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  • 51.
    Cao, Jun
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Sun, Yi-Qian
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Berglindh, Thomas
    Mellgård, Björn
    Li, Zhao-qi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Mårdh, Bibbi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Mårdh, Sven
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Helicobacter pylori-antigen-binding fragments expressed on the filamentous M13 phage prevent bacterial growth2000In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1474, no 1, p. 107-113Article in journal (Refereed)
    Abstract [en]

    Colonization of the human stomach by Helicobacter pylori is associated with the development of gastritis, duodenal ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. H. pylori-antigen-binding single-chain variable fragments (ScFv) were derived from murine hybridomas producing monoclonal antibodies and expressed as a g3p-fusion protein on a filamentous M13 phage. The recombinant ScFv-phage reacted specifically with a 30-kDa monomeric protein of a H. pylori surface antigen preparation and by means of immunofluorescence microscopy the phage was shown to bind to both the spiral and coccoid forms of the bacterium. In vitro, the recombinant phage exhibited a bacteriocidal effect and inhibited specifically the growth of all the six strains of H. pylori tested. When H. pylori was pretreated with the phage 10 min before oral inoculation of mice, the colonization of the mouse stomachs by the bacterium was significantly reduced (P<0.01). The results suggest that genetic engineering may be used to generate therapy-effective phages.

  • 52. Chen, H
    et al.
    Nyström, Fredrik
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology. Östergötlands Läns Landsting, MKC-2, GE: endomed.
    Dong, LQ
    Cong, L
    Li, Y
    Liu, F
    Insulin-stimulated activation of phosphoinositide-dependent Kinase-1 (PDK1): potential role in translocation of CLUT4 in rat adipose cells.2001In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 30, p. 11851-11859Article in journal (Refereed)
  • 53.
    Chen, Yun
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Smooth muscle hypertrophy and the IGF-system1996Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Insulin-like growth factor-! (IGF-I) has both metabolic and mitogenic effects on smooth muscle cells (SMCs). The effects of IGF-I are modified by a group of binding proteins (IGFBPs). The present study was devoted to smooth muscle hypertrophy and the IGF-system in smooth muscle under different conditions.

    In urinary bladder, smooth muscle hypertrophy, initiated by partial outletobstruction, was associated with a transient increase in IGF-I mRNA, and pronounced, sustained increases oflGFBP-2 and IGFBP-4 mRNA, as well as increased protein contents of IGF-I and IGFBP-2. Regression of smooth muscle hypertrophy was associated with normalization of levels ofiGF-I, IGFBP-2 and IGFBP-4 mRNA. Expression of the IGF-I receptor did not change significantly.

    In portal vein, IGF-I mRNA and IGF-1 immunoreactivity were increased inhypertrophy induced by partialligation of the portal vein.

    Abdominal coarctation caused a rapid hypertensive response accompanied by an increased wet weight of aortic media. This was coincident with a progressive increase in aortic IGFBP-2 mRNA, about 10-fold after 14 days.

    The levels of IGFBP-4 mRNA in different muscle tissues and liver were decreased by diabetes and fasting, while IGFBP-2 mRNA was regulated in an organspecific 1nanner: with a sustained increase in liver and a decrease in aortic smooth muscle.

    Smooth muscle hypertrophy also occured in the urinary bladder of diabetic rats. DNA synthesis was increased and peaked at 2 days after induction of diabetes. DNA content per bladder wet weight was decreased by 7 days. Initially there was no changes in IGF-I mRNA, while IGFBP-2 mRNA and protein in the bladders were increased and peaked by 7 days. IGFBP-4 mRNA increased only on day 7. The changes of mRNA in bladder differed from that in liver and aorta, and suggested an early effect of stretching of the bladder due to diuresis, and later a contribution by the diabetic state.

    In cultured vascular SMCs, mechanical strain stimulated protein synthesis, but had little effect on DNA synthesis. However, mechanical strain potentiated the actions of IG:F'-1 and serum on both protein- and DNA synthesis, and influenced the effects of IGFBP-2.

    In conclusion, development of smooth muscle hypertrophy is associated with specific changes in IGF-I, IGFBP-2 and IGFBP-4, suggesting that the IGF-system may play a role in this process.

  • 54. Chernyshova, IN
    et al.
    Borisova, TK
    Emelyanzeva, JA
    Sidorova, EV
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Role of different lymphocyte subpopulations in the formation of non-specific immunoglobulins induced by antigen injection.1999In: Human Antibodies, ISSN 1093-2607, E-ISSN 1875-869X, Vol. 9, p. 107-110Article in journal (Refereed)
  • 55. Craig, AD
    et al.
    Blomqvist, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Is there a specific lamina I spinothalamocortical pathway for pain and temperature sensations in primates?2002In: Journal of Pain, ISSN 1526-5900, E-ISSN 1528-8447, Vol. 3, no 2Article in journal (Refereed)
    Abstract [en]

    [No abstract available]

  • 56. Craig, AD
    et al.
    Zhang, ET
    Blomqvist, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    A distinct thermoreceptive subregion of lamina I in nucleus caudalis of the owl monkey.1999In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 404, p. 221-234Article in journal (Refereed)
  • 57. Craig, AD
    et al.
    Zhang, ET
    Blomqvist, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Association of spinothalamic lamina I neurons and their ascending axons with calbindin-immunoreactivity in monkey and human2002In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 97, no 1-2, p. 105-115Article in journal (Refereed)
    Abstract [en]

    The calbindin-immunoreactivity of spinothalamic (STT) lamina I neurons and their ascending axons was examined in two experiments. In the first experiment, lamina I STT neurons in macaque monkeys were double-labeled for calbindin and for retrogradely transported WGA*HRP following large (n=2) or small (n=1) injections that included the posterior thalamus. Most, but not all (78%) of the contralateral retrogradely labeled lamina I STT cells were positive for calbindin. Calbindin-immunoreactivity was not selectively associated with any particular anatomical type of lamina I STT cell, 82% of the fusiform cells, 78% of the pyramidal cells and 67% of the multipolar cells were double-labeled. In the second experiment, oblique transverse sections from upper cervical spinal segments of three macaque monkeys, one squirrel monkey and five humans were stained for calbindin-immunoreactivity. In each case, a distinct bundle of fibers was densely stained in the middle of the lateral funiculus. This matches the location of anterogradely labeled ascending lamina I axons observed in prior work in cats and monkeys, and it matches the location of the classically described 'lateral spinothalamic tract' in humans. This bundle had variable shape across cases, an observation that might have clinical significance. These findings support the view that lamina I STT neurons are involved in spinal cordotomies that reduce pain, temperature and itch sensations. ⌐ 2002 International Association for the study of Pain. Published by Elsevier Science B.V. All rights reserved.

  • 58.
    Dahle, Lars
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology.
    Brynhildsen, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Behrbohm Fallsberg, M
    Rundquist, Ingemar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Hammar, Mats
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Pros and cons of vertical integration between clinical medicine and basic science within a problem-based undergraduate medical curriculum: Examples and experiences from Link÷ping, Sweden2002In: Medical teacher, ISSN 0142-159X, E-ISSN 1466-187X, Vol. 24, no 3, p. 280-285Article in journal (Refereed)
    Abstract [en]

    Problem-based learning (PBL), combined with early patient contact, multiprofessional education and emphasis on development of communications skills, has become the basis for the medical curriculum at the Faculty of Health Sciences in Link÷ping (FHS), Sweden, which was started in 1986. Important elements in the curriculum are vertical integration, i.e. integration between the clinical and basic science parts of the curriculum and horizontal integration between different subject areas. This article discusses the importance of vertical integration in an undergraduate medical curriculum, according to experiences from the Faculty of Health Sciences in Link÷ping, and also give examples on how it has been implemented during the latest 15 years. Results and views put forward in published articles concerning vertical integration within undergraduate medical education are discussed in relation to the experiences in Link÷ping. Vertical integration between basic sciences and clinical medicine in a PBL setting has been found to stimulate profound rather than superficial learning, and thereby stimulates better understanding of important biomedical principles. Integration probably leads to better retention of knowledge and the ability to apply basic science principles in the appropriate clinical context. Integration throughout the whole curriculum entails a lot of time and work in respect of planning, organization and execution. The teachers have to be deeply involved and enthusiastic and have to cooperate over departmental borders, which may produce positive spin-off effects in teaching and research but also conflicts that have to be resolved. The authors believe vertical integration supports PBL and stimulates deep and lifelong learning.

  • 59.
    Dahlfors, Gunilla
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Action and interaction of growth factors and regulatory molecules in vascular cells: With special reference to the IGF-I-system2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Vascular function is greatly influenced by growth factors and regulatory molecules that can interact with each other in a complex pattern in the vascular wall. In this thesis we studied how different substances of special interest in the pathogenesis of vascular disease interact and regulate each other's expressions in endothelial cells and vascular smooth muscle cells (VSMCs).

    In VSMCs, angiotensin II was shown to delay PDGF-BB induced cell growth. This transient inhibitory effect of angiotensin II was mediated by the AT1-receptor, did not involve autocrine action of transforming growth factor-ß1 (TGF-ß1) and acted at a site downstream of PDGF-ß receptor phosphorylation.

    The interaction of the insulin-like growth factor-system (IGF-system) with various growth factors, glucose and nitric oxide (NO) was studied in vascular cells. Vascular endothelial growth factor (VEGF) and transforming growth factor-ß1 (TGF-ß1) regulated the expression of insulin-like growth factor-binding proteins (IGFBPs) in large vessel endothelial cells in a way that might cause an increased bioavailability of IGF-I locally in the subendothelial space. Angiotensin II, IGF-I and insulin did not affect IGFBP expression in these cells. The expression of IGFBPs was studied for the first time in human micro vessel endothelial cells. No effect of high glucose treatment on IGFBP expression was seen in either large vessel endothelial cells or microvessel endothelial cells. A possible interaction between NO and the IGF-system was studied in VSMCs. IGF-I did not have any significant effect on NO production in VSMCs and neither exogenous nor endogenous NO had any effect on IGFBP expression.

