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  • 1.
    Berzina, L.
    et al.
    Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Ludvigsson, Johnny
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Saduaskaite-Kühne, Vaiva
    Laboratory of Pediatric Endocrinology, Kaunas University of Medicine, Kaunas, Lithuania.
    Nelson, Nina
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Shtauvere-Brameus, A.
    Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Sanjeevi, C. B.
    Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    DR3 is associated with type 1 diabetes and blood group ABO incompatibility2002In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 958, p. 345-348Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes is associated with autoimmunity against pancreatic β cells. ABO incompatibility is associated with ABO immunization during pregnancy. Type 1 diabetes is associated with certain HLA DR and DQ haplotypes. The mechanism by which blood group incompatibility is associated with the risk of type 1 diabetes is not known. We propose that certain HLA alleles contribute to the development of both type 1 diabetes and ABO blood group incompatibility. We studied 57 children with ABO blood group incompatibility, 118 children with type 1 diabetes, and 98 age- and sex-matched unrelated healthy controls from Linköping. Typing of HLA DQA1, DQB1, and DRB1 was done on DNA extracted from peripheral blood, by PCR amplification, manual dot-blotting onto nylon membranes, synthetic sequence-specific oligonucleotide (SSO) probe 3′ end-labeling with 32P-dCTP, and hybridization followed by stringency washes and autoradiography. We observed that DR3 allele was more frequent in patients with ABO incompatibility when compared to healthy controls (OR = 2.7, Pc < 0.05). Patients with type 1 diabetes had significantly higher frequency of DR3, DQ2, DR4, and DQ8 alleles when compared to healthy controls. No significant difference was observed in frequency of DR3 between ABO blood group incompatibility and type 1 diabetes patients. We conclude that DR3 is associated with both the development of type 1 diabetes and ABO incompatibility.

  • 2. Berzina, L
    et al.
    Shtauvere-Brameus, S
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Sanjeevi, CB
    Newborn screening for high-risk human leukocyte antigen markers associated with insulin-dependent diabetes mellitus: The ABIS study2002In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 958, p. 312-316Article in journal (Refereed)
    Abstract [en]

    Type 1 (insulin-dependent) diabetes mellitus is associated with specific high-risk HLA DQ and DR haplotypes and islet cell antibodies. IDDM susceptibility in Caucasians is more strongly associated with DQ2/DQ8 (DQA1*0501-DQB1*0201/DQA1*0301-DQB1*0302) and DQ6 (B1*0604) than with DRB1*03/DRB1*04, while a single copy of DQ6 (B1*0602) gives sufficient protection against type 1 diabetes. As a part of the ABIS (All Babies in Southeast Sweden) study we have done typing of DQA1, DQB1, and DRB1 by polymerase chain reaction (PCR) amplification of the second exon of the genes, manually dot-blotting onto nylon membranes synthetic sequence-specific oligonucleotide (SSO) probes, 3' end-labeling with 32P-dCTP, and hybridization followed by stringency washes and autoradiography using the SSO probe. Among 3756 newborns born in southeast Sweden we have found the high-risk genotype DQ2/DR3-DO8/DR4 to be present in 1%, haplotype DQ8/DR4 in 7.8%, and haplotype DQ2/DR3 in 9.6%. DQ2/DR3 or DQ8/DR4 was carried by 16.4% of newborns, the low-risk DQ6 molecule was carried by newborns as follows: DQ2/DR3-DQ6/DR15, 1.3%, DQ8/DR4-DQ6/DR15, 1.3%, and DQ6/DR15, 9.4%. We conclude from our results that the high incidence of IDDM in Sweden is at least in part due to increased prevalence of high-risk HLA haplotypes compared to protective haplotypes (20% vs. 13%) in the general population.

  • 3.
    Gimm, Oliver
    et al.
    Department of General, Visceral and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, 06097 Halle/Saale, Germany.
    Krause, Ulf
    Institute of Pathology, Martin-Luther-University Halle-Wittenberg, 06097 Halle/Saale, Germany.
    Brauckhoff, Michael
    Department of General, Visceral and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, 06097 Halle/Saale, Germany.
    Hoang-Vu, Cuong
    Department of General, Visceral and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, 06097 Halle/Saale, Germany.
    Dralle, Henning
    Department of General, Visceral and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, 06097 Halle/Saale, Germany.
    Distinct expression of galectin-3 in pheochromocytomas.2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1073, p. 571-7Article in journal (Refereed)
    Abstract [en]

    Unless distant metastases or local invasion are present, the diagnosis of malignant pheochromocytoma is challenging. Hence, biological markers are sought after and we thought to examine galectin-3 in such a role. Four malignant and 24 benign (10 sporadic, 14 hereditary) pheochromocytomas were analyzed for the expression of galectin-3. One malignant pheochromocytoma with distant metastases showed strong and one malignant undifferentiated pheochromocytoma with local invasion showed partly strong cytoplasmic staining. Nine of 10 sporadic and all hereditary benign pheochromocytomas had absent/weak staining. One benign sporadic pheochromocytoma had moderate cytoplasmic staining. The distinct expression in various types of pheochromocytomas is intriguing and requires further investigation.

  • 4.
    Gullberg, Elisabet
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    Söderholm, Johan D
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Peyer's patches and M cells as potential sites of the inflammatory onset in Crohn's disease2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1072, p. 218-232Article in journal (Refereed)
    Abstract [en]

    Clinical observations suggest that the sites of initial inflammation in ileal Crohn's disease (CD) are the lymphoid follicles, where the aphtoid lesions originate from small erosions of the follicle-associated epithelium (FAE). Lymphoid follicles and Peyer's patches (PPs) consist of a number of B-cell follicles with intervening T cell areas. The T cell follicular area is also populated by dendritic cells (DCs) and macrophages. A single layer of epithelial cells covering each follicle forms a dome between the surrounding villi. This FAE differs from normal villus epithelium in several ways that make the epithelial cells of the FAE more exposed to the luminal contents, more accessible to antigens, and in closer contact with the immune system. The most prominent feature is the presence of specialized M cells, which are optimized for antigen adherence and transport. M cells play an important role in the surveillance of the intestinal lumen, but also provide a route of entry for various pathogens. In this article we review the current knowledge on the epithelial phenotype of the human FAE, and changes of the FAE and M cells in intestinal inflammation, leading to a hypothesis of the role of the FAE and M cells in the pathogenesis of CD.

