vs 81% +/- 2%, P < .0001) and overall survival (74% +/- 2% vs 89% +/- 1%, P < .0001). Independent favorable prognostic factors include age <6 years (hazard ratio [HR] = 0.58, P = .002), white blood cell (WBC) count <10 x 10(9)/L (HR = 0.60, P = .005), and ETV6-RUNX1 (HR = 0.14, P = .006) for EFS and age (HR = 0.48, P < .001), ETV6-RUNX1 (HR = 0.1, P = .016) and high hyperdiploidy (HeH) (HR = 0.29, P = .04) for relapse-free survival. TRM was the major cause of death in ETV6-RUNX1 and HeH DS-ALLs. Thus, while relapse is the main contributor to poorer survival in DS-ALL, infection-associated TRM was increased in all protocol elements, unrelated to treatment phase or regimen. Future strategies to improve outcome in DS-ALL should include improved supportive care throughout therapy and reduction of therapy in newly identified good-prognosis subgroups.

  • 17.
    Burstedt, Marie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Central Retinal Findings in Bothnia Dystrophy Caused by RLBP1 Sequence Variation2010Inngår i: Archives of ophthalmology (1960), ISSN 0003-9950, Vol. 128, nr 8, 989-995 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: To describe the central retinal findings early in the course of Bothnia dystrophy caused by the homozygous missense R234W sequence variation in the RLBP1 gene. Methods: In 8 young patients with Bothnia dystrophy (aged 9-34 years), high- and low-contrast distance visual acuity and visual fields were measured with Humphrey central (24-2) threshold testing and Goldmann perimetry. Central retinal thickness was measured with optical coherence tomography. Cross-sectional images were analyzed and a linear scanning protocol was applied to examine retinitis punctata albescence in the posterior pole. Results: Affected visual acuity (4 of 8 cases) and poor low-contrast visual acuity (8 of 8 cases) were found. Significant foveal depression and visual field loss were evident with Humphrey threshold testing at all ages, and paracentral and central scotomata in the second decade of life advanced in adulthood as verified with Goldmann perimetry. Optical coherence tomography showed generalized retinal thinning in the central foveal, foveal (innermost ring diameter [empty set], 1 mm), and inner ring (empty set, 3 mm) areas in all ages, and early retinal thinning was found in the inferior areas of the outer macula (empty set, 6 mm). Foveal and extrafoveal thinning of the retinal layers and outer nuclear layer were found. Homogeneous retinitis punctata albescence changes were visualized in and/or adjacent to the retinal pigment epithelium choriocapillaris complex with high reflectance. Conclusions: In the RLBP1 Bothnia dystrophy phenotype, a loss of function and thinning of the central macula are found, indicating early damage of the cone photoreceptors in this disease of the visual cycle. Retinitis punctata albescence spots in the posterior pole are situated close to or in the retinal pigment epithelium-choriocapillaris complex.

  • 18.
    Burstedt, Marie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Jonsson, Frida
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Köhn, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Burstedt, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Kivitalo, Markus
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Genotype-phenotype correlations in Bothnia dystrophy caused by RLBP1 gene sequence variations2013Inngår i: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 91, nr 5, 437-444 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: To evaluate phenotypes caused by different RLBP1 mutations in autosomal recessive retinitis pigmentosa of Bothnia type. Methods: Compound heterozygotes for mutations in the RLBP1 gene [c.677T>A]+[c.700C>T] (p.M226K+p.R234W), n=10, aged 7-84years, and homozygotes c.677T>A (p.M226K), n=2, aged 63 and 73years, were studied using visual acuity (VA), low-contrast VA, visual fields (VFs) and optical coherence tomography (OCT). Retrospective VA and VFs, standardized dark adaptation and full-field electroretinograms (ERGs) were analysed and prolonged dark adaptometry and ERG (at 24hr) were performed. Results: Progressive decline of VA and VF areas was age-dependent. Retinal degenerative maculopathy, peripheral degenerative changes and retinitis punctata albescens (RPA) were present. Early retinal thinning in the central foveal, foveal (O 1mm), and inner ring (O 3mm) in the macular region, with homogenous, high-reflectance RPA changes, was visualized in and adjacent to the retinal pigment epithelium/choriocapillaris using OCT. Reduced dark adaptation and affected ERGs were present in all ages. Prolonged dark adaptation and ERG (at 24hr), an increase in final threshold, and ERG rod and mixed rod/cone responses were found. Conclusions: The two RLBP1 genotypes presented a phenotypical and electrophysiological expression of progressive retinal disease similar to that previously described in homozygotes for the c.700C>T (p.R234W) RLBP1 mutation. The uniform phenotypical expression of RLBP1 mutations is relevant information for the disease and of importance in planning future treatment strategies.