    In conclusion, we found that angiotensin II interacts with PDGF-BB in the regulation of VSMC growth. The IGF-system is regulated by VEGF and TGF-ß1 in endothelial cells while no effect of angiotensin II, IGF-I, insulin or high glucose was seen. We found no evidence for interaction of NO and the IGF-system in VSMCs.

  • 60.
    Dahlfors, Gunilla
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Growth factors and their interaction in the regulation of vascular cells: with special reference to diabetes1999Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Proliferation of vascular smooth muscle cells plays an important role in the development of atherosclerosis and in restenosis following balloon angioplasty. This study focuses on growth factors associated with diabetic vascular disease and their interaction in the regulation of vascular smooth muscle cell growth.

    The effect of streptozotocin-induced diabetes on proliferation of cells in aortic media two days after balloon angioplasty was studied. All proliferating cells in the aortic media were smooth muscle cells. In diabetic rats, the amount of proliferating cells was lower than in control rats. This was not accompanied by a change of transforming growth factor-ß1 (TGF-ß1) gene expression. Total TGF-ß1 levels in serum of diabetic rats was slightly lower and might possibly contribute to the inhibited proliferation of smooth muscle cells.

    The effect of angiotensin II on platelet-derived growth factor-BB(PDGF-BB)-induced growth was studied in cultured rat vascular smoothmuscle cells. Angiotensin II, acting through the AT1 receptor, transientlyinhibited the growth effect of PDGF-BB for approximately 6 hours. Thiswas not due to an autocrine effect of TGF-ß1, a growth factor consideredto mediate growth inhibitory actions of angiotensin II. Inhibition wasneither due to inhibition of PDGF-ß receptor phosphorylation.

    Large vessel endothelial cells from bovine aorta were shown to express and secrete insulin-like growth factor binding proteins (IGFBPs). Vascular endothelial growth factor (VEGF) and TGF-ß1, both associated with diabetic vascular complications, modulated the expression of IGFBPs in a way that might suggest increased bioavailability of insulin-like growth factor-I (IGF-I) locally in the vessel wall. VEGF, which is highly specific for endothelial cells, and TGF-ß1, might in this way indirectly regulate smooth muscle cell growth.

    In conclusion, we have shown that experimental diabetes has an inhibitory effect on smooth muscle cell proliferation in vivo, that interaction of growth factors, as shown for angiotensin II and PDGF-BB, might be of great importance for regulation of smooth muscle cell growth and that VEGF and TGF-ß1 regulate the IGF-system in large vessel endothelial cells with possible implications for regulation of smooth muscle cell function.

  • 61.
    Dahlfors, Gunilla
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans J.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Expression of insulin-like growth factor binding proteins and transforming growth factor-ß1 in human microvascular endothelial and bovine aortic endothelial cells, no effects of high glucoseManuscript (preprint) (Other academic)
    Abstract [en]

    Vascular complications are the major cause of morbidity and mortality in patients with diabetes mellitus. Insnlin-like growth factor-I (IGF-I) and transforming growth factor-ß1 (TGF-ß1) are two growth factors that regnlate vascular smooth muscle cell function in vivo and might be involved in the development of diabetic vascnlar complications. In this study we measnred the expression of IGF-binding proteins (IGFBPs) and TGF-ß1 in human dermal microvessel endothelial cells (HDMEC). We also studied the effect of high glucose levels on the expression of IGFBPs and TGF-ß1 in cnltured HDMEC and bovine aortic endothelial cells (BAEC). Gene expression was measured by an RNase-protection assay and proteins secreted into conditioned medium by ELISA or Western blot. The HDMEC expressed mRNAs for IGF-I and IGFBP-2 through -6 of which IGFBP-4 was the most excessively expressed and IGFBP-2 and -4 were detected in conditioned medium. Culture of HDMEC in high glucose (25 mM) for two passages did not change mRNA expressions for IGFBP-2, -3 or -4 significantly. Neither did low glucose+ mannitol (5.6 mM+ 20 mM) have any effect. In BAEC, high glucose (25 mM) for 48 h or 96 h did not affect IGFBP-3, -4 or -5 mRNA or protein and exposnre of BAEC to high glucose for two passages did also not affect IGFBP mRNA. TGF-ß1 mRNA was expressed by both BAEC and HDMEC. High glucose for two passages did not alter TGF-ß1 gene expression in either BAEC or HDMEC. In conclusion, we show that HDMEC express IGFBPs and TGF-ß1 andthat high glucose does not affect the expression in either HDMEC or BAEC.

  • 62.
    Dahlfors, Gunilla
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans J.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Vascular Endothelial Growth Factor and Transforming Growth Factor-β1 Regulate the Expression of Insulin-Like Growth Factor-Binding Protein-3, -4, and -5 in Large Vessel Endothelial Cells2000In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 141, no 6, p. 2062-2067Article in journal (Refereed)
    Abstract [en]

    We investigated the effect of diabetes-associated growth factors on the expression of insulin-like growth factor-I (IGF-I) and IGF-binding proteins (IGFBPs) in cultured endothelial cells from bovine aorta. Gene expression was measured by solution hybridization, and proteins were measured by enzyme-linked immunosorbent assay, RIA, or Western blot. The cells expressed messenger RNA (mRNA) for IGFBP-2 through -6 and IGFBP-2 through -5 proteins were detected in conditioned medium. Vascular endothelial growth factor inhibited IGFBP-3 mRNA (P < 0.01) and protein expression and increased IGFBP-5 mRNA (P < 0.001) and protein. Transforming growth factor-β1 inhibited IGFBP-3 (P < 0.01), IGFBP-4 (P < 0.01), and IGF-I mRNA expression, whereas at the protein level only IGFBP-3 was significantly decreased. IGF-I, insulin, or angiotensin II did not affect IGF-I or IGFBP mRNA expression. At the protein level, IGF-I clearly increased IGFBP-5 levels in conditioned medium. In conclusion, vascular endothelial growth factor and transforming growth factor-β1 regulate IGFBP expression in bovine aortic endothelial cells. These observations provide a new aspect of regulation for the IGF-system in macrovascular endothelium, with possible implications for subendothelial smooth muscle cells and development of diabetic angiopathy.

  • 63.
    Dahlfors, Gunilla
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Chen, Yun
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Gustafsson, Bertil
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, MKC-2, GE: endomed. Linköping University, Faculty of Health Sciences.
    Inhibitory effect of diabetes on proliferation of vascular smooth muscle after balloon injury in rat aorta2000In: Experimental Diabetes Research, ISSN 1687-5214, E-ISSN 1687-5303, Vol. 1, no 2, p. 101-109Article in journal (Refereed)
    Abstract [en]

    The effect of streptozotocin-induced diabetes on cell proliferation in rat aortic intima-media, as well as on local gene expression of transforming growth factor-β1 (TGF-β1) was studied. TGF-β1 mRNA was measured by solution hybridization and TGF-β1 protein by ELISA. Proliferation was measured by bromodeoxyuridine incorporation into DNA two days after balloon injury. All BrdU-labelled cells observed were smooth muscle cells. After a diabetes duration of 2 and 4 weeks, labelled cells were significantly fewer compared with controls. Circulating levels of total TGF-β1 were lowered in rats with 2 weeks diabetes. Although the balloon injury procedure by itself stimulated the gene expression of TGF-β1, no significant difference in TGF-β1 mRNA content between diabetic and control rats after injury was found. In conclusion: vascular smooth muscle proliferation in vivo is inhibited by the diabetic state in this model of insulin deficient diabetes and this inhibition is not related to an impaired local expression of TGF-β1.

  • 64.
    Dahlfors, Gunilla
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Chen, Yun
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Wasteson, Maria
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans J.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    PDGF-BB-induced DNA synthesis is delayed by angiotensin II in vascular smooth muscle cells1998In: American Journal of Physiology. Heart and Circulatory Physiology, ISSN 0363-6135, E-ISSN 1522-1539, Vol. 274, no 5, p. H1742-H1748Article in journal (Refereed)
    Abstract [en]

    The interaction of ANG II with platelet-derived growth factor (PDGF)-BB-induced DNA synthesis was studied in cultured rat aortic smooth muscle cells. PDGF-BB-induced DNA synthesis was delayed (∼6–8 h) by ANG II as shown by a time-course experiment. Losartan, an AT1-receptor antagonist, blocked the transient inhibitory effect of ANG II, whereas the AT2-receptor antagonist PD-123319 had no effect. Autocrine- or paracrine-acting transforming growth factor-β1 (TGF-β1), believed to be a mediator of ANG II-induced inhibitory effects, was not responsible for the delay of PDGF-BB-induced DNA synthesis, because a potent TGF-β1 neutralizing antibody could not reverse this effect of ANG II, nor was the delay of the PDGF-BB effect caused by inhibition of PDGF-β-receptor phosphorylation as shown by Western blot analysis of immunoprecipitated PDGF-β receptor. In conclusion, our results show that ANG II can exert a transient inhibitory effect on PDGF-BB-induced proliferation via the AT1 receptor.