  • 5. Gupta, M
    et al.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Sanjeevi, CB
    Frequency of MICA in all babies in southeast Sweden (ABIS) positive for high-risk HLA-DQ associated with type 1 diabetes2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1037, p. 138-144Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes mellitus (T1DM) is an autoimmune disease known to occur in genetically susceptible individuals after exposure to certain unknown environmental factors. HLA-DR3-DQ2 or DR4-DQ8 are established genetic markers for the disease. MHC class I chain-related gene-A (MICA) gene polymorphism has been proposed to be associated with T1DM. To identify the environmental factors and for implementing intervention trials to prevent T1DM, it is important to screen subjects at genetically increased risk for developing T1DM. The All Babies in Southeast Sweden (ABIS) study aims to assess the risk of future progression to T1DM in the general child population. In the present report, we studied the frequency of MICA alleles among newborn babies carrying high-risk HLA DQ2 or DQ8. Of 2821 newborns, we found 563 subjects positive for DQ2, 583 subjects positive for DQ8, 133 subjects positive for DQ2-DQ8 (heterozygous), and 1013 subjects positive for either DQ2 or DQ8. Of these 1013 babies, we typed 499 babies for MICA. Frequency of MICA5 was 38% among DQ8+9 35% among for DQ2-DQ8 (heterozygous) positives, and 22.5% among DQ2+ babies. Frequency of MICA5.1 was 81% among DQ+, 62% among DQ8+, and 71% among DQ2.-DQ8 (heterozygous) positives. Frequency of MICA6 was between 20% and 22% among the three groups. Frequency of MICA5/5.1 was 19% among DQ2-DQ8 (heterozygous) positives and between 12% and 13% among those positive for DQ2, DQ89 DQ2, or DQ8. The results from genetic typing in this study would be useful, in conjunction with results from autoantibody analysis that are prospectively being followed-up in all the babies, to develop an approach for identifying children at risk for developing T1DM. Inclusion of MICA typing in addition to HLA could be useful for screening of genetic markers associated with T1DM.

  • 6.
    Gustafsson Stolt, Ulrica
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Liss, Per-Erik
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Parents want to know if their child is at high risk of getting diabetes2003In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1005, p. 395-399Article in journal (Refereed)
    Abstract [en]

    Not least among professionals, voices have been raised against screening research projects, which have been regarded as involving a risk of being unethical as they may disturb, scare, or even harm the included people without giving enough benefit. This problem with large-scale screening should be especially pronounced if increased risk of a serious disease like type 1 diabetes is identified when no effective prevention is available, and even more problematic if children were involved. ABIS (All Babies in Southeast Sweden) is a screening project including 17,000 newborn babies in the general population, followed prospectively to identify children at risk to get diabetes, and to study the influence of environmental factors causing the disease process. Four hundred randomly selected ABIS families received a questionnaire on attitudes and ethical questions regarding the project to be answered anonymously: 293/400 (73.3%) answered; 279/293 (95.3%) stated that they regarded it their right to be informed of results in the study and 278/293 (94.9%) said they really want to know. In fact, 254/293 (86.7%) report wanting to know if their child has increased risk of getting diabetes even if there is no preventive measure available. This clear result supports the view that this type of study may well be ethically justified as long as informed consent can be given based on adequate understanding and voluntariness. The results may have implications for the design of future screening studies.

  • 7.
    Johansson, AnnaKarin
    et al.
    Linköping University, Department of Medicine and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Hermansson, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Tobacco Exposure and Diabetes-Related Autoantibodies in Children Results from the ABIS Study2008In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1150, p. 197-199Article in journal (Refereed)
    Abstract [en]

    Passive smoking has decreased in recent years ("increased hygiene"). Less environmental tobacco smoke (ETS) gives increased hygiene that, if the hygiene hypothesis is true, in turn might give more autoimmune diseases. The presence of auto antibodies is considered to be an early indicator of type 1 diabetes (T1D). Because tobacco exposure may influence the immune system, we analyzed the relation between passive smoking and development of autoantibodies. A subsample (n = 8794) of the children in the ABIS study was used for this analysis. The parents answered questionnaires on smoking from pregnancy and onwards, and blood samples from the children aged 2.5-3 years were analyzed for GADA and IA-2A. Results showed that there was no significant difference in the prevalence of GADA or IA-2A (> 95 percentile) between tobacco-exposed and nonexposed children. It was concluded that passive smoking does not seem to influence development of diabetes-related autoantibodies early in life.

  • 8.
    Keita, Åsa V.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Söderholm, Johan D.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery UHL.
    Barrier dysfunction and bacterial uptake in the follicle-associated epithelium of ileal Crohns disease2012In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1258, no 1, p. 125-134Article in journal (Refereed)
    Abstract [en]

    The ability to control uptake across the mucosa and protect from harmful substances in the gut lumen is defined as intestinal barrier function. The etiology of Crohns disease is unknown, but genetic, environmental, and immunological factors all contribute. The frontline between these factors lies in the intestinal barrier. The most important inflammation-driving environmental factor in Crohns disease is the microbiota, where Esherichia coli strains have been assigned a key role. The first observable signs of Crohns disease are small aphtoid ulcers over Peyers patches and lymphoid follicles. The overlaying follicle-associated epithelium (FAE) is specialized for luminal sampling and is an entry site for antigens and bacteria. We have demonstrated increased E. coli uptake across the FAE in Crohns disease, which may initiate inflammation. This short review will discuss barrier dysfunction and bacteria in the context of ileal Crohns disease, and how the FAE might be the site of initial inflammation.

  • 9.
    Kivling, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Fälth-Magnusson, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Sollvander, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Johanson, Calle
    Ryhov Jonkoping City Hospital.
    Faresjö, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Diverse FOXP3 Expression in Children with Type 1 Diabetes and Celiac Disease2008In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1150, p. 273-277Article in journal (Refereed)
    Abstract [en]

    Imbalance between different types of T lymphocytes, such as T helper (Th) and regulatory T cells (Tregs), has been reported to play a part in the pathogenesis behind such autoimmune diseases as type 1 diabetes (T1D) and celiac disease (CD). Defects in Tregs are proposed to at least partly explain the imbalance of Th cells found in children with immunologic diseases. Peripheral blood mononuclear cells from 24 children with T1D and/or CD, and reference children (that is, those without any of these diseases) were stimulated with disease-associated antigens (insulin, gluten, transglutaminase [tTG]), and phytohemagglutinin (PHA). The mRNA expression of the Treg-associated marker FOXP3 was analyzed with multiplex real-time RT-PCR. Children with T1D showed both a low spontaneous (P < 0.05) and PHA-induced (P < 0.01) expression of FOXP3 mRNA compared to children with CD. Children with T1D also had a low PHA-induced FOXP3 mRNA expression compared to the group of children diagnosed with both T1D and CD (P < 0.05). Spontaneous (P < 0.05) and PHA-induced (P < 0.05) FOXP3 mRNA expression was high in children with CD compared to reference children. In contrast, stimulation with insulin tended to induce high FOXP3 mRNA expression in T1D children compared to reference children (P = 0.057). In conclusion, children with only T1D generally showed a lower FOXP3 mRNA expression than did children with CD, or with T1D in combination with CD, which suggests impaired regulation of the immune system in children with T1D.