  • 19.
    Burstedt, Marie S I
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Sandgren, Ola
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Medicinsk och klinisk genetik.
    Wachtmeister, Lillemor
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Effects of prolonged dark adaptation in patients with retinitis pigmentosa of Bothnia type: an electrophysiological study.2008Inngår i: Doc Ophthalmol, ISSN 0012-4486, Vol. 116, nr 3, 193-205 s.Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Bothnia dystrophy (BD) is a variant of recessive retinitis punctata albescens (RPA), caused by the missense mutation R233W in cellular retinaldehyde-binding protein (CRALBP), which is localized in the retinal pigment epithelium (RPE) and Müller cells of the retina. The purpose of this study was, by examining the electrophysiological responses of the retina, to evaluate the capacity of recovery of the whole retinal area and different cell types induced by extremely prolonged dark adaptation (DA) in BD disease and to gain further understanding of the pathogenesis of BD. Six young patients underwent bilateral full-field ERGs after 24 h of DA in one eye and standard DA in the fellow eye. The results were also compared with the effect of prolonged DA (10 h), previously studied in the same patients. After extremely prolonged DA (24 h) the rod b-wave and the mixed rod-cone a-wave responses reached normal though delayed amplitudes. An increase, up to normal level, in the oscillatory response was found. There was no obvious recovery of the cone response. We conclude that in young BD patients during extremely prolonged DA there is a significant additional capacity of recovery of rod function and also significant gain of activity in the inner retinal layer. A continuous but slow regeneration of rod photopigment seems to occur at least up to 24 h. The visual process in the RPE is retarded and CRALBP acts in this process; also, the Müller cells of the retina seem to be involved. The findings also support an extremely slow synthesis of photopigments and irreversibly disturbed cone function early in BD.

  • 20. Calado, Dinis Pedro
    et al.
    Paixáo, Tiago
    Holmberg, Dan
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Haury, Matthias
    Stochastic monoallelic expression of IL-10 in T cells.2006Inngår i: J Immunol, ISSN 0022-1767, Vol. 177, nr 8, 5358-64 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 21.
    Campino, S
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Bagot, S
    Bergman, M-L
    Almeida, P
    Sepúlveda, N
    Pied, S
    Penha-Goncalves, C
    Holmberg, D
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Cazenave, P-A
    Genetic control of parasite clearance leads to resistance to Plasmodium berghei ANKA infection and confers immunity.2005Inngår i: Genes Immun, ISSN 1466-4879, Vol. 6, nr 5, 416-21 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 22.
    Carlsson, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Nylander, P-O
    Hellman, Urban
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Forsman-Semb, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Holmgren, Gösta
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Holmberg, Monica
    Umeå universitet, Medicinska fakulteten, Molekylärbiologi (Teknat- och Medfak).
    Identification of a susceptibility locus for migraine with and without aura on 6p12.2-p21.1.2002Inngår i: Neurology, ISSN 0028-3878, Vol. 59, nr 11, 1804-1807 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 23.
    Cederquist, Kristina
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Emanuelsson, Monica
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Göransson, Ingela
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Holinski-Feder, Elke
    Müller-Koch, Yvonne
    Golovleva, Irina
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Grönberg, Henrik
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Mutation analysis of the MLH1, MSH2 and MSH6 genes in patients with double primary cancers of the colorectum and the endometrium: a population-based study in northern Sweden2004Inngår i: International Journal of Cancer, ISSN 0020-7136, Vol. 109, nr 3, 370-376 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder that predisposes to predominantly colorectal and endometrial cancers due to germline mutations in DNA mismatch repair genes, mainly MLH1, MSH2 and in families with excess endometrial cancer also MSH6. In this population-based study, we analysed the mutation spectrum of the MLH1, MSH2 and MSH6 genes in a cohort of patients with microsatellite unstable double primary tumours of the colorectum and the endometrium by PCR, DHPLC and sequencing. Fourteen of the 23 patients (61%) had sequence variants in MLH1, MSH2 or MSH6 that likely affect the protein function. A majority (10/14) of the mutations was found among probands diagnosed before age 50. Five of the mutations (36%) were located in MLH1, 3 (21%) in MSH2 and 6 (43%) in MSH6. MSH6 seem to have larger impact in our population than in other populations, due to a founder effect since all of the MSH6 families originate from the same geographical area. MSH6 mutation carriers have later age of onset of both colorectal cancer (62 vs. 51 years) and endometrial cancer (58 vs. 48 years) and a larger proportion of endometrial cancer than MLH1 or MSH2 mutation carriers. We can conclude that patients with microsatellite unstable double primary cancers of the colorectum and the endometrium have a very high risk of carrying a mutation not only in MLH1 or MSH2 but also in MSH6, especially if they get their first cancer diagnosis before the age of 50. Copyright 2004 Wiley-Liss, Inc.

  • 24.
    Cederquist, Kristina
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Emanuelsson, Monica
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Wiklund, Fredrik
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Golovleva, Irina
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Palmqvist, Richard
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Grönberg, Henrik
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Two Swedish founder MSH6 mutations, one nonsense and one missense, conferring high cumulative risk of Lynch syndrome.2005Inngår i: Clinical Genetics, ISSN 0009-9163, Vol. 68, nr 6, 533-541 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Lynch syndrome, or hereditary non-polyposis colorectal cancer (HNPCC), is a cancer susceptibility syndrome caused by germline mutations in mismatch-repair genes, predominantly MLH1, MSH2 and MSH6. A majority of the mutations reported are truncating, but for MSH6, missense mutations constitute over one third. Few have been proven pathogenic in functional studies or shown to segregate in families. In this study, we show segregation of the putative pathogenic MSH6 missense mutation c.1346T>C p.Leu449Pro with microsatellite instability-high Lynch syndrome-related tumours lacking MSH6 expression in a large 17th century pedigree. Another large family with the MSH6 nonsense c.2931C>G, p.Tyr977X mutation is similar in tumour spectra, age of onset and cumulative risk. These MSH6 families, despite their late age of onset, have a high lifetime risk of all Lynch syndrome-related cancers, significantly higher in women (89% by age 80) than in men (69%). The gender differences are in part explained by high endometrial (70%) and ovarian (33%) cancer risks added upon the high colorectal cancer risk (60%). The several occurrences of breast cancer are not due to the MSH6 mutations. These findings are of great importance for counselling, management and surveillance of families with MSH6 mutations.