  • 65.
    Dahlfors, Gunilla
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans J.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Effect of nitric oxide on vascular smooth muscle cell proliferation and insulin-like growth factor binding protein expressionManuscript (preprint) (Other academic)
    Abstract [en]

    A possible interaction between nitric oxide (NO) and the insulin-like growth factor (IGF)-system was studied in cultured rat aortic smooth muscle cells. The NO-donor SNAP markedly inhibited basal and sernm-induced DNA synthesis while addition of L-NAME, an inhibitor of endogenous NO production, had no effect. L-NAME did also not significantly affect IGF-I, angiotensin II or TGF-ß1- induced effects on DNA synthesis. IGF-I was shown to stimulate the expression of IGFBP-4 mRNA, as measured by an RNase-protection assay, and angiotensin II inhibited expression of IGFBP-2 mRNA. Addition of L-NAME did not significantly change the effect of IGF-I or angiotensin II on IGFBP mRNA expression, neither did L-NAME or SNAP affect basal expression of IGFBP-2, -4 or -6 mRNA. In conclusion, we found no evidence for interaction of NO with the IGF-system in smooth muscle cells. Nitric oxide did not regulate the expression of IGFBPs and IGF-I-induced smooth muscle cell proliferation was not affected by inhibition of endogenous NO production.

  • 66.
    Dahlström, Maria
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Capala, J
    Lindström, Annelie
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Differences in BPA uptake in vitro: Relevance for BNCT and BNCS2002In: Rapportklass C eller D samt Impactvärde 0,000 sätts om ISSN inte kan uppges.,2002, 2002, p. 861-864Conference paper (Refereed)
  • 67.
    Dekker Nitert, Marloes
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    IGF-I receptors, insulin receptors and insulin/IGF-I hybrid receptors in human endothelial cells: with special reference to diabetes2005Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Patients with diabetes mellitus are known to develop vascular complications, which occur as macroangiopathy, atherosclerosis and mediasclerosis, as well as microangiopathy, e.g. retinopathy and nephropathy. The precise mechanisms causing these complications have not yet been elucidated. The microvascular complications are closely associated with the glycaemic control, which also is a risk factor for the diabetic macroangiopathy. The possible roles of insulin and the related peptide IGF-I, whose levels are affected by diabetes mellitus, are not clear. This study aims to characterise the presence and function of insulin and IGF-I receptors in human endothelial cells.

    Two types of human endothelial cells were studied; human umbilical vein endothelial cells (HUVEC) and human coronary artery endothelial cells (HCAEC). The presence of insulin receptors and IGF-I receptors was studied at mRNA level by real-time PCR and at protein level by ligand binding and by Western blot analysis after immunoprecipitation. Receptor activation was determined as tyrosine phosphorylation.

    Both HUVEC and HCAEC were found to express IGF-I receptors and insulin receptors at mRNA and protein levels. The amount of IGF-I receptor mRNA exceeded insulin receptor mRNA by 3.5 and 14-fold in HUVEC and HCAEC, respectively. In HUVEC, the higher expression of IGF-I receptor mRNA compared to insulin receptor mRNA was present in both freshly isolated and cultured cells. Ligand binding studies showed a higher specific binding of 125I-IGF-I than of 125I-insulin which also suggest the presence of more IGF-I receptors than insulin receptors. In HUVEC, the specific binding was 0.64 ± 0.25% (mean ± SEM) for 125I-IGF-I and 0.25 ± 0.092% for 125I-insulin. The EC50 for 125I-IGF-I displacement was 3.6 x 10-10 M for IGF-I vs. 8.25 x 10-8 M for insulin. The EC50 for 125I-insulin displacement was 2.6 x 10-10 M for insulin and 7.39 x 10-9 M for IGF-I. In HCAEC, the specific binding was 1.37 ± 0.09% and for insulin 0.17 ± 0.03%. The EC50 value for IGF-I displacement were 6.9 X 10-10 M for IGF-I, 8.7 X 10-6 M for insulin and 7.5 X 10-8 M for the insulin analogue glargine. Due to the very low specific binding of 125I-insulin, it was not possible to calculate the concentration needed to give half-maximal displacement, EC50, of 125I-labelled insulin. Both cell types expressed insulin/IGF-I hybrid receptors. Receptor phosphorylation studies showed that IGF-I receptor could be activated by 10-10 to 10-8 M IGF-I in both cell types. Insulin receptors were activated by 10-9 to 10-8 M insulin in HUVEC and HCAEC. IGF-I was able to activate insulin receptor phosphorylation at low concentrations, 10-9 to 10-8 M, which also is an indication of the presence of hybrid receptors.

    In conclusion, two types of human endothelial cells, HUVEC and HCAEC, express more IGF-I receptors than insulin receptors, and they also express insulin/IGF-I hybrid receptors. IGF-I and insulin were found to phosphorylate their own receptor while IGF-I also seemed to be able to phosphorylate hybrid receptors. The results suggest an important role of the IGF-I receptor in human endothelial cells.

  • 68.
    Dimberg, J
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Samuelsson, A
    Hugander, A
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Differential expression of cyclooxygenase 2 in human colorectal cancer.1999In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 45, p. 730-732Article in journal (Refereed)
  • 69.
    Dimberg, Jan
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Hugander, A
    Univ Jonkoping, Coll Hlth Sci, Dept Nat Sci & Biomed, S-55111 Jonkoping, Sweden Fac Hlth Sci, Div Cell Biol, Dept Biomed & Surg, Linkoping, Sweden Ryhov Cty Hosp, Dept Surg, Jonkoping, Sweden Karolinska Hosp, Karolinska Inst, Ctr Mol Med, S-10401 Stockholm, Sweden.
    Sirsjo, A
    Univ Jonkoping, Coll Hlth Sci, Dept Nat Sci & Biomed, S-55111 Jonkoping, Sweden Fac Hlth Sci, Div Cell Biol, Dept Biomed & Surg, Linkoping, Sweden Ryhov Cty Hosp, Dept Surg, Jonkoping, Sweden Karolinska Hosp, Karolinska Inst, Ctr Mol Med, S-10401 Stockholm, Sweden.
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Enhanced expression of cyclooxygenase-2 and nuclear beta-catenin are related to mutations in the APC gene in human colorectal cancer2001In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 21, no 2A, p. 911-915Article in journal (Refereed)
    Abstract [en]

    Mutational inactivation of the human tumour suppressor gene adenomatous polyposis coli (APC) results in constitutive activation of beta -catenin/T cell factor-4 (Tcf-4) mediated transcription of target genes. Up-regulation of cyclooxygenase-2 (COX-2) protein is frequently found in human colorectal cancer (CRC). We analysed 38 CRC for mutations in APC and beta -catenin and found an association between APC mutations and elevated COX-2 levels. Furthermore, APC mutations were predominantly observed in tumour tissues from the rectum compared to tumours of colonic origin. Western blot analysis revealed that nuclear beta -catenin levels were generally higher in tumours with APC mutations compared to tumours with wild type APC. However, there was also a higher level of nuclear beta -catenin in tumour compared to normal tissue, hut nuclear Tcf-4 protein was constitutively expressed in tumour and normal tissue and showed no differences. An identified putative Tcf-4 binding element in the COX-2 promoter may partly explain the enhanced level of COX-2 and support the idea that COX-2 may be a downstream target of the APC/beta -catenin/Tcf-4 pathway.

  • 70. Dimberg, Jan
    et al.
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Letters to the Editor: Differential expression of cyclooxygenase 1 in human colorectal cancer. Reply.2000In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 47, p. 154-154Article in journal (Other (popular science, discussion, etc.))
  • 71.
    Edoff, Karin
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Sensory nerve fibres, neuropeptides and cartilage: Experimental studies in the rat2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    During development, maintenance and repair after injury, reciprocal interactions occur between the peripheral nervous system and the target tissues. In the Papers presented in this thesis, different aspects of such netvetarget influences between peripheral nerve fibres and skeletal tissues dtuing development and repair have been investigated in the rat. Developing rat cartilaginous bone primordia have a richly innervated and vascularised perichondriwn. In addition, larger bones exhibit cartilage canals containing blood vessels and putative sensory nerve fibres. Tills evoked the question if there is a nervous regulation of skeletal development. Denervation of the hind paws of young rats resulted in a deficient length growth but had no influence on the progress of secondary ossification. Since growth is mainly due to events in cartilage, cartilage projecting sensory neurones were identified and examined. Sensory neurones projecting to the rat cartilaginous distal femoral epiphyses were located mainly in the dorsal root ganglia (DRG) L3 and L4 and exhibited small or medium-sized diameters. A large proportion of these neurones contained the neuropeptides CGRP and/or SP. However, application of CGRP to cartilage explants in vitro did not stimulate the chondrocytes in terms of an elevation of the level of cyclic AMP. Another possibility would be that the neuropeptides affect the developmental growth of bone and chondrocytes indirectly via effects on the blood vessels. Experiments .involving tracing as above and eo-culture of labelled DRG neurones and perichondrial cells in combination with immunohistochenllstty or electrophysiology showed that the traced cultured neurones contained CGRP and/or SPin in vivo-like proportions and that most of the cartilage-projecting neurones were proton sensitive, This prompted the suggestion that the nerve fibres in the perichondrium and in cartilage canals might release CGRP and SP in response to local tissue acidosis, thereby promoting tissue homeostasis by monitoring the balance between vascular supply and metabolic load and by influencing angiogenesis and blood flow. Subsequently, possible target influences on the local presence of perichondrial sensory nerve fibres were investigated. Application of inflammation related cytokines (IL-1ß, IL-6 and LIF) affected sensory neurones eo-cultured with perichondrium- or skin-derived fibroblast-like cells in terms of survival and neurite growth. These effects were strongly influenced by the origin of the target cells. Finally, experiments using the adult rat patella showed that osteochondral defects heal spontaneously but incompletely and that healing is not accompanied by an increase of local nerve fibres at the times examined. In conclusion, the present results indicate that cartilagerelated sensory nerve fibres influence skeletal growth, that a high proportion of these neurones contain CGRP and SP, that CGRP does not activate chondrocytes in cartilage slices, that many cartilage related sensory nerve fibres are proton-sensitive· and likely have a vasoregulatory role, that inflammatory mediators have distinct effects on sensory neurones eo-cultivated with perichondrial cells and that healing of an osteochondral defect in the rat patella does not involve a local increase of cartilage-related nerve fibres.