  • 10.
    Koch, Christian A
    et al.
    Division of Endocrinology and Nephrology, University of Leipzig, Germany.
    Gimm, Oliver
    Department of Surgery, University of Halle, Germany.
    Vortmeyer, Alexander O
    National Institutes of Health, NINDS, Bethesda, Maryland, USA.
    Al-Ali, Haifa K
    Division of Hematology and Oncology, University of Leipzig, Germany.
    Lamesch, Peter
    Department of Surgery, Sankt Georg Hospital, Leipzig, Germany.
    Ott, Rudolf
    Department of Surgery II, University of Leipzig, Germany.
    Kluge, Regine
    Department of Nuclear Medicine, University of Leipzig, Germany.
    Bierbach, Uta
    Division of Pediatric Hematology and Oncology, University of Leipzig, Germany.
    Tannapfel, Andrea
    Ruhr University of Bochum, Bochum, Germany.
    Does the expression of c-kit (CD117) in neuroendocrine tumors represent a target for therapy?2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1073, p. 517-26Article in journal (Refereed)
    Abstract [en]

    Neuroendocrine tumors are very heterogeneous, develop from a variety of tissues, and can be difficult to diagnose. Without the clinical manifestation of metastases, it is often difficult to characterize them as malignant. Even so-called completely (R0) resected tumors can spread clinically visible metastases within a few months after initial surgery. Treatment options for neuroendocrine tumors including pheochromocytoma are limited. Molecular targeted therapies using tyrosine kinase inhibitors might prove to be helpful in patients with these tumors. In an immunohistochemical study, we examined KIT in 26 pheochromocytomas, 8 of which were malignant (3 adrenal pheochromocytomas, 5 paragangliomas). KIT expression was found in one of these 8 malignant tumors. This 2.5-cm-large adrenal pheochromocytoma originated from a woman with neurofibromatosis type 1 and spread into spine, skull, and lung. KIT expression could be demonstrated in 5% of tumor cells. On the basis of KIT expression immunohistochemically, we treated patients with neuroendocrine (i.e., medullary thyroid cancer) and other tumors with imatinib 400 mg per day, but without efficacy after 2 months of therapy. Similar results were shown by other investigators. Therefore, monotherapy with imatinib may not be efficacious in patients with neuroendocrine tumors that express KIT. Tyrosine kinase inhibitors such as sorafenib that targets several receptors in addition to KIT may be more efficacious in treating patients with neuroendocrine tumors.

  • 11.
    Koch, Stefan
    et al.
    Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA.
    Nusrat, Asma
    Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA.
    Dynamic regulation of epithelial cell fate and barrier function by intercellular junctions2009In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1165, p. 220-227Article in journal (Refereed)
    Abstract [en]

    In the intestine, a single layer of epithelial cells effectively separates potentially harmful luminal content from the underlying tissue. The importance of an intact mucosal layer is highlighted by pathological disorders of the gut such as inflammatory bowel disease, in which disruption of the epithelial barrier leads to severe inflammation of the submucosal tissue compartments. Epithelial barrier function is provided by tightly regulated intercellular junctions, which consist of a plethora of membrane-associated and transmembrane proteins organized in discreet, spatially restricted complexes. Classically, these complexes are known to be dynamic seals for fluids and small molecules, as well as to provide mechanical strength by anchoring cell-cell contacts to the cytoskeleton. Rather than just acting as simple gates and adapters, however, junctional complexes themselves can relay extracellular stimuli to the epithelium and initiate cellular responses such as differentiation and apoptosis. In this review, we will highlight recent studies by our group and others which discuss how junctional proteins can promote outside-to-inside signaling and modulate epithelial cell fate. Unraveling the complex crosstalk between epithelial cells and their intercellular junctions is essential to understanding how epithelial barrier function is maintained in vivo and might provide new strategies for the treatment of inflammatory disorders of the intestine.

  • 12.
    Kurz, Tino
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Leake, Alan
    von Zglinicki, Thomas
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Lysosomal redox-active iron is important for oxidative stress-induced DNA damage2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1019, p. 285-288Article in journal (Refereed)
    Abstract [en]

    Data show that specifically chelating lysosomal redox-active iron can prevent most H2O2-induced DNA damage. Lysosomes seem to contain the major pool of redox-active labile iron within the cell. Under oxidative stress conditions, this iron may then relocate to the nucleus and play an important role for DNA damage by taking part in Fenton reactions.

  • 13.
    Li, Wei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences.
    Hellsten, Anna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery.
    Nyhalah, JD
    Yuan, Ximing
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Enhanced expression of natural resistance-associated macrophage protein 1 in atherosclerotic lesions may be associated with oxidized lipid-induced apoptosis2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1030, p. 202-207Article in journal (Refereed)
    Abstract [en]

    The natural resistance-associated macrophage proteins (Nramps) can modulate inflammatory reactions. Nramps are not only responsible for intracellular divalent metal transport but also determine the macrophage functions in inflammatory processes. In the present study we tested whether Nramp1 is involved in macrophage apoptosis induced by oxidized lipids in atherogenesis. Arterial segments of Watanabe heritable hyperlipidemic rabbits were used for an examination of Nramp1 mRNA by in situ RT-PCR and macrophage immunohistochemistry. Annexin V/PI staining and terminal dUTP nick-end labeling (TUNEL) techniques were used for apoptosis detection. We found that, in macrophage-rich areas (positive to RMA-11) of the rabbit atherosclerotic aorta, there were lesion-dependent increases in Nramp1 mRNA, which are mainly apoptotic foamy macrophages that are positive to TUNEL staining. U937 cells were treated with 7 beta-hydroxycholesterol (7 beta-OH) in the presence or absence of the redox-active iron chelator desferrioxamine (DFO) or 1,10-phenanthroline. The cellular iron chelators considerably reduced, whereas iron compounds enhanced, 7 beta-OH-induced apoptosis and necrosis. DFO also decreased mRNA levels of Nramp1, whereas both iron compounds and 7 beta-OH dramatically enhanced the expression of Nramp1 mRNA, particularly among 7 beta-OH-induced apoptotic cells. We conclude that the enhanced expression of Nramp1 in macrophage regions of atherosclerotic lesions may be associated with ferrous iron-enhanced, oxidized lipid-induced apoptosis. This finding reveals a novel function of Nramp1 in atherogenesis.

  • 14.
    Li, Wei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences.
    Xu, Lihua
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Yuan, Ximing
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Macrophage hemoglobin scavenger receptor and ferritin accumulation in human atherosclerotic lesions2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1030, p. 196-201Article in journal (Refereed)
    Abstract [en]

    We previously proposed that erythrophagocytosis and iron metabolism by macrophages may contribute to iron-driven oxidative stress in atherogenesis. Recent studies have indicated that the macrophage hemoglobin scavenger receptor (HbSR/CD 163) is a key molecule in the process of removing hemoglobin released from senescent erythrocytes. In this study we investigated crythrophagocytosis and its relation to ferritin accumulation and the involvement of CD163 in ferritin induction in human atheroma lesions. Normal and atherosclerotic human arterial segments obtained at autopsy and surgery were collected for iron histochemistry, hemoglobin and ferritin immunohistochemistry, and computerized image analysis. The lesion-dependent accumulation of ferritin and hemoglobin was seen in atherosclerotic carotid and coronary arteries. The immunoreactivity of hemoglobin was significantly correlated to the same regions of ferritin immunoreactivity on serial sections. The staining intensity of hemoglobin and ferritin was also significantly correlated. Hemoglobin deposition is often associated with microvessels adjacent to the lipid core areas in advanced lesions, where most CD68-positive macrophages were. CD163 expression appeared in both early and advanced lesions. The accumulation of tissue iron and ferritin also frequently occurs in CD163-positive and vessel-rich regions in the advanced atheroma. Although they were not always correspondingly positive on the serial sections, tissue iron and ferritin were significantly correlated. We conclude that erythrophagocytosis and hemoglobin catabolism by macrophages contribute to iron deposition and ferritin induction in human atheroma. The involvement of CD163 during ferritin induction may play an important role in modulating inflammatory processes in atherogenesis.