  • 25.
    Cederquist, Kristina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Palmqvist, Richard
    Emanuelsson, Monica
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Grönberg, Henrik
    Retained immunohistochemical staining in a large Swedish HNPCC family with a pathogenic MLH1 missense mutationManuskript (preprint) (Annet vitenskapelig)
  • 26. Cisse, Babacar
    et al.
    Caton, Michele L
    Lehner, Manfred
    Maeda, Takahiro
    Scheu, Stefanie
    Locksley, Richard
    Holmberg, Dan
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Zweier, Christiane
    den Hollander, Nicolette S
    Kant, Sarina G
    Holter, Wolfgang
    Rauch, Anita
    Zhuang, Yuan
    Reizis, Boris
    Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development.2008Inngår i: Cell, ISSN 1097-4172, Vol. 135, nr 1, 37-48 s.Artikkel i tidsskrift (Annet vitenskapelig)
  • 27. Dahlquist, Gisela
    et al.
    Stattin, Eva-Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Rudberg, S
    Urinary albumin excretion rate and glomerular filtration rate in the prediction of diabetic nephropathy; a long-term follow-up study of childhood onset type-1 diabetic patients.2001Inngår i: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 16, nr 7, 1382-1386 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    At a mean diabetes duration of 29 years the cumulative incidence of macroalbuminuria was 12%; however, another 20% had persistent microalbuminuria. A screening value of 24-h AER >15 mg/min was a strong predictor, whereas increased GFR was a weaker but significant predictor for micro and macroalbuminuria.

  • 28.
    Dahlqvist, Solbritt Rantapää
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Nordenson, I
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Chromosomal changes in rheumatoid arthritis patients treated with CPH821996Inngår i: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949, Vol. 15, nr 6, 584-589 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chromosomal changes were assessed in 19 patients with rheumatoid arthritis (RA) treated with CPH82, a benzylidated podophyllotoxin glycoside, for up to one ve:lr. The frequency of chromosomal aberrations (CA) and sister chromatid exchanges (SCE) in peripheral lymphocytes increased significantly after 12 weeks of treatment and remained elevated after 48 weeks treatment in peripheral lymphocytes. The number of CA and SCE were significantly increased in CPH82 treated patients compared with the RA patients treated with other disease modifying anti-rheumatic drugs (sulphasalazine, gold, D-penicillamine, azathioprine, methotrexate, cyclophosphamide). Only two patients treated with cyclophosphamide and azathioprine had changes of comparable levels, The results of this study suggest a mutagenic potential of CPH82 similar to that described for other immunosuppressive drugs and the newer podophyllotoxin derivatives, etoposide and teniposide.

  • 29.
    Degerman, Sofie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Siwicki, Jan Konrad
    Revie, John
    Borssen, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Evelönn, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Chrzanowska, Krystyna H.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Keith, W. Nicol
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Immortalization of T-Cells Is Accompanied by Gradual Changes in CpG Methylation Resulting in a Profile Resembling a Subset of T-Cell Leukemias2014Inngår i: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 16, nr 7, 606-615 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have previously described gene expression changes during spontaneous immortalization of T-cells, thereby identifying cellular processes important for cell growth crisis escape and unlimited proliferation. Here, we analyze the same model to investigate the role of genome-wide methylation in the immortalization process at different time points pre-crisis and post-crisis using high-resolution arrays. We show that over time in culture there is an overall accumulation of methylation alterations, with preferential increased methylation close to transcription start sites (TSSs), islands, and shore regions. Methylation and gene expression alterations did not correlate for the majority of genes, but for the fraction that correlated, gain of methylation close to TSS was associated with decreased gene expression. Interestingly, the pattern of CpG site methylation observed in immortal T-cell cultures was similar to clinical T-cell acute lymphoblastic leukemia (T-ALL) samples classified as CpG island methylator phenotype positive. These sites were highly overrepresented by polycomb target genes and involved in developmental, cell adhesion, and cell signaling processes. The presence of non-random methylation events in in vitro immortalized T-cell cultures and diagnostic T-ALL samples indicates altered methylation of CpG sites with a possible role in malignant hematopoiesis.

  • 30.
    Diamant, Ulla-Britt
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Jensen, Steen M
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Winbo, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Stattin, Eva-Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Vectorcardiographic recordings of the Q-T interval in a pediatric long Q-T syndrome population2013Inngår i: Pediatric Cardiology, ISSN 0172-0643, E-ISSN 1432-1971, Vol. 34, nr 2, 245-249 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Measurements of the Q-T interval are less reliable in children than in adults. Identification of superior diagnostic tools is warranted. This study aimed to investigate whether a vectorcardiogram (VCG) recorded from three orthogonal leads (X, Y, Z) according to Frank is superior to a 12-lead electrocardiogram (ECG) in providing a correct long Q-T syndrome (LQTS) diagnosis in children. This LQTS group consisted of 35 genetically confirmed carriers of mutations in the KCNQ1 (n = 29) and KCNH2 (n = 6) genes. The control group consisted of 35 age- and gender-matched healthy children. The mean age was 7 years in the LQTS group and 6.7 years in the control group (range, 0.5-16 years). The corrected Q-T interval (QT(c)) was measured manually (QT(man)) by one author (A.W.). The 12-lead ECG automatic measurements (QT(ECG)) and interpretation (QT(Interpret)) of QT(c) were performed with the Mac5000 (GE Medical System), and the VCG automatic measurements (QT(VCG)) were performed with the Mida1000, CoroNet (Ortivus AB, Sweden). By either method, a QT(c) longer than 440 ms was considered prolonged and indicative of LQTS. Of the 35 children with genetically confirmed LQTS, 30 (86 %) received a correct diagnosis using QT(VCG), 29 (82 %) using QT(man), 24 (69 %) using QT(ECG), and 17 (49 %) using QT(Interpret). Specificity was 0.80 for QT(VCG), 0.83 for QT(man), 0.77 for QT(ECG), and 0.83 for QT(Interpret). The VCG automatic measurement of QT(c) seems to be a better predictor of LQTS than automatic measurement and interpretation of 12-lead ECG.