  • 72.
    Edoff, Karin
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Granseth, Björn
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Neuropeptide content and physiological properties of rat cartilage-projecting sensory neurones co-cultured with perichondrial cells2001In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 315, no 3, p. 141-144Article in journal (Refereed)
    Abstract [en]

    In young rats the cartilaginous epiphyses forming the knee joint are supplied with blood vessels and peptidergic sensory nerve fibres through the perichondrium and cartilage canals. In the present study we show that cartilage-related dorsal root ganglion neurones co-cultured with perichondrial cells develop extensive neurite trees and express calcitonin gene-related peptide (CGRP) and substance P (SP) in in vivo-like proportions using retrograde tracing and immunohistochemistry. Moreover, whole cell patch clamp recordings from these cells showed that the majority is depolarised by application of H+-ions. These results are compatible with the hypothesis that a local imbalance of blood flow and metabolism during normal skeletal maturation may cause tissue acidosis eliciting release of CGRP/SP from sensory nerve endings.

  • 73.
    Edoff, Karin
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Hildebrand, Claes
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Retrograde tracing and neuropeptide immunohistochemistry of sensory neurones projecting to the cartilaginous distal femoral epiphysis of young rats2000In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 299, no 2, p. 193-200Article in journal (Refereed)
    Abstract [en]

    Although cartilage is considered to be devoid of innervation, axons occur in the perichondrium and during development in cartilage canals, thereby having a relatively close spatial relationship to chondroblasts and chondrocytes. The present study locates the source of the sensory innervation of the femoral cartilaginous epiphyses of young rats and investigates whether the neuropeptide calcitonin gene-related peptide (CGRP) can influence chondrocytes. Retrograde tracing from the distal femoral epiphysis of young rats with Fast Blue (FB) showed labelled neuronal profiles in the L2-L5 dorsal root ganglia. Sample countings indicated that 50% of the FB-labelled neuronal profiles were located at the L3 level and 25% at the L4 level. The labelled neurones had diameters of 15-40 µm, with a peak at 25-30 µm. Immunohistochemistry showed that about 50% of the FB-labelled profiles contained CGRP. Together with the finding that CGRP influences bone cells to generate the second messenger cAMP, this result suggested the hypothesis that chondrocytes might be similarly influenced by CGRP. However, stimulation of cartilage slices with CGRP in vitro followed by an assay of the cAMP content did not provide support for this hypothesis. We conclude that primary sensory neurones containing CGRP project to the perichondrium and to cartilage canals of growing cartilage, and that exogenous CGRP does not elevate the cAMP content of cartilage slices in vitro.

  • 74.
    Edoff, Karin
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Hellman, John
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Persliden, Jan
    Linköping University, Department of Medicine and Care, Radio Physics. Linköping University, Faculty of Health Sciences.
    Hildebrand, Claes
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    The developmental skeletal growth in the rat foot is reduced after denervation1997In: Anatomy and Embryology, ISSN 0340-2061, E-ISSN 1432-0568, Vol. 195, no 6, p. 531-538Article in journal (Refereed)
    Abstract [en]

    It has long been known that bone is innervated. In recent years it has been suggested that the local nerves may influence the growth and metabolism of bone by way of neuropeptides. The transient local presence of nerve-containing cartilage canals just before formation of secondary ossification centres in rat knee epiphyses seems to support that view. The purpose of the present study was to see if denervation affects the developmental growth of metatarsal bones in the rat hindfoot. We made sciatic and femoral neurectomies in 7- day-old rat pups and examined the hindfeet at various times after surgery. Immunohistochemical analysis showed that denervation was complete. Radiographic examination revealed that the metatarsal bones were significantly shorter in denervated hindfeet 30 days after denervation (average relative shortening 9.9±2.3%). Measurements of total foot length showed that denervated feet were subnormally sized already five days postoperatively, before the onset of secondary ossification. The timing of the latter was not affected by denervation. Control rats subjected to tenotomies exhibited normal metatarsal bone lengths. On the basis of these results we suggest that the local nerves may influence the growth of immature bones but do not affect secondary ossification.

  • 75.
    Edoff, Karin
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Hildebrand, Claes
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Neuropeptide effects on rat chondrocytes and perichondrial cells in vitro2003In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 37, no 5, p. 316-318Article in journal (Refereed)
    Abstract [en]

    This study examines if cultured chondrocytes and perichondrial cells change the level of cAMP and/or cGMP in response to application of the neuropeptide calcitonin gene-related peptide (CGRP). Cells collected from the knee region of 4–8 days old rat pups were cultured in vitro. Cultures were exposed to 10−10–10−6 M CGRP during 10 minutes. The levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in the cultures and in controls were determined by radioimmunoassay. The results show that application of CGRP causes a distinctly increased level of cAMP, that was absent when CGRP was applied together with the CGRP1 receptor antagonist. The level of cGMP was not obviously altered. Hence, it is possible that terminals of primary sensory neurones present in developing cartilage influence chondrocytes and perichondrial cells via local release of CGRP.

  • 76.
    Edoff, Karin
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Jerregård, Helena
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Effects of IL-1β, IL-6 or LIF on rat sensory neurons co-cultured with fibroblast-like cells2002In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 67, no 2, p. 255-263Article in journal (Refereed)
    Abstract [en]

    Inflammation may affect the local presence of sensory nerve fibers in situ and inflammatory mediators influence sensory neurons in vitro. In the present study we have investigated effects of the cytokines interleukin-1β (IL-1β, interleukin-6 (IL-6), and leukemia inhibitory factor (LIF) on survival of and neurite growth from neonatal rat sensory neurons co-cultured with fibroblast-like cells prepared from neonatal rat skin (sFLCs) or perichondrium (pFLCs). The results showed that both FLC types expressed receptors for all three cytokines. Five ng/ml of either cytokine, but not lower or higher concentrations, supported survival of DRG neurons co-cultured with sFLCs. Neuronal survival was also enhanced by addition of the soluble IL-6 receptor (rsIL-6R) with or without IL-6. In co-cultures with pFLCs neuronal survival was promoted by IL-6, increasing with cytokine concentration. Addition of rsIL-6R without IL-6 did also stimulate neuronal survival. The growth of neurites from DRG neurons co-cultured with sFLCs was stimulated by 0.5 ng/ml LIF, unaffected by 5 ng/ml LIF and inhibited by 50 ng/ml LIF. Considering DRG neurons co-cultured with pFLCs, 50 ng/ml of either of the three cytokines, as well as rsIL-6R conditioned medium, stimulated neurite outgrowth. Some of the cytokine effects observed were reduced by application of antibodies against nerve growth factor (NGF). We conclude that that the cytokines examined affect DRG neurons in terms of survival or neuritogenesis, that the effects are influenced by cytokine concentration and the origin of the FLCs and that some of the effects are indirect, probably being mediated by factors released from FLCs.

  • 77.
    Edoff, Karin
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Lundberg, Magnus
    Department of Orthopaedic Surgery, Karolinska Institute, Huddinge University Hospital, Sweden.
    Does healing of an osteochondral defect with or without a periosteal autograft involve a local sprouting of nerve fibres?: An experimental study on the rat patellaManuscript (preprint) (Other academic)
    Abstract [en]

    Repair of articular cartilage is an important clinical problem. Availability of chondrogenic stem cells has been pointed out as one key factor in cartilage repair and application of periosteal autografts has been used clinically to improve healing. In addition, neuropeptide containing nerve fibres may contribute to healing by stimulating cell proliferation and/or differentiation. In the rat, peptidergic nerve fibres invade the callus formation during fracture healing and peptidergic nerve fibres are abundant in cartilage related connective tissue during skeletal development in young mammals. The purposes of the present study were to evaluate healing of an experimental full thickness osteochondral defect in the rat patella with and without application of a periosteal autograft, and to find out if a local nerve sprouting is part of the healing process. Osteochondral healing was evaluated with a histological score and the presence of nerve fiber profiles in relation to the defect was assessed by protein gene product 9.5 immunohistochemistry. The results showed (i) that osteochondral defects in the rat patella heal spontaneously but incompletely, (ii) that healing consistently is less satisfactory with application of a periosteal autograft than without and (iii) that healing is not accompanied by nerve fibre sprouting.

  • 78.
    Ek, Monica
    et al.
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Engblom, David
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Saha, Sipra
    Department of Medical Biochemistry and Biophysics, The Karolinska Institute, Stockholm, Sweden.
    Blomqvist, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Jakobsson, Per-Johan
    Department of Medical Biochemistry and Biophysics, The Karolinska Institute, Stockholm, Sweden.
    Ericsson-Dahlstrand, Anders
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Inflammatory response: pathway across the blood–brain barrier2001In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 410, p. 430-431Article in journal (Refereed)
    Abstract [en]

    No abstract available.

  • 79.
    Eklund, Lena
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Molecular alterations in squamous cell carcinomas of the skin: emphasis on genes on chromosome 9q2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Skin cancer is the most common type of cancer in the western world. The incidence of melanoma and non-melanoma skin cancer is continuously increasing and, in Sweden, 2300 new cases per year are diagnosed of squamous cell carcinoma (SCC) alone. In this thesis, we have investigated genes and proteins from signal transduction pathways important for tumor development. Special emphasis has been put on chromosomal region 9q22-q31 where frequent loss of heterozygosity has been observed in non-melanoma skin cancers.