  • 15.
    Li, Wei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences.
    Yuan, Ximing
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Increased expression and translocation of lysosomal cathepsins contribute to macrophage apoptosis in atherogenesis2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1030, p. 427-433Article in journal (Refereed)
    Abstract [en]

    It has been recently reported that atherosclerotic lesions in both humans and mice express several lysosomal proteases, including cathepsins B, D, L, and S, which may affect plaque development and stability. The mechanisms responsible for the extralysosomal expression of lysosomal cathepsins and the related atherogenic implications remain unknown. We rind that the lesion-dependent expression of cathepsins B and L is mainly in macrophage-infiltrated areas of human carotid atheroma. These enzymes appear in the cytoplasm and nuclei of apoptotic macrophages (normally confined to the lysosomal compartment) and in the extracellular areas. After exposure to oxidized low-density lipoprotein (oxLDL) or 7 beta-hydroxycholesterol (7 beta-OH), macrophages initially transform into foam cells and then undergo apoptotic cell death. The oxidized lipids induce lysosomal destabilization, with leakage to the cytosol of lysosomal enzymes (cathepsins B, D, and L), as detected by cytochemistry and immunocytochemistry. A remarkable increase in cathepsin D mRNA levels was observed after 7 beta-OH exposure. Like macrophages within atheroma, intralysosomal cathepsins B and L are translocated to the cytoplasm and nuclei of 7B-OH-exposed cells. Our results suggest that endocytosed oxLDL and oxysterols not only destabilize the acidic vacuolar compartment but also cause the upregulation and translocation of lysosomal cathepsins, which may act as cleaving enzymes during the apoptotic process. The increased macrophage apoptosis and nuclear and matrix degradation by lysosomal enzymes in atheroma may play important roles in plaque development and rupture.

  • 16.
    Ljungberg, Martin
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Korpela, Riita
    Valio Ltd, Helsinki, Finland.
    Ilonen, Jorma
    Department of Clinical Microbiology, University of Kuopio, Kuopio, Finland and Immunogenetics Laboratory, University of Turku, Turku, Finland.
    Ludvigsson, Johnny
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Vaarala, Outi
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland.
    Probiotics for the Prevention of Beta Cell Autoimmunity in Children at Genetic Risk of Type 1 Diabetes—the PRODIA Study2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1079, p. 360-364Article in journal (Refereed)
    Abstract [en]

    The final aim of the PRODIA study is to determine whether the use of probiotics during the first 6 months of life decreases the appearance of type 1 diabetes mellitus (T1DM)-associated autoantibodies in children with genetic risk for T1DM. A pilot study including 200 subjects was planned to show whether the use of probiotics during the first 6 months of life is safe and feasible. The prevalence of autoantibodies among the study subjects at 6, 12, and 24 months of age was at levels close to the expected and the clinical follow-up did not either indicate problems in the feasibility of the study.

  • 17.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Why diabetes incidence inereases- A unifying theory2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1079, p. 374-382Article in journal (Refereed)
    Abstract [en]

    There is a wide spectrum within the diabetes syndrome. Type I diabetes may have a slow progression with good residual insulin secretion and without autoantibodies, while phenotypic type 2 diabetes may have autoantibodies. A single patient may have traits of both types of diabetes. Their incidence increases in parallel. The etiology is mainly unknown, but environmental factors play an important role in genetically predisposed individuals. The search for just one single cause of manifest diabetes may be confusing. Different mechanism may be important in different parts of the world. Furthermore, certain mechanisms may lead to islet inflammation while other/additional mechanisms may increase insulin demand and cause insulin deficiency with manifestation of clinical diabetes. Several hypothesis of etiology may fit different parts of the disease process. Thus, increased hygiene may contribute to an imbalance of the immune system, facilitating autoimmune reactions when virus infections, or proteins like cow's milk or gluten, provoke. Increased insulin demand because of rapid growth, or insulin resistance caused by stress, infections, puberty, etc., lead to beta cell stress, antigen presentation and may cause both an autoimmune reaction in genetically predisposed individuals, and insulin deficiency leading to manifest diabetes in individuals who have lost beta cell function. Vitamins may modulate the immune process, but we know too little to give vitamin substitution. However, we do know that low physical exercise, obesity, and stress, increases insulin demand resulting in insulin deficiency. Now we can therefore intervene to prevent the diabetic syndrome.

  • 18.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Gustafsson Stolt, Ulrica
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Liss, Per-Erik
    Linköping University, Department of Department of Health and Society. Linköping University, Faculty of Health Sciences.
    Svensson, Tommy
    Linköping University, Department of Behavioural Sciences, Sociology. Linköping University, Faculty of Health Sciences.
    Mothers of children in ABIS, a population-based screening for prediabetes, experience few ethical conflicts and have a positive attitude2002In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 958, p. 376-381Article in journal (Refereed)
    Abstract [en]

    Screening is supposed to create less anxiety among first-degree relatives of diabetic patients where the risk of developing diabetes already is well known. It has also been argued that screening of a general child population should never be performed unless identified high-risk individuals can be offered intervention to prevent diabetes. However, the empirical data are scarce, especially regarding what opinions patients or their parents have of these matters/issues themselves. We have therefore tried to evaluate mothers' attitudes to and ethical views on participation in a research screening for prediabetes in an unselected birth cohort. All 21,700 mothers of children in southeast Sweden born between 1 October 1997 and 1 October 1999 were asked to participate in ABIS (All Babies in Southeast Sweden). They were given information about the design of the study and that HLA types and autoantibodies will be determined in order to predict diabetes, but that no prevention of diabetes will be offered unless future studies show effective methods. After informed consent, 78.6% of mothers let their babies participate (17,055 children) despite a quite laborious study protocol. Explorative in-depth semistructured interviews were performed in 21 mothers, of whom 15 were strategically selected to get as many various attitudes as possible and of whom 6 chose not to participate in ABIS. All interviewed mothers were positive to the ABIS project. We conclude that a well-designed screening program to detect individuals in the general population with high risk of developing diabetes does not evoke anxiety nor severe ethical conflicts.