  • 31.
    Diamant, Ulla-Britt
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Vahedi, Farzad
    Sahlgrenska Akademin Göteborgs Universitet.
    Winbo, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Stattin, Eva-Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Jensen, Steen M
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Bergfeldt, Lennart
    Sahlgrenska Akademin Göteborgs Universitet.
    Electrophysiological phenotype in the LQTS mutations Y111C and R518X in the KCNQ1 gene2013Inngår i: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 115, nr 10, 1423-1432 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Long QT syndrome is the prototypical disorder of ventricular repolarization (VR), and a genotype-phenotype relation is postulated. Furthermore, although increased VR heterogeneity (dispersion) may be important in the arrhythmogenicity in long QT syndrome, this hypothesis has not been evaluated in humans and cannot be tested by conventional electrocardiography. In contrast, vectorcardiography allows assessment of VR heterogeneity and is more sensitive to VR alterations than electrocardiography. Therefore, vectorcardiography was used to compare the electrophysiological phenotypes of two mutations in the LQT1 gene with different in vitro biophysical properties, and with LQT2 mutation carriers and healthy control subjects. We included 99 LQT1 gene mutation carriers (57 Y111C, 42 R518X) and 19 LQT2 gene mutation carriers. Potassium channel function is in vitro most severely impaired in Y111C. The control group consisted of 121 healthy subjects. QRS, QT, and T-peak to T-end (Tp-e) intervals, measures of the QRS vector and T vector and their relationship, and T-loop morphology parameters were compared at rest. Apart from a longer heart rate-corrected QT interval (QT heart rate corrected according to Bazett) in Y111C mutation carriers, there were no significant differences between the two LQT1 mutations. No signs of increased VR heterogeneity were observed among the LQT1 and LQT2 mutation carriers. QT heart rate corrected according to Bazett and Tp-e were longer, and the Tp-e-to-QT ratio greater in LQT2 than in LQT1 and the control group. In conclusion, there was a marked discrepancy between in vitro potassium channel function and in vivo electrophysiological properties in these two LQT1 mutations. Together with previous observations of the relatively low risk for clinical events in Y111C mutation carriers, our results indicate need for cautiousness in predicting in vivo electrophysiological properties and the propensity for clinical events based on in vitro assessment of ion channel function alone.

  • 32.
    Diamant, Ulla-Britt
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Winbo, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Stattin, Eva-Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Kesek, Milos
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Jensen, Steen M
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Two automatic QT algorithms compared with manual measurement in identification of long QT syndrome2010Inngår i: Journal of Electrocardiology, ISSN 0022-0736, E-ISSN 1532-8430, Vol. 43, nr 1, 25-30 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Long QT syndrome (LQTS) is an inherited disorder that increases the risk of syncope and malignant ventricular arrhythmias, which may result in sudden death.

    METHODS: We compared manual measurement by 4 observers (QT(manual)) and 3 computerized measurements for QT interval accuracy in the diagnosis of LQTS: 1. QT measured from the vector magnitude calculated from the 3 averaged orthogonal leads X, Y, and Z (QTVCG) and classified using the same predefined QTc cut-points for classification of QT prolongation as in manual measurements; 2. QT measured by a 12-lead electrocardiogram (ECG) program (QTECG) and subsequently classified using the same cut-points as in (1) above; 3. The same QT value as in (2) above, automatically classified by a 12-lead ECG program with thresholds for QT prolongation adjusted for age and sex (QTinterpret). The population consisted of 94 genetically confirmed carriers of KCNQ1 (LQT1) and KCNH2 (LQT2) mutations and a combined control group of 28 genetically confirmed noncarriers and 66 unrelated healthy volunteers.

    RESULTS: QT(VCG) provided the best combination of sensitivity (89%) and specificity (90%) in diagnosing LQTS, with 0.948 as the area under the receiver operating characteristic curve. The evaluation of QT measurement by the 4 observers revealed a high interreader variability, and only 1 of 4 observers showed acceptable level of agreement in LQTS mutation carrier identification (kappa coefficient >0.75).

    CONCLUSION: Automatic QT measurement by the Mida1000/CoroNet system (Ortivus AB, Danderyd, Sweden) is an accurate, efficient, and easily applied method for initial screening for LQTS.