    Mutation analysis of the PTCH1 and XPA genes, connected to the familial cancer syndromes nevoid basal cell carcinoma syndrome and xeroderma pigmentosum, respectively, was performed. Based on lack of mutation or altered mRNA expression, we conclude that these two genes are not likely to be involved in development of sporadic SCCs. Next, we studied the correlation of the two phenotypes, anchorage independence and tumorigenicity, to the loss of chromosome 9 material in a panel of somatic cell hybrids. By microsatellite analysis, we show that the anchorage independence gene is located distal to the marker D9S155. The mapping of the gene for tumor suppression revealed three commonly deleted regions on chromosome regions 9p23-p22, 9p21-p12 and 9q31-q33. Another two candidates from the 9q22-q31 region, CORO2A and TßR-I, were investigated both at the gene and the protein level. We did not detect any alterations in the TßR-I gene or protein, but CORO2A protein was over-expressed in 4 of 40 (10%) tumors, indicating an involvement in sec carcinogenesis in a subset of tumors. In one healthy individual from the control population, we found a heterozygous germline mutation in CORO2A creating a stop codon, which results in a truncated protein. Thus, one functional allele might be sufficient to sustain a normal cellular function. When investigating occurrence of aberrant protein expression in the interconnected Wnt and Notch pathways, Notch1 was found to be expressed in only 5 of 40 (14%) of the normal epidermal cells, while strong staining was displayed in all the tumors. No altered expression of the most central protein of the Wnt pathway, ß-catenin, was observed, but the up-stream Dvl-1 protein was found to be up-regulated in 8 of 38 (21%) tumors. Dvl-1 was also detected in the nucleus in the majority of normal and tumor cases and a potential nuclear localization signal was identified in the Dvl-1 A isoform.

    None of the genes from the chromosomal region 9q22-q31 displayed alterations consistent with those of a tumor suppressor gene. Most likely, this gene remains to be identified.

  • 80.
    Eklund, Lena
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Islam, Khaleda
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Islam, Quamrul
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Regional mapping of suppressor loci for anchorage independence and tumorigenicity on human chromosome 92001In: Cancer Genetics and Cytogenetics, ISSN 2210-7762, E-ISSN 2210-7770, Vol. 130, no 2, p. 118-126Article in journal (Refereed)
    Abstract [en]

    By microcell-mediated chromosome transfer to the malignant Syrian hamster cell line BHK-191-5C, we previously identified two suppressor functions on human chromosome 9 (HSA9), one for anchorage independence and another for tumorigenicity. However, the precise chromosomal locations of these suppressor functions were not determined. The present study was undertaken to define the regional location of these suppressor loci using a panel of microcell hybrids containing structurally altered HSA9 with different deleted regions in the BHK-191-5C background. DNA derived from the cell hybrids was analyzed by PCR for verification of the presence of HSA9 genetic material by amplifying 62 microsatellite markers and 13 genes, covering the entire length of HSA9. Our deletion mapping data on anchorage independent and tumorigenic hybrids suggest that the suppressor function for anchorage independence is located in the region between 9q32 to 9qter. The suppressor for tumorigenicity may be located in one of three deleted regions on HSA9, the first one between the markers D9S162 and D9S1870, the second one between the markers D9S1868 and TIGRA002I21, and the third one between the markers D9S59 and D9S155.

  • 81.
    Eklund, Lena K.
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Lindström, Erika
    Karolinska Institute, Department of Biosciences at Novum, Center for Nutrition and Toxicology, Huddinge, Sweden.
    Undén, Anne Birgitte
    Karolinska Institute, Department of Biosciences at Novum, Center for Nutrition and Toxicology, Huddinge, Sweden and Department of Dermatology, Karolinska Hospital, Stockholm, Sweden.
    Lundh-Rozell, Barbro
    Department of Pathology, Huddinge University Hospital, Huddinge, Sweden.
    Ståhle-Bäckdahl, Mona
    Department of Dermatology, Karolinska Hospital, Stockholm, Sweden.
    Zaphiropoulos, Peter G.
    Karolinska Institute, Department of Biosciences at Novum, Center for Nutrition and Toxicology, Huddinge, Sweden.
    Toftgård, Rune
    Karolinska Institute, Department of Biosciences at Novum, Center for Nutrition and Toxicology, Huddinge, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Mutation analysis of the human homologue of drosophila patched and the xeroderma pigmentosum complementation group A genes in squamous cell carcinomas of the skin1998In: Molecular Carcinogenesis, ISSN 0899-1987, E-ISSN 1098-2744, Vol. 21, no 2, p. 87-92Article in journal (Refereed)
    Abstract [en]

    The human homologue of Drosophila patched (PTCH), located at chromosome 9q22.3, was recently identified as a candidate tumor suppressor gene for familial and sporadic basal cell carcinomas. Squamous cell carcinomas (SCCs) of the skin display allelic loss in this chromosomal region, which, in addition to the PTCH gene, contains the DNA repair gene xeroderma pigmentosum complementation group A (XPA). Patients with xeroderma pigmentosum are predisposed to non-melanoma skin tumors because of deficient excision repair of ultraviolet-induced DNA damage. Mutation analysis by single-strand conformation analysis and direct DNA sequencing of all 23 exons of the PTCH gene and all six exons of the XPA gene in 14 SCCs did not reveal structural alterations in any of these genes. Additionally, analysis of PTCH expression by in situ hybridization in SCCs revealed no evidence of upregulation of PTCH mRNA, confirming the lack of mutations in this gene. These findings suggest that another, yet to be identified gene or genes on chromosome 9q are involved in SCC tumorigenesis. 

  • 82.
    Eklund, Lena K.
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Lirvall, M.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Abnormal expression of proteins in Notch and Wnt pathways in human squamous cell carcinoma of the skinManuscript (preprint) (Other academic)
    Abstract [en]

    Background Members of the Notch pathway are involved in various differentiation processes. Signalling via the Wnt/ß-catenin-pathway controls transcription of genes involved in proliferation events. These two pathways are interconnected through the cytoplasmic protein Dishevelled (Dvl-1).

    Objectives To evaluate the expression patterns of Notch1, Dvl-1 and ß-catenin proteins in human squamous cell carcinomas of the skin.

    Methods 40 formalin-fixed paraffin-embedded SCCs were included in this study. Expression was detected with immunohistochemistry using avidin-biotin and DAB visualization.

    Results The majority of the normal epidermal cells lacked expression of Notch1, while the dysplastic and invasive tumour cells showed strong staining. Expression of Dvl-1 was observed in normal human epidermis, with a more intense staining indysplastic cells in 8 of 38 (21%) cases. Besides the expected cytoplasmic staining, 27 of 38 (71%) secs displayed nuclear staining and a potential nuclear localisation signal was identified. ß-catenin showed membranous and weak cytoplasmic staining in normal as well as tumour cells.

    Conclusions We have found enhanced expression of Notch1 in the majority of SCCs, indicating a disturbed differentiation process. We have also for the first time showed over-expression of Dvl-1 in dysplastic epidermal cells as well as normal staining of the nucleus. A classical nuclear localization signal is also identified in the Dvl-1 isoform A, whereas two other isoforms lack this recognition sequence.

  • 83.
    Eklund, Lena K.
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Undén, Anne Birgitte
    Karolinska Intitute, Department of Biosciences at Novum, Center for Nutrition and Toxicology, Huddinge, Sweden and Department of Dermatology, Karolinska Hospital, Stockholm, Sweden.
    Lundin, Kristing B.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Zaphiropoulos, Peter G.
    Karolinska Institute, Department of Biosciences at Novum, Center for Nutrition and Toxicology, Huddinge, Sweden.
    Toftgård, Rune
    Karolinska Institute, Department of Biosciences at Novum, Center for Nutrition and Toxicology, Huddinge, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Over-expression of coronin 2a and lack of alterations in transforming growth factor ß receptor I in squamous cell carsinomas of the skinManuscript (preprint) (Other academic)
    Abstract [en]

    Allelic losses in several regions of chromosome 9q have been connected to the development of squamous cell carcinoma (SCC) of the skin. We have studied two candidate genes in the 9q22 region using mutational analysis of genomic DNA as well as immunohistochemistry for assessment of changes in protein expression. The coronin 2A (CORO2A) protein shows strong resemblance to actin-binding proteins, implying a role in cytokinesis or cell motility. It has also been found to be part of the nuclear receptor co-repressor complex involved in transcriptional regulation. We elucidated the exon-intron structure by sequence alignment of the mRNA to a "high-throughput genomic sequence" entry in GenBank. By using single strand conformation analysis and DNA sequencing we found eight silent mutations in tumor DNA, one of which was found in a subset of a normal control population. Surprisingly, immunostaining revealed over-expression in 4/40 tumors. This cannot explain the high frequency of allelic loss in cutaneous secs, but is yet indicating a possible involvement of CORO2A in cutaneous SCC development. The gene for transforming growth factor ß receptor 1 (TßR-I) has previously been positioned to the 9q22 region. TßR-I is part of a protein complex necessary for binding of the TGFß ligand initiating a signaling cascade, which affects downstream targets important for cell cycle regulation. We could not identify any alterations at either protein or DNA level and therefore exclude TßR-I as candidate for cutaneous sec development.