  • 19.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Wahlberg, Jeanette
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Diabetes-related autoantibodies in cord blood from children of healthy mothers have disappeared by the time the child is one year old2002In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 958, p. 289-292Article in journal (Refereed)
    Abstract [en]

    Autoantibodies found in cord blood in children who later develop diabetes might be produced by the fetus. If so, continuous autoantibody production would still be expected in these children at one year of age. We decided to determine autoantibodies in cord blood and to see whether they persisted in these children at one year. Autoantibodies against GAD65 (glutamic acid decarboxylase) and IA-2 (tyrosine phosphatase) in cord blood were determined in 2,518 randomly selected children. Forty-nine (1.95%) were positive for GAD65 antibodies, 14 (0.56%) were positive for IA-2 antibodies, and 3 of them were positive for both GAD and IA-2. Four of the mothers of children with GAD65 autoantibodies in cord blood (8.2%) had type 1 diabetes as did 5 mothers of children with IA-2 antibodies (35.7 %), but only 0.4% of the mothers had type 1 diabetes in the autoantibody-negative group (P < 0.001). Information on infections during pregnancy was available in 2,169 pregnancies. In the autoantibody-positive group, 31.5% had an infection during pregnancy, which was more common than in the autoantibody-negative group of 500 children with the lowest values (20.1%; P < 0.04). At one year follow-up nobody of those with positive cord blood had GAD65 or IA-2 autoantibodies. We conclude that most autoantibodies found in cord blood samples of children are probably passively transferred from mother to child. Antibody screening of cord blood cannot be used to predict diabetes in the general population. Infections during pregnancy may initiate an immune process related to diabetes development.

  • 20.
    Lugering, Andreas
    et al.
    Department of Medicine B, University of Münster, Münster, Germany.
    Lebiedz, Pia
    Department of Medicine B, University of Münster, Münster, Germany.
    Koch, Stefan
    Department of Medicine B, University of Münster, Münster, Germany.
    Kucharzik, Torsten
    Department of Medicine B, University of Münster, Münster, Germany.
    Apoptosis as a therapeutic tool in IBD?2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1072, p. 62-77Article in journal (Refereed)
    Abstract [en]

    Defective apoptosis of mucosal cell populations seems to be a relevant pathogenetic mechanism in inflammatory bowel disease (IBD). It has been suggested that the induction of apoptosis in various effector cells may be a relevant therapeutic mechanism in IBD. Indeed, it was shown that different drugs used for treatment of IBD have the capacity to induce apoptosis in T cells or monocytes in vitro and in vivo. However, it remains unclear whether these observations are related to clinical efficacy of these agents. TNF-alpha is one of the most relevant proinflammatory mediators in IBD and anti-TNF treatment has been shown to be of particular benefit for patients with IBD. It could subsequently be shown that various anti-TNF-alpha agents, such as infliximab and adalimumab, can induce apoptosis in activated monocytes and lymphocytes in vitro and in vivo. This mechanism requires reverse signaling via transmembranous TNF, thereby eliciting a signal transduction cascade that results in programmed cell death. Although other mechanisms might also contribute to the clinical effect of anti-TNF-alpha, current data suggest that apoptosis is a relevant mechanism that is associated with clinical efficacy of anti-TNF agents. Induction of apoptosis in activated monocytes or T cells may be regarded as therapeutic tool not only for anti-TNF agents, but also for other drugs used in IBD. Future strategies should focus on identification of mechanisms that prevent apoptosis in the mucosa of patients with IBD and in targeting apoptotic pathways as a therapeutic strategy in IBD.

  • 21.
    Lundberg, Peter
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Division of Biochemistry, University of Calgary, Calgary, Canada.
    Vogel, H. J.
    Division of Biochemistry, University of Calgary, Calgary, Canada.
    NMR as a Noninvasive Tool in Meat Research1987In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 508, p. 516-522Article in journal (Refereed)
    Abstract [en]

    NMR has been used for some time for in vivo measurements of biological tissues and has established itself as a valuable and complementary method to be used in parallel with traditional extraction methods. To date most attention has been paid to problems such as central biochemical pathways, energy metabolism in simple organisms and organs, and of course to problems encountered in medicine. There has been relative little interest in applying NMR to problems in food technology, even if these questions can have a tremendous impact on everyday life. Following a suggestion by Gadian,' we show here that multinuclear metabolic NMR is a useful method for studying post-mortem events in carcasses of slaughtered animals.

    The treatment and storage of carcasses during the first hours after slaughter is of extreme importance for the final quality and tenderness of the meat. Mistreatment can cause large economical losses and waste of valuable food. For example, in order to reduce the risk of bacterial infections one would like to cool down a carcass as soon as possible. Nevertheless, if a muscle is cooled down below 15OC before the postmortem metabolism is completed it may shorten dramatically thus decreasing the tenderness of the meat.' Therefore it is important to measure the rates of postmortem metabolism and to study the efficiency of methods that are aimed at speeding up this process.

  • 22.
    Machens, Andreas
    et al.
    Department of General, Visceral and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, 06097 Halle (Salle), Germany.
    Brauckhoff, Michael
    Department of General, Visceral and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, 06097 Halle (Salle), Germany.
    Gimm, Oliver
    Department of General, Visceral and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, 06097 Halle (Salle), Germany.
    Dralle, Henning
    Department of General, Visceral and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, 06097 Halle (Salle), Germany.
    Risk-oriented approach to hereditary adrenal pheochromocytoma.2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1073, p. 417-28Article in journal (Refereed)
    Abstract [en]

    Hereditary adrenal pheochromocytoma is caused by germline mutations in RET, VHL, SDHB, SDHD, and NF1. As these genes differ in function, so may their pheochromocytoma phenotypes, suggesting gene-specific patterns of age-related progression to pheochromocytoma. This possibility was explored for gene carriers with a lifetime risk of pheochromocytoma in excess of 50%. Published age-standardized penetrance rates of VHL-, SDHB-, and SDHD-associated pheochromocytoma were gauged against age-standardized penetrance rates of MEN2-associated pheochromocytoma in 219 institutional carriers of RET mutations conferring highest (codon 918), high (codons 609, 611, 618, 620, 630, and 634) and least high risk (codons 768, 790, 791, 804, and 891). The highest-risk category included SDHB, SDHD, and the highest-risk RET genotype; the high-risk category VHL missense mutations and the high-risk RET genotypes; and the least-high risk category VHL truncating mutations and least-high risk RET genotypes. Detailed information on recurrence rates and intervals was available only for the RET carriers (19-31% and means of 4.3-5.5 years; all RET risk categories combined). Ipsilateral recurrences in adrenal remnants, and contralateral recurrences in virgin adrenals were comparable in incidence (27% and 39%, P=0.69; high-risk RET category) and time to recurrence (means of 4.3 vs. 5.4 year; P>0.99; high-risk RET category), discounting a major effect of tumor spillage at primary subtotal adrenalectomy on pheochromocytoma recurrence. The risk of malignancy usually is low, except for SDHB (38%). For most hereditary pheochromocytomas, endoscopic subtotal adrenalectomy is the procedure of choice. Grouping hereditary pheochromocytoma into preliminary risk categories may improve the management of gene carriers at risk of developing pheochromocytomas.