  • 33.
    Djusberg, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Lundberg, Pia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Brattsand, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    High Levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases2017Inngår i: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 77, nr 6, 625-638 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR variants and steroid-converting enzymes has been poorly examined. Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying novel molecular targets for treatment. METHODS: Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases (n = 40) and by PCR-based copy number variation analysis. Whole genome mRNA expression was analyzed using H12 Illumina Beadchip arrays and specific transcript levels were quantified by qRT-PCR. Protein localization was analyzed using immunohistochemistry and confocal microscopy. The YIPF6 mRNA expression was transiently knocked down and stably overexpressed in the 22Rv1 cell line as representative for CRPC, and effects on cell proliferation, colony formation, migration, and invasion were determined in vitro. Extracellular vesicles (EVs) were isolated from cell cultures using size-exclusion chromatography and enumerated by nanoparticle tracking analysis. Protein content was identified by LC-MS/MS analysis. Blood coagulation was measured as activated partial thromboplastin time (APTT). Functional enrichment analysis was performed using the MetaCore software. RESULTS: AR amplification was detected in 16 (53%) of the bone metastases examined from CRPC patients (n = 30), and in none from the untreated patients (n = 10). Metastases with AR amplification showed high AR and AR-V7 mRNA levels, increased nuclear AR immunostaining, and co-amplification of genes such as YIPF6 in the AR proximity at Xq12. The YIPF6 protein was localized to the Golgi apparatus. YIPF6 overexpression in 22Rv1 cells resulted in reduced cell proliferation and colony formation, and in enhanced EV secretion. EVs from YIPF6 overproducing 22Rv1 cells were enriched for proteins involved in blood coagulation and, accordingly, decreased the APTT in a dose-dependent fashion. CONCLUSIONS: AR amplified CRPC bone metastases show high AR-V7 expression that probably gives resistance to AR-targeting drugs. Co-amplification of the Golgi protein coding YIPF6 gene with the AR may enhance the secretion of pro-coagulative EVs from cancer cells and thereby stimulate tumor progression and increase the coagulopathy risk in CRPC patients.

  • 34.
    Duarte, Nadia
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Stenström, Martin
    Campino, Susana
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Bergman, Marie-Louise
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Lundholm, Marie
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Holmberg, Dan
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Cardell, Susanna L
    Prevention of diabetes in nonobese diabetic mice mediated by CD1d-restricted nonclassical NKT cells.2004Inngår i: Journal of Immunology, ISSN 0022-1767, Vol. 173, nr 5, 3112-3118 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A role for regulatory lymphocytes has been demonstrated in the pathogenesis of type 1 diabetes in the NOD mouse but the nature of these cells is debated. CD1d-restricted NKT lymphocytes have been implicated in this process. Previous reports of reduced diabetes incidence in NOD mice in which the numbers of NKT cells are artificially increased have been attributed to the enhanced production of IL-4 by these cells and a role for classical NKT cells, using the Valpha14-Jalpha18 rearrangement. We now show that overexpression in NOD mice of CD1d-restricted TCR Valpha3.2(+)Vbeta9(+) NKT cells producing high levels of IFN-gamma but low amounts of IL-4 leads to prevention of type 1 diabetes, demonstrating a role for nonclassical CD1d-restricted NKT cells in the regulation of autoimmune diabetes.

  • 35.
    Duarte, Nádia
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik. Medicinsk och klinisk genetik. Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap.
    Lundholm, Marie
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik. Medicinsk och klinisk genetik.
    Holmberg, Dan
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik. Medicinsk och klinisk genetik.
    The Idd6.2 diabetes susceptibility region controls defective expression of the Lrmp gene in nonobese diabetic (NOD) mice2007Inngår i: Immunogenetics, ISSN 0093-7711, Vol. 59, nr 5, 407-416 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The identification of genes mediating susceptibility to type 1 diabetes (T1D) remains a challenging task. Using a positional cloning approach based on the analysis of nonobese diabetic (NOD) mice congenic over the Idd6 diabetes susceptibility region, we found that the NOD allele at this locus mediates lower mRNA expression levels of the lymphoid restricted membrane protein gene (Lrmp/Jaw1). Analysis of thymic populations indicates that Lrmp is expressed mainly in immature thymocytes. The Lrmp gene encodes a type 1 transmembrane protein that localizes to the ER membrane and has homology to the inositol 1,4,5-triphosphate receptor-associated cGMP kinase substrate gene, which negatively regulates intracellular calcium levels. We hypothesize that the observed decrease in expression of the Lrmp gene in NOD mice may constitute a T1D susceptibility factor in the Idd6 region.

  • 36.
    Einarsdottir, Elisabet
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Carlsson, Anna
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Minde, Jan
    Toolanen, Göran
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Ortopedi.
    Svensson, Olle
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Ortopedi.
    Solders, Göran
    Holmgren, Gösta
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Holmberg, Dan
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Holmberg, Monica
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception.2004Inngår i: Human Molecular Genetics, ISSN 0964-6906, Vol. 13, nr 8, 799-805 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Identification of genes associated with pain insensitivity syndromes can increase the understanding of the pathways involved in pain and contribute to the understanding of how sensory pathways relate to other neurological functions. In this report we describe the mapping and identification of the gene responsible for loss of deep pain perception in a large family from northern Sweden. The loss of pain perception in this family is characterized by impairment in the sensing of deep pain and temperature but with normal mental abilities and with most other neurological responses intact. A severe reduction of unmyelinated nerve fibers and a moderate loss of thin myelinated nerve fibers are observed in the patients. Thus the cases in this study fall into the class of patients with loss of pain perception with underlying peripheral neuropathy. Clinically they best fit into HSAN V. Using a model of recessive inheritance we identified an 8.3 Mb region on chromosome 1p11.2-p13.2 shared by the affected individuals in the family. Analysis of functional candidate genes in the disease critical region revealed a mutation in the coding region of the nerve growth-factor beta (NGFB) gene specific for the disease haplotype. This NGF mutation seems to separate the effects of NGF involved in development of central nervous system functions such as mental abilities, from those involved in peripheral pain pathways. This mutation could therefore potentially provide an important tool to study different roles of NGF, and of pain control.