  • 84.
    Ekman, Bertil
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    IGF-I in growth hormone deficiency and in type 1 diabetes2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Both GH-deficiency and type 1 diabetes are associated with low IGF-I levels. The aim with our studies was to develop a dose titration model to obtain physiological IGF-I levels in growth hormone deficiency and to evaluate the relationship between glycaemic control and IGF-I in diabetes. First we established reference values for insulin like growth factor-I (IGF-I) and insulin like growth factor bindingprotein-1 (IGFBP-1) from 101 women and 101 men randomly selected from the population registry. No gender differences in IGF-I levels were fmmd. IGF-1 decreases with advancing age in both sexes, whereas IGFBP-1 increases with age.

    Titrating the GH dose according to population based reference values of IGF-I might be a way to obtain a fairly physiological substitution dose of GH. We hypothesised that a safe and probably effective maintenance dose of GH should increase IGF-I to the mean or slightly below the mean according to age adjusted reference levels. Eighteen adult hypopituitary patients with severe GH deficiency were titrated in steps, according to age adjusted IGF-I levels, to an individual dose of recombinant GH. For comparison 17 untreated healthy control subjects were evaluated. Similar IGF-1 levels armmd the mean for corresponding age were obtained in both sexes, but the maintenance median GH dose was more than twice in the women compared to men. The :individual dose differed markedly and elderly patients needed lower GH doses due to unchanged GH-sensitivity. Six months on the maintenance GH dose induced changes in blood-glucose, lipids, and insulin sensitivity index, indicating increased insulin resistance, which compared with the controls, were a normalisation. No major changes were seen in the variables of the renin-angiotensin-system. A significant increase in atrial natriuretic peptide seems also to be a normalisation if compared with the controls. The patients had less muscle strength and endmance at baseline compared with the controls and increased the muscle strength and endmance about 10 % after GH-substitution, an effect associated with the increase in IGF-I.

    Paradoxically circulating IGF-I is decreased in type 1 diabetes despite increased GH levels. We studied 134 adult patients with type I diabetes (aged 20-60 years), without endogenous insulin secretion, and found that circulating IGF-I were decreased to about 70 % of the values in the reference population. No con·elation between glycaemic control and IGF-I levels was found.

    To conclude the GH dose obtained when normalising circulating IGF-I according to population-based IGF-I levels, depends on GH-sensitivity (gender) and the IGF-1 level aimed for (age). In comparison with matched controls several OR-dependent variables are improved. In type 1 diabetes, our results suggests that the low IGF-I levels are independent of glycaemic control, and can not be corrected with subcutaneous insulin substitution.

  • 85.
    Ekman, Bertil
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, MC - Medicincentrum, EMT-endo.
    Gerdle, Björn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Rehabilitation Medicine. Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology. Östergötlands Läns Landsting, MC - Medicincentrum, EMT-endo.
    Growth hormone substitution titrated to obtain IGF-I levels in the physiological range in hypopituitary adults: Effects upon dynamic strength, endurance and EMG2003In: European Journal of Applied Physiology, ISSN 1439-6319, E-ISSN 1439-6327, Vol. 90, no 5-6, p. 496-504Article in journal (Refereed)
    Abstract [en]

    We studied the effects of individualised growth hormone (GH) substitution, aiming at normal insulin-like growth factor I (IGF-I) levels, on biomechanical output and surface electromyogram (EMG) of isokinetic muscle strength and endurance performance in 18 hypopituitary adults and compared with 17 matched healthy controls. The muscle function tests consisted of isokinetic contractions of the right knee extensors, from which torque and EMG were recorded. Three patients were excluded from the final analysis of the muscle function tests due to technical errors and one control subject moved from the area during the study. We found that GH-deficient adults without GH substitution were weaker and had less endurance than healthy control subjects. At the group level, plasma levels of IGF-I were normalised but generally no significant effects upon biomechanical output and EMG were found after dose titration and 6 months of a constant GH dose. However, subjects with the largest changes in IGF-I had significantly better biomechanical output and EMG compared to those with small changes in IGF-I. This finding may indicate that the net increase in IGF-I levels is critical for improvements in biomechanical output, EMG and perception of fatigue to occur.

  • 86.
    Ekman, Bertil
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Gerdle, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Rehabilitation Medicine. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans J.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Improved muscle function in GH substituted adults is related to increase in circulating IGF-IManuscript (preprint) (Other academic)
    Abstract [en]

    We studied the effects of individualized growth hormone substitution, aiming at normal IGF-I levels, on biomechanical output and EMG of isokinetic muscle strength and endurance performance in 18 hypopituitary adults compared with matched controls. The muscle function tests consisted of isokinetic contractions of the dght knee extensors, and torque and EMG were recorded. Plasma levels of IGF-I were normalized, and peak torque at 90° s-1, and peak torque endurance level increased after dose titration and 6 months constant GH-dose. The change in IGF-I correlated positively with the changes in biomechanical output and EMG variables and a negative correlation existed with the perception of fatigue. Despite improvement during GH-substitution the patients still had about 10-20 % less muscle strength and endurance compared with the controls at the study end. In summary we found that individualized GH substitution improves muscle function and that the net increase in IGF-I levels indicates generally increases in biomechanical output and EMG variables and a lower perception of fatigue.

  • 87.
    Ekman, Bertil
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Lindström, Torbjörn
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Nyström, Fredrik
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Olsson, Anders
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Toss, Göran
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    A dose titration model for recombinant GH substitution aiming at normal plasma concentrations of IGF-I in hypopituitary adults2002In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 147, no 1, p. 49-57Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate a dose titration model for recombinant human GH substitution in adult patients with GH deficiency, aiming at normal plasma levels of IGF-I.

    DESIGN AND METHODS: Eighteen patients participated and a start dose of 0.17 mg GH/day was used except by two men who started with 0.33 mg/day. To demonstrate a clear GH effect the patients were first titrated, with steps of 0.17 mg GH/day every 6-8 weeks, to IGF-I levels in the upper range of age-adjusted reference values. The GH dose was then reduced 1 dose step and kept for a further 6 months. For comparison we investigated 17 healthy control subjects.

    RESULTS: Plasma IGF-I was increased after 2 weeks on the start dose and did not increase further for up to 8 weeks. Women had significantly lower GH sensitivity than men measured as net increment of IGF-I on the start dose of GH. GH sensitivity was not changed by age. The plasma IGF-I levels increased from 76.3+/-47.0 (s.d.) to 237+/-97 microg/l at the end of the study (P<0.001), and similar IGF-I levels were obtained in both sexes. The maintenance median GH dose was 0.33 mg/day in males and 0.83 mg/day in females (P=0.017). The GH dose correlated negatively with age in both sexes. Body weight, very low density triglycerides, lipoprotein(a) (Lp(a)), and fasting insulin increased, whereas insulin sensitivity index (QUICKI) decreased significantly. In comparison with the controls, the patients had lower fasting blood glucose, fasting insulin and Lp(a) levels at baseline, but these differences disappeared after GH substitution. The two groups had equal insulin sensitivity (QUICKI), but 2 h oral glucose tolerance test values of blood glucose and insulin were significantly higher in the patients at the end of the study.

    CONCLUSIONS: In conclusion our data suggest that the starting dose of GH substitution and the dose titration steps should be individualised according to GH sensitivity (gender) and the IGF-I level aimed for (age). The reduced insulin sensitivity induced by GH substitution could be viewed as a normalisation if compared with control subjects.

  • 88.
    Ekman, Bertil
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Nyström, Fredrik
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Circulating IGF-I concentrations are low and not correlated to glycaemic control in adults with type 1 diabetes2000In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 143, no 4, p. 505-510Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To study plasma concentrations of insulin-like growth factor-I (IGF-I) in adults with type 1 diabetes (IDDM) in comparison with a reference population, and the influence of glycaemic control, dose of insulin, and sex on the concentration of circulating IGF-I in IDDM.

    DESIGN AND METHODS: Patients with type 1 diabetes were recruited consecutively from our outpatient diabetes unit. In all, 79 men and 55 women aged 20-60 years with a disease duration >/=6 years (range 6-51 years) took part in the study. A reference population of 80 men and 83 women aged 20-60 years was randomly obtained from the population registry. IGF-I was measured with radioimmunoassay after acid-ethanol extraction.

    RESULTS: Mean +/- s. d. values of IGF-I were lower in patients with diabetes (146+/-66 microg/l) than in controls (238+/-83 microg/l, P<0.001). Those with diabetes had lower IGF-I concentrations in all age groups and the differences were highly significant in all decades except in women aged 50-59 years. IGF-I was negatively correlated with age in patients and controls. No correlation was found between IGF-I and glycaemic control measured as haemoglobin A(1c) (HbA(1c)) in the patients. IGF-I was positively associated with the dose of insulin/kg body weight in male patients independently of age, HbA(1c) and body mass index (P<0.03), but not in female patients (P=0.14).

    CONCLUSIONS: Our data show that IGF-I concentrations are low in adult patients with type 1 diabetes with a disease duration >/=6 years, independently of glycaemic control. This suggests that subcutaneous insulin substitution is inadequate to normalize circulating IGF-I concentrations in patients without endogenous insulin secretion.

