Publikationer 2013 – Københavns Universitet

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Publications 2013

The list of publications by scientists from Center for Healthy Aging is only in English as most publications are published in English.

Listen over videnskablige publikationer af forskere fra Center for Sund Aldring er kun på engelsk, da de fleste publikationer kun bliver offentliggjort på engelsk.

 Program 1a - Molecular and Cellular: Molecular AgingTil toppen

Relationships between human vitality and mitochondrial respiratory parameters, reactive oxygen species production and dNTP levels in peripheral blood mononuclear cells. Maynard S*, Keijzers G*, Gram M, Desler C, Bendix L, Budtz-Jørgensen E, Molbo D, Croteau DL, Olser M, Stevsner T, Rasmussen LJ, Dela F, Avlund K, Bohr VA (2013). (*co-first authors). Aging. 2013 Nov 30 Nov;5(11):850-64. 

Low vitality (a component of fatigue) in middle-aged and older adults is an important complaint often identified as a symptom of a disease state or side effect of a treatment. No studies to date have investigated the potential link between dysfunctional mitochondrial ATP production and low vitality. Therefore, we measured a number of cellular parameters related to mitochondrial activity in peripheral blood mononuclear cells (PBMCs) isolated from middle-aged men, and tested for association with vitality. These parameters estimate mitochondrial respiration, reactive oxygen species (ROS) production, and deoxyribonucleotide (dNTP) balance in PBMCs. We conclude that self-reported persistent low vitality is not associated with specific aspects of mitochondrial oxidative phosphorylation capacity in PBMCs, but may have other underlying cellular dysfunctions that contribute to dNTP imbalance and altered ROS production...

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Modulation of DNA base excision repair during neuronal differentiation. Sykora P, Yang JL, Ferrarelli LK, Tian J, Tadokoro T, Kulkarni A, Weissman L, Keijzers G, Wilson DM 3rd, Mattson MP, Bohr VA (2013). Neurobiol Aging. 2013 Jul;34(7):1717-27. doi: 10.1016/j.neurobiolaging.2012.12.016. Epub 2013 Feb 1. 

Neurons are terminally differentiated cells with a high rate of metabolism and multiple biological properties distinct from their undifferentiated precursors. Previous studies showed that nucleotide excision DNA repair is downregulated in postmitotic muscle cells and neurons. Here, we characterize DNA damage susceptibility and base excision DNA repair (BER) capacity in undifferentiated and differentiated human neural cells. The results show that undifferentiated human SH-SY5Y neuroblastoma cells are less sensitive to oxidative damage than their differentiated counterparts, in part because they have robust BER capacity, which is heavily attenuated in postmitotic neurons...

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Cockayne syndrome group B protein stimulates NEIL2 DNA glycosylase activity. Aamann MD., Hvitby C., Popuri V., Muftuolgu M., Lemminger L., Skeby CK., Keijzers G., Ahn B., Bjørås M., Bohr VA., and Stenvsner T. Mechanism of Ageing and Development 2014 Jan 7 pii: S0047-6374(13)00146-2. 

Cockayne Syndrome is a segmental premature aging syndrome, which can be caused by loss of function of the CSB protein. CSB is essential for genome maintenance and has numerous interaction partners with established roles in different DNA repair pathways including transcription coupled nucleotide excision repair and base excision repair. Here, we describe a new interaction partner for CSB, the DNA glycosylase NEIL2. Using both cell extracts and recombinant proteins, CSB and NEIL2 were found to physically interact independently of DNA. We further found that CSB is able to stimulate NEIL2 glycosylase activity on a 5-hydroxyl uracil lesion in a DNA bubble structure substrate in vitro...

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A small molecule inhibitor of the BLM helicase modulates chromosome stability in human cells. Nguyen, G.H., Dexheimer, T.S., Rosenthal, A.S., Chu, W-K., Singh, D.K., Mosedale, G., Bachrati, C.Z., Schultz, L., Sakurai M., Savitsky, P., Abu, M., McHugh, P.J., Bohr, V.A., Harris, C.C., Jadhav, A., Gileadi, O., Maloney, D.J., Simeonov, A. and Hickson, I.D. Chemistry and Biology 20, 55-62, 2013. 