  • 37.
    Einarsdottir, Elisabet
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Egerbladh, Inez
    Beckman, Lars
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Andersson Escher, Stefan
    The genetic population structure of northern Sweden and its implications for mapping genetic diseases.2007Inngår i: Hereditas, ISSN 1601-5223, Vol. 144, nr 5, 171-180 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The northern Swedish population has a history of admixture of three ethnic groups and a dramatic population growth from a relatively small founder population. This has resulted in founder effects that together with unique resources for genealogical analyses provide excellent conditions for genetic mapping of monogenic diseases. Several recent examples of successful mapping of genetic factors underlying susceptibility to complex diseases have suggested that the population of northern Sweden may also be an important tool for efficient mapping of more complex phenotypes. A potential factor contributing to these effects may be population sub-isolates within the large river valleys, constituting a central geographic characteristic of this region. We here provide evidence that marriage patterns as well as the distribution of gene frequencies in a set of marker loci are compatible with this notion. The possible implications of this population structure on linkage- and association based strategies for identifying genes contributing risk to complex diseases are discussed.

  • 38.
    Einarsdottir, Elisabet
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Medicinsk och klinisk genetik.
    Mayans, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Medicinsk och klinisk genetik.
    Ruikka, Karin
    Andersson Escher, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Medicinsk och klinisk genetik.
    Lindgren, Petter
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Medicinsk och klinisk genetik.
    Ågren, Åsa
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning. Näringsforskning.
    Eliasson, Mats
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Medicinsk och klinisk genetik.
    Linkage but not association of calpain-10 to type 2 diabetes replicated in northern Sweden2006Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 55, nr 6, 1879-1883 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 39.
    Einarsdottir, Elisabet
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Söderström, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Löfgren-Burström, Anna
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Unit for Genome Research, Umeå University.
    Haraldsson, Susann
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Unit for Genome Research, Umeå University.
    Nilsson-Ardnor, Sofie
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Unit for Genome Research, Umeå University.
    Penha-Goncalves, Carlos
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Gulbenkian Institute for Science, Oeiras, Portugal.
    Lind, Lisbet
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Unit for Genome Research, Umeå University.
    Holmgren, Gösta
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Holmberg, Monica
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Asplund, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Unit for Genome Research.
    The CTLA4 region as a general autoimmunity factor: an extended pedigree provides evidence for synergy with the HLA locus in the etiology of type 1 diabetes mellitus, Hashimoto's thyroiditis and Graves' disease2003Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 11, nr 1, 81-84 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have identified a large family in the northern part of Sweden with multiple cases of autoimmune diseases, namely type 1 diabetes (T1D), Graves' disease (GD) and Hashimoto's thyroiditis (HT). The family members affected by any of these diseases share a region of 2.4 Mb that comprises among others the CTLA4 gene. We determined that all affected members of the family shared the HLA susceptibility haplotype (DR4-DQA1*0301-DQB1*0302). Analysis of genetic interaction conditioning for HLA haplotype provided strong evidence that the critical region which includes the CTLA4 gene acts together with the HLA locus on the etiology of disease (lodscore 4.20 (theta=0.0). The study of this family allowed us to: (1) reinforce a number of reports on linkage and association of the CTLA4 region to T1D and AITD; (2) demonstrate that a single haplotypic variant in this region constitutes an etiological factor to disease susceptibility in T1D, GD and HT; (3) reveal a strong genetic interaction of the CTLA4 and HLA loci in the genetic architecture of autoimmune disease; (4) emphasise the value of large pedigrees drawn from isolated populations as tools to single out the effect of individual loci in the etiology of complex diseases.

  • 40.
    Entesarian, Miriam
    et al.
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Carlsson, Birgit
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Mansouri, Mahmoud Reza
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Stattin, Eva-Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Holmberg, Eva
    Department of Clinical Genetics, Sahlgrenska University Hospital/East, Gothenburg, Sweden.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Stefansson, Hreinn
    CNS Division, deCODE Genetics, Reykjavik, Iceland.
    Klar, Joakim
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Dahl, Niklas
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    A chromosome 10 variant with a 12 Mb inversion [inv(10)(q11.22q21.1)] identical by descent and frequent in the Swedish population2009Inngår i: American Journal of Medical Genetics, ISSN 0148-7299, E-ISSN 1096-8628, Vol. 149A, nr 3, 380-386 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We identified a paracentric inversion of chromosome 10 [inv(10)(q11.22q21.1)] in 0.20% of Swedish individuals (15/7,439) referred for cytogenetic analysis. A retrospective analysis of 8,896 karyotypes from amniocenteses in Sweden revealed a carrier frequency of 0.079% (7/8,896) for the inversion. Cloning and detailed analysis of the inversion breakpoint regions show enrichment for interspersed repeat elements and AT-stretches. The centromeric breakpoint coincides with that of a predicted inversion from HapMap data, which suggests that this region is involved in several chromosome 10 variants. No known gene or predicted transcript are disrupted by the inversion which spans approximately 12 Mb. Carriers from four non-related Swedish families have identical inversion breakpoints and haplotype analysis confirmed that the rearrangement is identical by descent. Diagnosis was retrieved in 6 out of the 15 carriers referred for cytogenetic analysis. No consistent phenotype was found to be associated with the inversion. Our study demonstrates that the inv(10)(q11.22q21.1) is a rare and inherited chromosome variant with a broad geographical distribution in Sweden.