  • 89.
    Ekman, Bertil
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Öhman, Peter K
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Lindström, Torbjörn
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Nyström, Fredrik
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Individualized growth hormone substitution with normalized IGF-I levels does not stimulate the renin–angiotensin–aldosterone system2002In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 57, no 4, p. 473-479Article in journal (Refereed)
    Abstract [en]

    objective To study the effects of individualized recombinant GH substitution, aiming at normal circulating IGF-I levels, in GH-deficient adults on blood pressure, the renin–angiotensin–aldosterone system (RAAS), natriuretic peptides and urine free cortisol.

    study design Open study with control group. The patients were titrated in dose steps of 0·17 mg GH/day every 6–8 weeks until an IGF-I level around the mean + 1 SD was attained (Tmax). After another month the dose was reduced by 0·17 mg (minimum dose 0·17 mg/day) to produce IGF-I levels at or slightly below the age-related mean (Tend), and this maintenance dose was held constant for 6 months.

    subjects Eighteen patients (11 males and seven females) with GH deficiency participated. For comparison we also prospectively evaluated 17 matched control subjects.

    measurements Blood pressure and heart rate, circulating levels of IGF-I, plasma renin activity (PRA), immunoreactive active renin (IRR), angiotensin II, aldosterone, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and 24-h urine aldosterone and urine free cortisol levels.

    results Blood pressure was unchanged by GH substitution but heart rate increased significantly (P < 0·03). PRA was elevated on the highest GH dose (Tmax) compared to baseline (P < 0·01), but returned to baseline and levels of controls at Tend. Four patients developed transient oedema and tended to have higher PRA levels than the rest of the subjects (P = 0·09). The circulating levels of IRR, angiotensin II, aldosterone, BNP and 24-h urine aldosterone and urine free cortisol levels were unchanged by GH substitution, and did not differ from the levels in the control subjects. Baseline ANP levels in the patients were lower than in the controls (P < 0·01), but increased after GH substitution (P < 0·01) to levels found in with the controls.

    conclusions We found no major changes of the variables in the circulating renin–angiotensin–aldosterone system and a normalization of atrial natriuretic peptide when an individualized dose of GH was titrated to near-normal IGF-I levels.

  • 90.
    Elinder, Fredrik
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences. Karolinska Inst, Dept Neurosci, Nobel Inst Neurophysiol, Stockholm.
    Nilsson, J
    Karolinska Inst, Dept Neurosci, Nobel Inst Neurophysiol, Stockholm.
    Arhem, P
    Karolinska Inst, Dept Neurosci, Nobel Inst Neurophysiol, Stockholm.
    On the opening of voltage-gated ion channels2007In: Physiology and Behavior, ISSN 0031-9384, E-ISSN 1873-507X, Vol. 92, no 1-2, p. 1-7Article in journal (Refereed)
    Abstract [en]

    Voltage-gated ion channels are key players in fast neuronal signalling Detailed knowledge about channel gating is essential for our understanding of channel function in general and of drug action of channels in particular. Despite a number of recent atomic channel structures, the opening of voltage-gated channels is the subject of heated debates. Here we will discuss two of the controversies: one concerning the mechanism of opening and closing the pore, and the other concerning the location and movement of the voltage sensor. The channels were originally suggested to open at a conserved proline rich sequence (PVP) at the intracellular end of the transmembrane segment 6 (S6). The crystallization of a channel in the open state instead suggested an opening involving a conserved glycine hinge located in the middle portion of S6. Based on pharmacological studies, autodocking and molecular dynamics simulations we have found support for the PVP-bend model. The voltage sensor, transmembrane segment 4 (S4), was originally suggested to be buried in the channel protein, undergoing a helical-screw-like motion to open the channel. A recent crystallographic study suggested that S4 is located in the periphery, facing lipid, and undergoing a paddle-like motion to open the channel We have found experimental evidence for a novel helical-screw model; with the voltage sensor moving in a screw-like fashion but being located in the periphery of the channel. This model opens up for understanding how lipophilic drugs and toxins directly affect the voltage sensor.

  • 91.
    Engblom, David
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Prostaglandin E2 in immune-to-brain signaling2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Upon immune-challenge, signaling from the immune system to the brain triggers an array of central nervous responses that include fever, anorexia, hyperalgesia and activation of the hypothalamus-pituitary adrenal axis. These symptoms are dependent on cytokines produced at the site of inflammation. However, because cytokines cannot penetrate the blood-brain barrier, the mechanism by which cytokines activate the central nervous system has remained elusive. Among several hypotheses, it has been suggested that prostaglandin E2 (PGE2) synthesized at the blood-brain interface and subsequently binding to PGE2 receptors expressed on deep neural structures may be responsible for the immune-to-brain signaling.

    During inflammatory conditions PGE2 is produced from prostaglandin H2 by the inducible isomerase microsomal prostaglandin E synthase-1 (mPGES-1). By using in situ hybridization, we investigated the expression of this enzyme in the brain of rats subjected to immune challenge induced by intravenous injection of interleukin-1ß. We found that mPGES-1 mRNA had a very restricted and low expression in the brain of naive rats. However, in response to inunune challenge it was rapidly and heavily induced in cells of the cerebral vasculature. Further, we found that the cells expressing mPGES-1 co-expressed cyclooxygenase-2 mRNA and interleukin-1 receptor type 1 mRNA. Thus, circulating interleukin-1 may bind to brain vascular cells and induce the expression of cyclooxygenase-2 and mPGES-1, leading to the production of PGE2 that can diffuse into the brain and trigger central nervous responses. We also showed that the same mechanism may be operating in a model for autoimmune disease. Thus, rats with adjuvant-induced arthritis, a model of rheumatoid arthritis, displayed a similar mPGES-1 and cyclooxygenase-2 induction in interleukin-1 receptor bearing brain endothelial cells.

    To examine the functional role of the central induction of mPGES-1, we studied the febrile response in mice deficient in the gene encoding mPGES-1. These mice showed no fever and no central PGE2 production in response to immune challenge induced by intraperitoneal injection of the bacterial fragment lipopolysaccharide, demonstrating that PGE2 synthesized by mPGES-1 is critical for immune-induced fever.

    We also studied the expression of receptors for PGE2 in the parabrachial nucleus, an autonomic brain stem structure involved in the regulation of food intake, blood pressure and nociceptive processing. We found that neurons in the para brachial nucleus express PGE2 receptors of type EP3 and EP4 and that many of the EP3 and some of the EP4 expressing neurons in this nucleus are activated by immune challenge. The PGE2 receptor expressing neurons also expressed mRNAs for various neuropeptides, such as dynorphin, enkephalin, calcitonin gene related peptide and substance P. Taken together with previous observations, these findings indicate that the PGE2 receptor expressing cells in the parabrachial nucleus are involved in alterations in food intake and in nociceptive processing during immune challenge.

    In summary, these data show the presence of a mechanism, involving cerebrovascular induction of mPGES-1, that conveys an inflammatory message from the blood-stream through the blood-brain barrier to relevant deep neural structures. Further, the findings show that this mechanism is critical for the febrile response and is activated during both acute and prolonged inflammatory conditions. This identifies mPGES-1 as a potential drug target for the alleviation of central nervous symptoms of inflammatory disease, such as fever, pain and anorexia.

  • 92.
    Engblom, David
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Ek, Monica
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Andersson, Ingela
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Saha, Sipra
    Center for Structural Biochemistry, The Karolinska Institute, Huddinge, Sweden.
    Dahlström, Marie
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Jakobsson, Per-Johan
    Department of Biochemistry and Biophysics, The Karolinska Institute, Stockholm, Sweden.
    Ericsson-Dahlstrand, Anders
    5 AstraZeneca R&D - Södertälje, Molecular Sciences, Novum, Huddinge, Sweden.
    Blomqvist, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Induction of microsomal prostaglandin E synthase in the rat brain endothelium and parenchyma in adjuvant-induced arthritis2002In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 452, no 3, p. 205-214Article in journal (Refereed)
    Abstract [en]

    Although central nervous symptoms such as hyperalgesia, fatigue, malaise, and anorexia constitute major problems in the treatment of patients suffering from chronic inflammatory disease, little has been known about the signaling mechanisms by which the brain is activated during such conditions. Here, in an animal model of rheumatoid arthritis, we show that microsomal prostaglandin E-synthase, the inducible terminal isomerase in the prostaglandin E2-synthesizing pathway, is expressed in endothelial cells along the blood-brain barrier and in the parenchyma of the paraventricular hypothalamic nucleus. The endothelial cells but not the paraventricular hypothalamic cells displayed a concomitant induction of cyclooxygenase-2 and expressed interleukin-1 type 1 receptors, which indicates that the induction is due to peripherally released cytokines. In contrast to cyclooxygenase-2, microsomal prostaglandin E synthase had very sparse constitutive expression, suggesting that it could be a target for developing drugs that will carry fewer side effects than the presently available cyclooxygenase inhibitors. These findings, thus, suggest that immune-to-brain communication during chronic inflammatory conditions involves prostaglandin E2-synthesis both along the blood-brain barrier and in the parenchyma of the hypothalamic paraventricular nucleus and point to novel avenues for the treatment of the brain-elicited disease symptoms during these conditions.

  • 93.
    Engblom, David
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Ek, Monica
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Ericsson-Dahlstrand, Anders
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Blomqvist, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Activation of prostanoid EP3 and EP4 receptor mRNA-expressing neurons in the rat parabrachial nucleus by intravenous injection of bacterial wall lipopolysaccharide2001In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 440, no 4, p. 378-386Article in journal (Refereed)
    Abstract [en]

    Systemic inflammation activates central autonomic circuits, such as neurons in the pontine parabrachial nucleus. This activation may be the result of afferent signaling through the vagus nerve, but it may also depend on central prostaglandin-mediated mechanisms. Recently, we have shown that neurons in the parts of the parabrachial nucleus that are activated by immune challenge express prostaglandin receptors of the EP3 and EP4 subtypes, but it remains to be determined if the prostaglandin receptor-expressing neurons are identical to those that respond to immune stimuli. In the present study, bacterial wall lipopolysaccharide was injected intravenously in adult male rats and the expression of c-fos mRNA and of EP3 and EP4 receptor mRNA was examined with complementary RNA probes labeled with digoxigenin and radioisotopes, respectively. Large numbers of neurons in the external lateral parabrachial subnucleus, a major target of vagal-solitary tract efferents, expressed c-fos mRNA. Quantitative analysis showed that about 60% (range 40%–79%) of these neurons also expressed EP3 receptor mRNA. Conversely, slightly more than 50% (range 48%–63%) of the EP3 receptor-expressing neurons in the same subnucleus coexpressed c-fos mRNA. In contrast, few EP4 receptor-expressing neurons were c-fos positive, with the exception of a small population located in the superior lateral and dorsal lateral subnuclei. These findings show that immune challenge activates central autonomic neurons that could be the target of centrally produced prostaglandin E2, suggesting that synaptic signaling and paracrine mechanisms may interact on these neurons. J. Comp. Neurol. 440:378–386, 2001. © 2001 Wiley-Liss, Inc.