  • 23.
    Merzvinskyte, Rasa
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine.
    Treigyte, Grazina
    Savickiene, Jurate
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine.
    Magnusson, Karl-Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Navakauskiene, Ruta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Effects of histone deacetylase inhibitors, sodium phenyl butyrate and vitamin B3, in combination with retinoic acid on granulocytic differentiation of human promyelocytic leukemia HL-60 cells2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1091, p. 356-367Article in journal (Refereed)
    Abstract [en]

    Water-soluble vitamin B3, niacin, and its related compounds were suggested to be applicable for medical use. In this article, we examined the anti-leukemic effects of two distinct histone deacetylase (HDACI and Sir2) inhibitors, sodium phenyl butyrate (PB) and vitamin B3, respectively, on human promyelocytic leukemia cells HL-60, using HDACIs alone and in combination with all trans retinoic acid (RA). We demonstrated that the HDACI combinations exert different effects on cell cycle arrest and differentiation as determined by nitro blue reduction and the expression of the early myeloid differentiation marker CD11b. The most beneficial effects were found by use of 6-h pretreatment with PB and vitamin B3 before the exposition to RA alone or in combination with vitamin B3, showing significant acceleration and a high level of granulocytic differentiation. The effects were associated with a rapid histone 114 acetylation and later histone H3 modifications. Our results suggest that the use of two HDACI altogether before the induction of differentiation and acting via chromatin remodeling may be promising for the treatment of acute promyelocytic leukemia.

  • 24.
    Navakauskiene, Ruta
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Treigyte, G
    Gineitis, A
    Magnusson, Karl-Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Assessment of p16, p21, and p27 in granulocytic differentiation of human promyelocytic HL-60 cell line2002In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 973, p. 284-286Article in journal (Refereed)
    Abstract [en]

    [No abstract available]

  • 25.
    Navakauskiene, Ruta
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Treigyte, G
    Institute of Biochemistry, LT-08662 Vilnius.
    Savickiene, Jurate
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine.
    Gineitis, A
    Institute of Biochemistry, LT-08662 Vilnius.
    Magnusson, Karl-Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Alterations in protein expression in HL-60 cells during etoposide-induced apoptosis modulated by the caspase inhibitor ZVAD.fmk2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1030, p. 393-402Article in journal (Refereed)
    Abstract [en]

    DNA topoisomerase inhibitors induce a specific signaling cascade that promotes an active apoptotic caspase-dependent cell death process. However, little is known about the initial signals elicited by these agents. In the present study, we compared apoptosis in HL-60 cells treated either with the chemotherapeutic drug etoposide (VP16) alone or combined with the broad caspase inhibitor ZVAD.fmk. Apoptosis was assessed by changes in cell morphology and agarose gel electrophoresis of extracted cell DNA. We found that ZVAD.fmk prevents VP16-induced DNA fragmentation and the appearance of an increased number of apoptotic cells in the culture. We also compared the effects of etoposide alone or together with the pan-caspase inhibitor ZVAD.fmk on proliferating cell nuclear antigen, Bcl-2, and actin expression in human promyelocytic leukemia HL-60 cells. In addition, we screened for proteins that were initially upregulated in a caspase-dependent manner. Indeed, some proteins were induced in the cytoplasm and subsequently accumulated in the nuclei after etoposide treatment. This process was slightly inhibited by the caspase inhibitor ZVAD.fmk. We suggest that these proteins are associated with the induction of specific signaling cascades that characterize the apoptotic cell death process.

  • 26.
    Onipko, A
    et al.
    Lulea Univ Technol, Div Phys, S-97187 Lulea, Sweden Bogolyubov Inst Theoret Phy, UA-03143 Kiev, Ukraine.
    Malysheva, L
    Lulea Univ Technol, Div Phys, S-97187 Lulea, Sweden Bogolyubov Inst Theoret Phy, UA-03143 Kiev, Ukraine.
    Tunneling through a tilted tight-binding sand2002In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 960, p. 143-152Article in journal (Refereed)
    Abstract [en]

    In the single-band approximation, an explicit expression of the exponential factor, that governs tunneling through a thin crystal subjected to a constant electric field, is derived. The basic features of Wannier-Stark, Airy, and intermediate type of quantization, as they are displayed in the transmission spectrum and hence in tunneling current, are thus described analytically.

  • 27. Pollard, K Michael
    et al.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Kono, Dwight H
    Using single-gene deletions to identify checkpoints in the progression of systemic autoimmunity2003In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 987, p. 236-239Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus is a multigenic disorder of unknown etiology. To investigate the roles that specific genes play in lupus, we have examined the disease profiles in mice with single-gene deletions. In total, some 17 genes have been studied. Absence of certain genes, such as CD40L, CD28, or Igh6, abrogated induction of autoimmunity. Other genes, such as Igh5, IL-4, or ICAM-1, had little effect on the development of disease. Intermediate effects were observed in IL-6-deficient mice, while absence of β2-microglobulin resulted in loss of hypergammaglobulinemia and IgG1 autoantibodies, but produced little change in anti-chromatin antibodies or glomerular deposits. The most interesting observations were obtained with genes related to the expression or function of interferon-γ (IFN-γ). Reductions in IFN-γ levels in murine lupus are associated with reductions in both autoantibody levels and immune-complex- mediated pathology. Genes involved in up-regulation of IFN-γ expression, such as IL-12, STAT-4, or ICE, did not significantly influence autoimmunity, whereas absence of IFN-γ or IFN-γ receptor led to greatly reduced autoantibody response and immunopathology. Absence of IRF-1, a gene ex-pressed in response to IFN-γ, resulted in selective retention of anti-chromatin antibodies but little glomerular pathology. These studies suggest that the presence of a baseline level of IFN-γ, rather than increased expression, is important for autoimmunity. Furthermore, as the IRF-1 knockout demonstrates, specific defects in signaling pathways and gene expression subsequent to IFN-γ/IFN-γ receptor interaction may influence only certain disease parameters. It has not escaped our attention that IFN-γ influences the expression and function of other immunologically relevant genes, such as IL-4, IL-6, and β2-microglobulin. Thus, these genes may be part of the downstream events following IFN-γ/IFN-γ receptor interaction that promote the development of autoimmunity.

  • 28.
    Rökaeus, Åke
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Jiang, Kai
    Karolinska Institutet, NOVUM, Huddinge, Sweden.
    Spyrou, Giannis
    Karolinska Institutet, NOVUM, Huddinge, Sweden.
    Waschek, James A.
    University of California, Los Angeles, USA.
    Transcriptional control of the galanin gene. Tissue-specific expression and induction by NGF, protein kinase C, and estrogen1998In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 863, p. 1-13Article in journal (Refereed)
    Abstract [en]

    Galanin is a neuropeptide widely expressed in the central and peripheral nervous system where it acts as a neurotransmitter/neuromodulator and possibly an immunoregulator and growth factor. Galanin gene expression is highly regulated during development and by certain hormones and injury situations. We have examined transcriptional control mechanisms for this gene using chimeric bovine galanin/luciferase reporter genes. These were analyzed in cultured cells and in transgenic mice. The studies reveal that enhancer and silencer sequences are involved in conferring cell- and tissue-specific expression, and that specific elements close to the promoter are responsible for nerve growth factor and protein kinase C induction. So far, the studies have not revealed sequences on the bovine gene that mediate the action of estrogen.