  • 41.
    Falk Kieri, Catarina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Bergendal, Birgitta
    Lind, Lisbet K
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Schmitt-Egenolf, Marcus
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Dermatologi och venereologi.
    Stecksén-Blicks, Christina
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    EDAR-induced hypohidrotic ectodermal dysplasia: a clinical study on signs and symptoms in individuals with a heterozygous c.1072C > T mutation2014Inngår i: BMC Medical Genetics, ISSN 1471-2350, Vol. 15, 57- s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Mutations in the EDAR-gene cause hypohidrotic ectodermal dysplasia, however, the oral phenotype has been described in a limited number of cases. The aim of the present study was to clinically describe individuals with the c.1072C > T mutation (p. Arg358X) in the EDAR gene with respect to dental signs and saliva secretion, symptoms from other ectodermal structures and to assess orofacial function.

    METHODS: Individuals in three families living in Sweden, where some members had a known c.1072C > T mutation in the EDAR gene with an autosomal dominant inheritance (AD), were included in a clinical investigation on oral signs and symptoms and self-reported symptoms from other ectodermal structures (n = 37). Confirmation of the c.1072C > T mutation in the EDAR gene were performed by genomic sequencing. Orofacial function was evaluated with NOT-S.

    RESULTS: The mutation was identified in 17 of 37 family members. The mean number of missing teeth due to agenesis was 10.3 ± 4.1, (range 4-17) in the mutation group and 0.1 ± 0.3, (range 0-1) in the non-mutation group (p < 0.01). All individuals with the mutation were missing the maxillary lateral incisors and one or more of the mandibular incisors; and 81.3% were missing all four. Stimulated saliva secretion was 0.9 ± 0.5 ml/min in the mutation group vs 1.7 ± 0.6 ml/min in the non-mutation group (p < 0.01). Reduced ability to sweat was reported by 82% in the mutation group and by 20% in the non-mutation group (p < 0.01). The mean NOT-S score was 3.0 ± 1.9 (range 0-6) in the mutation group and 1.5 ± 1.1 (range 0-5) in the non-mutation group (p < 0.01). Lisping was present in 56% of individuals in the mutation group.

    CONCLUSIONS: Individuals with a c.1072C > T mutation in the EDAR-gene displayed a typical pattern of congenitally missing teeth in the frontal area with functional consequences. They therefore have a need for special attention in dental care, both with reference to tooth agenesis and low salivary secretion with an increased risk for caries. Sweating problems were the most frequently reported symptom from other ectodermal structures.

  • 42. Fogelstrand, Linda
    et al.
    Staffas, Anna
    Wasslavik, Carina
    Sjogren, Helene
    Soderhall, Stefan
    Frost, Britt-Marie
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Behrendtz, Mikael
    Heldrup, Jesper
    Karrman, Kristina
    Johansson, Bertil
    Heyman, Mats
    Abrahamsson, Jonas
    Palmqvist, Lars
    Prognostic Implications of Mutations in NOTCH1 and FBXW7 in Childhood T-ALL Treated According to the NOPHO ALL-1992 and ALL-2000 Protocols2014Inngår i: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 61, nr 3, 424-430 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background In children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis.

    Procedure We analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes.

    Results Forty-seven of the cases (59%) displayed mutations in NOTCH1 and/or FBXW7. There was no difference in overall (P=0.14) or event-free survival (EFS) (P=0.10) in patients with T-ALL with mutation(s) in NOTCH1/FBXW7 compared with patients with T-ALL without mutations in any of these genes. T-ALL carrying NOTCH1 mutations had increased HES1 and MYB mRNA expression (HES1 9.21.9 (mean +/- SEM), MYB 8.7 +/- 0.8 (mean +/- SEM)) compared to T-ALL with wild-type NOTCH1 (HES1 1.8 +/- 0.7, MYB 5.1 +/- 1.2, P=0.02 and 0.008, respectively). In cases of T-ALL with high HES1 expression, improved overall (P=0.02) and EFS (P=0.028) was seen.

    Conclusions Increased NOTCH activity, reflected by increased HES1 expression, is associated with improved outcome in pediatric T-ALL, but its role as a diagnostic tool or a therapeutic target in future clinical treatment protocols remains to be elucidated. Pediatr Blood Cancer 2014;61:424-430. (c) 2013 Wiley Periodicals, Inc.

  • 43.
    Forestier, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Heyman, Mats
    Andersen, Mette K
    Autio, Kirsi
    Blennow, Elisabeth
    Borgström, Georg
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Heim, Sverre
    Heinonen, Kristina
    Hovland, Randi
    Johannsson, Johann H
    Kerndrup, Gitte
    Nordgren, Ann
    Rosenquist, Richard
    Swolin, Birgitta
    Johansson, Bertil
    Outcome of ETV6/RUNX1-positive childhood acute lymphoblastic leukaemia in the NOPHO-ALL-1992 protocol: frequent late relapses but good overall survival.2008Inngår i: Br J Haematol, ISSN 1365-2141, Vol. 140, nr 6, 665-72 s.Artikkel i tidsskrift (Annet vitenskapelig)
  • 44. Fransen-Pettersson, Nina
    et al.
    Duarte, Nadia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. nstituto Gulbenkian de Sciencia, Oeiras, 2780–156 Oeiras, Portugal.
    Nilsson, Julia
    Lundholm, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Mayans, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Larefalk, Åsa
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Hannibal, Tine D.
    Hansen, Lisbeth
    Schmidt-Christensen, Anja
    Ivars, Fredrik
    Cardell, Susanna
    Palmqvist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Rozell, Bjoern
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. EMV Immunology, BMC, Lund University, Lund, Sweden; ISIM- Immunology, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark.
    A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis2016Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 7, e0159850Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF) mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT) induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders.