  • 94.
    Engblom, David
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Ek, Monica
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Ericsson-Dahlstrand, Anders
    AstraZeneca R and D–Södertälje, RA CNS and Pain Control, Department of Molecular Sciences, Novum, Huddinge, Sweden.
    Blomqvist, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    EP3 and EP4 receptor mRNA expression in peptidergic cell groups of the rat parabrachial nucleus2004In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 126, no 4, p. 989-999Article in journal (Refereed)
    Abstract [en]

    This study examines the distribution of prostaglandin E2 receptors of subtype EP3 and EP4 among brain stem parabrachial neurons that were characterized with respect to their neuropeptide expression. By using a dual-labeling in situ hybridization method, we show that preprodynorphin mRNA expressing neurons in the dorsal and central lateral subnuclei express EP3 receptor mRNA. Such receptors are also expressed in preproenkephalin, calcitonin gene related peptide and preprotachykinin mRNA positive neurons in the external lateral subnucleus, whereas preprodynorphin mRNA expressing neurons in this subnucleus are EP receptor negative. In addition, EP3 receptor expression is seen among some enkephalinergic neurons in the Kölliker-Fuse nucleus. Neurons in the central part of the cholecystokininergic population in the regions of the superior lateral subnucleus express EP4 receptor mRNA, whereas those located more peripherally express EP3 receptors. Taken together with previous findings showing that discrete peptidergic cell groups mediate nociceptive and/or visceral afferent information to distinct brain stem and forebrain regions, the present results suggest that the processing of this information in the parabrachial nucleus is influenced by prostaglandin E2. Recent work has shown that prostaglandin E2 is released into the brain following peripheral immune challenge; hence, the parabrachial nucleus may be a region where humoral signaling of peripheral inflammatory events may interact with neuronal signaling elicited by the same peripheral processes.

  • 95.
    Engblom, David
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ek, Monica
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Hallbeck, Martin
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Ericsson-Dahlstrand, Anders
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Distribution of prostaglandin EP3 and EP4 receptor mRNA in the rat parabrachial nucleus2000In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 281, no 2-3, p. 163-166Article in journal (Refereed)
    Abstract [en]

    By using in situ hybridization, the distribution of mRNA for the PGE2 receptors EP3 and EP4 was examined in the rat parabrachial nucleus (PB), a major brain stem relay for autonomic and nociceptive processing. EP3 receptor mRNA was present in most subnuclei, with the densest labeling in the external lateral, dorsal lateral, superior lateral, central lateral and Kölliker–Fuse nuclei. EP4 receptor mRNA expressing cells had a more restricted distribution, largely being confined to the superior lateral and adjacent parts of the dorsal and central lateral nuclei in a pattern complementary to that for EP3 receptor mRNA. These findings suggest that EP3 and EP4 receptors in PB have distinct functional roles that include nociceptive processing, blood pressure regulation and feeding behavior.

  • 96.
    Engblom, David
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Ek, Monica
    Saha, Sipra
    Ericsson-Dahlstrand, Anders
    Jakobsson, Per-Johan
    Blomqvist, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Prostaglandins as inflammatory messengers across the blood-brain barrier2002In: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 80, no 1Article in journal (Refereed)
    Abstract [en]

    Upon immune challenge the brain launches a wide range of responses, such as fever, anorexia, and hyperalgesia that serve to maintain homeostasis. While these responses are adaptive during acute infections, they may be destructive during chronic inflammatory conditions. Research performed during the last decade has given us insight into how the brain monitors the presence of a peripheral inflammation and the mechanisms underlying the brain-mediated acute-phase reactions. Here we give a brief review on this subject, with focus on the role of prostaglandin E2 produced in cells associated with the blood-brain barrier in immune-to-brain signaling. The recent advances in this field have not only elucidated the mechanisms behind the anti-pyretic and anti-hyperalgesic effects of cyclooxygenase inhibitors, but have also identified novel and more-selective potential drug targets.

  • 97.
    Engblom, David
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Saha, Sipra
    Center for Structural Biochemistry, Karolinska Institute, Huddinge, Sweden.
    Engström, Linda
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Westman, Marie
    Department of Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden..
    Audoly, Laurent
    Inflammation Unit, Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut, USA..
    Jakobsson, Per-Johan
    Department of Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden..
    Blomqvist, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis2003In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 6, no 11, p. 1137-1138Article in journal (Refereed)
    Abstract [en]

    We studied the febrile response in mice deficient in microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal isomerase expressed in cytokine-sensitive brain endothelial cells. These animals showed no fever and no central prostaglandin (PG) E2 synthesis after peripheral injection of bacterial-wall lipopolysaccharide, but their pyretic capacity in response to centrally administered PGE2 was intact. Our findings identify mPGES-1 as the central switch during immune-induced pyresis and as a target for the treatment of fever and other PGE2-dependent acute phase reactions elicited by the brain.

  • 98.
    Ericson, Ann-Charlott
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Kechagias, Stergios
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Öqvist, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Sjöstrand, Sven-Erik
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Morphological examination of the termination pattern of substance P-immunoreactive nerve fibers in human antral mucosa2002In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 107, no 1-3, p. 79-86Article in journal (Refereed)
    Abstract [en]

    The termination pattern of substance P (SP)-containing axons in human antral mucosa was examined using immunohistochemical techniques at the light and electron microscopic level. SP-immunoreactive (IR) axons were found to extend towards the pit region of the glands, where intraepithelial axons were observed. Electron microscopy showed immunostained axon profiles in close contact with the basement membrane of surface mucous cells. Membrane-to-membrane contacts between labeled axons and myofibroblast-like cells were identified, and SP-IR axons that were apposed to the epithelium were also in contact with subjacent myofibroblast-like cells. The anatomical relationship between SP-IR axons and the cells of the muscularis mucosae was investigated by light microscopy. Immunoreactivity for a-smooth muscle actin (a-sma) was used to visualize the smooth muscle cells, and the a-sma-IR cells were found to create a network that surrounded the gastric glands. Immunostained varicose axons ran alongside and in close apposition to the labeled muscle strands. Ultrastructural examination showed close contacts between SP-IR axon profiles and smooth muscle-like cells. In conclusion, SP-containing neurons may be important for sensory and secretomotor functions in the human antral mucosa.

  • 99.
    Eriksson, Ola
    et al.
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, The Institute of Technology.
    Backlund, Erik-Olof
    Linköping University, Department of Neuroscience and Locomotion, Neurosurgery. Linköping University, Faculty of Health Sciences.
    Lundberg, Peter
    Linköping University, Department of Medicine and Care, Radiation Physics. Linköping University, Faculty of Health Sciences.
    Lindstam, Håkan
    Linköping University, Department of Medicine and Care, Radiology. Linköping University, Faculty of Health Sciences.
    Lindström, Sivert
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Wårdell, Karin
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, The Institute of Technology.
    Experimental radiofrequency brain lesions: a volumetric study2002In: Neurosurgery, ISSN 0148-396X, E-ISSN 1524-4040, Vol. 51, no 3, p. 781-788Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE : This study describes the production, under strictly standardized and controlled conditions, of radiofrequency lesions with identical neurogenerator settings: in vitro in two different albumin solutions (nongelatinous and gelatinous) and in vivo in the thalamus of the pig.

    METHODS : The radiofrequency lesions were investigated in vitro by the use of a specially designed video system and in vivo by magnetic resonance imaging. Moreover, the size of the in vivo lesions was estimated with the use of histological sectioning. The statistical analysis included the calculation of a correlation coefficient for the length, width, and volume for each lesion estimation.

    RESULTS : A high correlation (R = 0.96, P < 0.005; n = 14) was found between clot sizes in the two albumin solutions. Albumin clots generated in gelatinous albumin showed systematically larger volumes. In the pig, two concentric zones were seen in all magnetic resonance images and all histological preparations. The width correlation of the completely coagulated brain tissue (inner zones) was R = 0.94, P < 0.005, and n = 7. The corresponding correlation between magnetic resonance images and gelatinous albumin was R = 0.93, P < 0.005, and n = 7. As a rule, the in vitro clots were smaller than the outer zone but larger than the inner zone of the magnetic resonance imaging-recorded lesions for all of the electrode and temperature combinations tested. In vivo lesions generated with the same electrode and parameter settings showed high reproducibility.

    CONCLUSION : The value of presurgical electrode tests to validate the electrode function and lesion size in vitro has become evident in this study, which shows a high correlation between the in vitro albumin clots and the in vivo lesions observed on magnetic resonance images.

  • 100. Erling Tjus, Staffan
    et al.
    Vibe Scheller, Henrik
    Andersson, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Lindberg Möller, Birger
    Active oxygen produced during selective excitation of photosystem I is damaging not only to photosystem I, but also to photosystem II.2001In: Plant Physiology, ISSN 0032-0889, E-ISSN 1532-2548, Vol. 125, p. 2007-2015Article in journal (Refereed)
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