  • 29.
    Savickiene, Jurate
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine.
    Treigyte, G
    Pivoriunas, A
    Navakauskiene, Ruta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Magnusson, Karl-Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Sp1 and NF-kappa B transcription factor activity in the regulation of the p21 and FasL promoters during promyelocytic leukemia cell monocytic differentiation and its associated apoptosis2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1030, p. 569-577Article in journal (Refereed)
    Abstract [en]

    Treatment of human acute promyelocytic leukemia cells with phorbol 12-myristate 13-acetate (PMA) results in growth arrest and differentiation toward monocytes, which subsequently die by apoptosis. However, the relationship between terminal differentiation and apoptosis remains unclear. Here we have studied Sp1 and nuclear factor B-K (NF-B-K) transcription factor activity in controlling promoters of cell cycle-regulating (p21/WAF1/CIP1) and cell death (FasL) genes during monocytic differentiation and apoptosis of the human acute promyelocytic leukemia cell lines NB4 and HL-60. Using the electrophoretic mobility shift assay, we observed that PMA treatment of NB4 cells caused an early response in Sp1 binding to the p21 and FasL promoters at 8 h. The firmly adherent cell phenotype, characteristic of differentiated cells, retained Sp1-binding activity to either promoter, but it was often lost completely in detached, apoptotic cells. The association of Sp1 with the p21 promoter during monocytic differentiation correlated with the levels of expressed p21 in the cytoplasmic fraction, as detected by immunoblotting. In HL-60 cells, very weak or no Sp1 binding to either promoter was observed. Low NF-B-K affinity for its consensus sites and to the FasL promoter was characteristic of apoptotic cells. The results of this study suggest a positive role of Sp1 and NF-B-K, as regulators of p21 and FasL genes, in leukemic cell survival and monocytic differentiation and a negative role in apoptotic cell death.

  • 30.
    Sepa, Anneli
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Frodi, Ann
    Linköping University, Department of Behavioural Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Mothers’ attachment insecurity and diabetes-related autoantibodies in their infants2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1037, p. 110-113Article in journal (Refereed)
    Abstract [en]

    Psychological stress may, via hormonal levels, increase insulin resistance. The aim of this study was to investigate whether mothers' attachment insecurity is associated with the induction or progression of diabetes-related autoimmunity in early childhood. Adult attachment interviews were conducted with 18 mothers of infants who were positive, and 32 mothers of infants who were negative, for glutamic acid decarboxylase, selected from ABIS, a large prospective population-based project. The proportion of children with insecure mothers was larger, but not significantly so, in the autoantibody-positive group than in the negative group. If an association exists between maternal attachment insecurity and diabetes-related autoimmunity during infancy, it does not appear to be strong.

  • 31.
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Catabolic insufficiency and aging2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1067, p. 27-36Article in journal (Refereed)
  • 32.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Dalen, Helge
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Brunka, UT
    Aging of cardiac myocytes in culture - Oxidative stress, lipofuscin accumulation, and mitochondrial turnover2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1019, p. 70-77Article in journal (Refereed)
    Abstract [en]

    Oxidative stress is believed to be an important contributor to aging, mainly affecting long-lived postmitotic cells such as cardiac myocytes and neurons. Aging cells accumulate functionally effete, often mutant and enlarged mitochondria, as well as an intralysosomal undegradable pigment, lipofuscin. To provide better insight into the role of oxidative stress, mitochondrial damage, and lipofuscinogenesis in postmitotic aging, we studied the relationship between these parameters in cultured neonatal rat cardiac myocytes. It was found that the content of lipofuscin, which varied drastically between cells, positively correlated with mitochondrial damage (evaluated by decreased innermembrane potential), as well as with the production of reactive oxygen species. These results suggest that both lipofuscin accumulation and mitochondrial damage have common underlying mechanisms, likely including imperfect autophagy and ensuing lysosomal degradation of oxidatively damaged mitochondria and other organelles. Increased size of mitochondria (possibly resulting from impaired fission due to oxidative damage to mitochondrial DNA, membranes, and proteins) also may interfere with mitochondrial turnover, leading to the appearance of so-called "giant" mitochondria. This assumption is based on our observation that pharmacological inhibition of autophagy with 3-methyladenine induced only moderate accumulation of large (senescent-like) mitochondria but drastically increased numbers of small, apparently normal mitochondria, reflecting their rapid turnover and suggesting that enlarged mitochondria are poorly autophagocytosed. Overall, our findings emphasize the importance of mitochondrial turnover in postmitotic aging and provide further support for the mitochondrial-lysosomal axis theory of aging.

  • 33.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Sandberg, Sandra
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Proteasome inhibition enhances lipofuscin formation2002In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 973, p. 309-312Article in journal (Refereed)
    Abstract [en]

    Lipofuscin, a hallmark of aged nondividing cells, is an undegradable autofluorescent intralysosomal substance composed essentially of oxidized, cross-linked proteins. To test whether impaired activity of proteasomes-which, along with lysosomes, belong to major cellular proteolytic systems-may contribute to lipofuscinogenesis, we exposed growth-arrested human fibroblasts to subapoptotic doses (2 and 5 nM) of a highly specific proteasome inhibitor, MG-262. This resulted in accelerated lipofuscin accumulation (especially when MG-262 exposure was combined with mild hyperoxia cultivation at 40% ambient oxygen versus 8% for controls), and enhanced immunostaining for ubiquitin, reflecting accumulation of modified cytosolic proteins subjected for degradation, and cathepsin L, reflecting enlargement of the lysosomal compartment. These data suggest that insufficient proteasomal function may contribute to lipofuscinogenesis by a compensatory increase in the amount of proteins that are difrected for lysosomal degradation. The findings may be helpful for the understanding of cellular aging as well as diseases associated with intralysosomal accumulation of undegradable material.

  • 34.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Central neuropeptide Y in anxiety- and stress-related behavior and in ethanol intake2008In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1148, p. 136-140Article in journal (Refereed)
    Abstract [en]

    One of the most profound properties of central neuropeptide Y (NPY) is its anxiolytic, or anti-anxiety, effect. This has been demonstrated repeatedly in a number of animal models. In addition, stressors affect NPY expression in the central nervous system, with acute and repeated (chronic) stress having differential effects. Here, a brief summary of some work performed in our laboratory is presented that supports a role for NPY in regulation of stress responses and behaviors.