  • 45. Fuchs, Uwe
    et al.
    Zittermann, Armin
    Suhr, Ole B
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Holmgren, Gösta
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Tenderich, Gero
    Minami, Kazutomo
    Koerfer, Reiner
    Heart transplantation in a 68-year-old patient with senile systemic amyloidosis.2005Inngår i: Am J Transplant, ISSN 1600-6135, Vol. 5, nr 5, 1159-62 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 46.
    Ghasimi, Soma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wibom, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Dahlin, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Genetic risk variants in the EGFR regions are associated with copy number variation in the EGFR gene as well as IDH1, and p53 protein expressionManuskript (preprint) (Annet vitenskapelig)
  • 47.
    Ghasimi, Soma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wibom, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Dahlin, Anna M.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Genetic risk variants in the CDKN2A/B, RTEL1 and EGFR genes are associated with somatic biomarkers in glioma2016Inngår i: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 127, nr 3, 483-492 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    During the last years, genome wide association studies have discovered common germline genetic variants associated with specific glioma subtypes. We aimed to study the association between these germline risk variants and tumor phenotypes, including copy number aberrations and protein expression. A total of 91 glioma patients were included. Thirteen well known genetic risk variants in TERT, EGFR, CCDC26, CDKN2A, CDKN2B, PHLDB1, TP53, and RTEL1 were selected for investigation of possible correlations with the glioma somatic markers: EGFR amplification, 1p/19q codeletion and protein expression of p53, Ki-67, and mutated IDH1. The CDKN2A/B risk variant, rs4977756, and the CDKN2B risk variant, rs1412829 were inversely associated (p = 0.049 and p = 0.002, respectively) with absence of a mutated IDH1, i.e., the majority of patients homozygous for the risk allele showed no or low expression of mutated IDH1. The RTEL1 risk variant, rs6010620 was associated (p = 0.013) with not having 1p/19q codeletion, i.e., the majority of patients homozygous for the risk allele did not show 1p/19q codeletion. In addition, the EGFR risk variant rs17172430 and the CDKN2B risk variant rs1412829, both showed a trend for association (p = 0.055 and p = 0.051, respectively) with increased EGFR copy number, i.e., the majority of patients homozygote for the risk alleles showed chromosomal gain or amplification of EGFR. Our findings indicate that CDKN2A/B risk genotypes are associated with primary glioblastoma without IDH mutation, and that there is an inverse association between RTEL1 risk genotypes and 1p/19q codeletion, suggesting that these genetic variants have a molecular impact on the genesis of high graded brain tumors. Further experimental studies are needed to delineate the functional mechanism of the association between genotype and somatic genetic aberrations.

  • 48. Goldberg, Ross F
    et al.
    Austen, William G
    Zhang, Xiaobo
    Munene, Gitonga
    Mostafa, Golam
    Biswas, Shaluk
    McCormack, Michael
    Eberlin, Kyle R
    Nguyen, John T
    Tatlidede, Hamit S
    Warren, H Shaw
    Narisawa, Sonoko
    Millán, Jose L
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Hodin, Richard A
    Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition.2008Inngår i: Proc Natl Acad Sci U S A, ISSN 1091-6490, Vol. 105, nr 9, 3551-3556 s.Artikkel i tidsskrift (Annet vitenskapelig)
  • 49.
    Golovleva, Irina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Köhn, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Burstedt, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Daiger, Stephen
    The University of Texas Health Science Center Houston, Human Genetics Center.
    Sandgren, Ola
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Mutation spectra in autosomal dominant and recessive retinitis pigmentosa in northern sweden.2010Inngår i: Advances in Experimental Medicine and Biology, ISSN 0065-2598, Vol. 664, 255-262 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Retinal degenerations represent a heterogeneous group of disorders affecting the function of the retina. The frequency of retinitis pigmentosa (RP) is 1/3500 worldwide, however, in northern Sweden it is 1/2000 due to limited migration and a 'founder' effect. In this study we identified genetic mechanisms underlying autosomal dominant and recessive RP present in northern Sweden. Several novel mutations unique for this region were found. In an autosomal recessive form of RP, Bothnia dystrophy caused by mutations in the RLBP1 gene, bi-allelic mutations R234W, M226K and compound heterozygosity, M226K+R234W was detected.In dominant form of RP mapped to 19q13.42 a 59 kb genomic deletion including the PRPF31 and three other genes was found.These data provide additional information on the molecular mechanisms of RP evolvement and in the future might be useful in development of therapeutic strategies. Identification of the disease-causing mutations allowed introducing molecular genetic testing of the patients and their families into the clinical practice.

  • 50.
    Goulley, Joan
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Naredi, Peter
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Kirurgi.
    Edlund, Helena
    Diabetes and β-cell hyperplasia in mice over-expressing the ATPase Asna-1Manuskript (Annet (populærvitenskap, debatt, mm))
12345 1 - 50 of 244
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