  • 35.
    Toman, Rudolf
    et al.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia.
    Skultety, Ludovit
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia.
    Ihnatko, Robert
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia.
    Coxiella burnetii glycomics and proteomics--tools for linking structure to function2009In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1166, p. 67-78Article in journal (Refereed)
    Abstract [en]

    Coxiella burnetii, the causative agent of Q fever, is an obligate intracellular bacterium and a highly infectious pathogen. The disease is a widespread zoonosis and is endemic throughout the world. An easy aerosol dissemination, environmental persistence, and high infectivity make the bacterium a serious threat for humans and animals. Lipopolysaccharide is considered one of the major factors of virulence expression and infection of the bacterium. Detailed glycomic studies enabled to better understand structural and functional peculiarities of this biopolymer and its role in pathogenesis and immunity of Q fever. Recent proteomic studies of C. burnetii have brought new approaches in accurate detection of the infectious agent and offered new insights into the inter- or intra-species relatedness. Thus, structure/function relationship studies are currently of utmost importance in the field. This paper will focus on glycomic and proteomic approaches providing information on unique glycan and protein species of the microorganism as the candidate molecules for the use in detection/diagnosis, therapy, and prophylaxis.

  • 36.
    Turner, Anthony
    Cranfield University, UK.
    Amperometric biosensors based on modified porous graphite electrodes1987In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 501, p. 283-287Article in journal (Refereed)
  • 37.
    TURNER, APF
    et al.
    Cranfield University, UK.
    DCOSTA, EJ
    ; .
    HIGGINS, IJ
    ; .
    ENZYMATIC ANALYSIS USING QUINOPROTEIN DEHYDROGENASES1987In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 501, p. 283-287Article in journal (Refereed)
    Abstract [en]

    n/a

  • 38.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Is it dietary insulin?2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1079, p. 350-359Article in journal (Refereed)
    Abstract [en]

    In humans the primary trigger of insulin-specific immunity is a modified self-antigen, that is, dietary bovine insulin, which breaks neonatal tolerance to self-insulin. The immune response induced by bovine insulin spreads to react with human insulin. This primary immune response induced in the gut immune system is regulated by the mechanisms of oral tolerance. Genetic factors and environmental factors, such as the gut microflora, breast milk-derived factors, and enteral infections, control the development of oral tolerance. The age of host modifies the immune response to oral antigens because the permeability of the gut decreases with age and mucosal immune response, such as IgA response, develops with age. The factors that control the function of the gut immune system may either be protective from autoimmunity by supporting tolerance, or they may induce autoimmunity by abating tolerance to dietary insulin. There is accumulating evidence that the intestinal immune system is aberrant in children with type I diabetes (T1D). Intestinal immune activation and increased gut permeability are associated with T1D. These aberrancies may be responsible for the impaired control of tolerance to dietary insulin. Later in life, factors that activate insulin-specific immune cells derived from the gut may switch the response toward cytotoxic immunity. Viruses, which infect P cells, may release autoantigens and potentiate their presentation by an infection-associated "danger signal." This kind of secondary immunization may cause functional changes in the dietary insulin primed immune cells, and lead to the infiltration of insulin-reactive T cells to the pancreatic islets.

  • 39.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    The gut immune system and type 1 diabetes2002In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 958, p. 39-46Article in journal (Refereed)
  • 40. Wahlberg, J.
    et al.
    Fredriksson, J.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Vaccinations may induce diabetes-related autoantibodies in one-year-old children2003In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1005, p. 404-408Conference paper (Other academic)
    Abstract [en]

    Vaccinations have been discussed as one among many environmental candidates contributing to the immune process that later may lead to type 1 diabetes. ABIS (All Babies in Southeast Sweden) is a prospective cohort study following a nonselected birth cohort of general population. In a randomly selected sample collection from 4400 children, GADA and IA-2A have been determined at the age of 1 year. The information on vaccinations was collected from questionnaires answered by the parents and was related to ß cell autoantibodies. When studying the induction of autoantibodies using the autoantibody level of 90th percentile as cutoff level, hemophdus influenza B (HIB) vaccination appeared to be a risk factor for IA-2A [OR 5.9 (CI 1.4-24.4, p = 0.01)] and for GADA [OR 3.4 (CI 1.1-10.8, p = 0.04)] in logistic regression analyses. Furthermore, the titers of IA-2A were significantly higher (p < 0.01 in Mann-Whitney test) in those children who had got HIB vaccination. When 99th percentile was used as cutoff to identify the children at risk of type 1 diabetes, BCG vaccination was associated with increased prevalence of IA-2A (p < 0.01). We conclude that HIB vaccination may have an unspecific stimulatory polyclonal effect increasing the production of GADA and IA-2A. This might be of importance under circumstances when the ß cell-related immune response is activated by other mechanisms.

  • 41.
    Wahlberg, Jeanette
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Fredriksson, Jenny
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Vaarala, Outi
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn. Linköping University, Faculty of Health Sciences.
    Vaccinations may induce diabetes-related autoantibodies in one-year-old children2003In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1005, p. 404-408Article in journal (Refereed)
    Abstract [en]

    Vaccinations have been discussed as one among many environmental candidates contributing to the immune process that later may lead to type 1 diabetes. ABIS (All Babies in Southeast Sweden) is a prospective cohort study following a nonselected birth cohort of general population. In a randomly selected sample collection from 4400 children, GADA and IA-2A have been determined at the age of 1 year. The information on vaccinations was collected from questionnaires answered by the parents and was related to β cell autoantibodies. When studying the induction of autoantibodies using the autoantibody level of 90th percentile as cutoff level, hemophdus influenza B (HIB) vaccination appeared to be a risk factor for IA-2A [OR 5.9 (CI 1.4-24.4; p = 0.01)] and for GADA [OR 3.4 (CI 1.1-10.8; p = 0.04)] in logistic regression analyses. Furthermore, the titers of IA-2A were significantly higher (p < 0.01 in Mann-Whitney test) in those children who had got HIB vaccination. When 99th percentile was used as cutoff to identify the children at risk of type 1 diabetes, BCG vaccination was associated with increased prevalence of IA-2A (p < 0.01). We conclude that HIB vaccination may have an unspecific stimulatory polyclonal effect increasing the production of GADA and IA-2A. This might be of importance under circumstances when the β cell-related immune response is activated by other mechanisms.

  • 42.
    Zheng, Lin
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Linköping University, Faculty of Health Sciences.
    Roberg, Karin
    Linköping University, Department of Neuroscience and Locomotion, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Jerhammar, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan
    Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Linköping University, Faculty of Health Sciences.
    Terman, Alexei
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Oxidative Stress Induces Intralysosomal Accumulation of Alzheimer Amyloid β-Protein in Cultured Neuroblastoma Cells2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1067, p. 248-251Article in journal (Refereed)
    Abstract [en]

    Oxidative stress is considered important for the pathogenesis of Alzheimer's disease (AD), which is characterized by the formation of extracellular senile plaques, mainly composed of amyloid β-protein (Aβ). Aβ also accumulates within AD neurons and is believed to exert cellular toxicity through lysosomal labilization. We report that the exposure of human neuroblastoma cells to hyperoxia (40% vs. 8% ambient oxygen) induced the accumulation of large (over 1 μM) Aβ-containing lysosomes, which were not typical of control cells, showing a distinct localization of Aβ and lysosomal markers. An inhibitor of autophagy, 3-methyladenine, suppressed the effect of hyperoxia. The results suggest a link between the involvement of oxidative stress and lysosomes in AD.

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