The Bloom's syndrome protein, BLM, is a member of the conserved RecQ helicase family. Although cell lines lacking BLM exist, these exhibit progressive genomic instability that makes distinguishing primary from secondary effects of BLM loss problematic. In order to be able to acutely disable BLM function in cells, we undertook a high throughput screen of a chemical compound library for small molecule inhibitors of BLM. We present ML216, a potent inhibitor of the DNA unwinding activity of BLM. ML216 shows cell-based activity and can induce sister chromatid exchanges, enhance the toxicity of aphidicolin, and exert antiproliferative activity in cells expressing BLM, but not those lacking BLM. These data indicate that ML216 shows strong selectivity for BLM in cultured cells. We discuss the potential utility of such a BLM-targeting compound as an anticancer agent.

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FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress. Fugger, K., Chu, W-K., Haahr, P., Kousholt, A.N., Beck, H., Payne, M.J., Hanada, K., Hickson, I.D. and Sørensen, C.S. Nature Communications 4, 1423, 2013. 

The molecular events occurring following the disruption of DNA replication forks are poorly characterized, despite extensive use of replication inhibitors such as hydroxyurea in the treatment of malignancies. Here, we identify a key role for the FBH1 helicase in mediating DNA double-strand break formation following replication inhibition. We show that FBH1-deficient cells are resistant to killing by hydroxyurea, and exhibit impaired activation of the pro-apoptotic factor p53, consistent with decreased DNA double-strand break formation. Similar findings were obtained in murine ES cells carrying disrupted alleles of Fbh1. Our data suggest that FBH1 helicase activity is required to eliminate cells with excessive replication stress through the generation of MUS81-induced DNA double-strand breaks...

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MUS81 promotes common fragile site expression. Ying, S., Minocherhomji, S., Chan, K.L., Palmai-Pallag, T., Chu, W.K., Wass, T., Mankouri, H.W., Liu, Y. and Hickson, I.D. Nature Cell Biology 15, 1001-1006, 2013. 

Fragile sites are chromosomal loci with a propensity to form gaps or breaks during early mitosis, and their instability is implicated as being causative in certain neurological disorders and cancers. Recent work has demonstrated that the so-called common fragile sites (CFSs) often impair the faithful disjunction of sister chromatids in mitosis. However, the mechanisms by which CFSs express their fragility, and the cellular factors required to suppress CFS instability, remain largely undefined. Here, we report that the DNA structure-specific nuclease MUS81-EME1 localizes to CFS loci in early mitotic cells, and promotes the cytological appearance of characteristic gaps or breaks observed at CFSs in metaphase chromosomes. These data indicate that CFS breakage is an active, MUS81-EME1-dependent process, and not a result of inadvertent chromatid rupturing during chromosome condensation. Moreover, CFS cleavage by MUS81-EME1 promotes faithful sister chromatid disjunction. Our findings challenge the prevailing view that CFS breakage is a nonspecific process that is detrimental to cells, and indicate that CFS cleavage actually promotes genome stability.

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PICH: a DNA translocase specially adapted for processing anaphase bridge DNA. Biebricher, A., Hirano, S., Enzlin, J.H., Wiechens, N., Streicher, W.W., Wang, L.H.C., Nigg, E.A., Owen-Hughes, T., Liu, Y., Peterman, E., Wuite, G.J.L. and Hickson, I.D. Molecular Cell 51, 691-701, 2013.

Synthesis and SAR studies of 5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine derivatives as potent inhibitors of Bloom helicase. Rosenthal, A.S., Dexheimer, T.S., Gileadi, O., Nguyen, G.H., Chu, W.K., Hickson, I.D., Jadhav, A., Simeonov, A. and Maloney, D.J. Bioorganic and Medicinal Chemistry Letters 23, 5660-5666, 2013. 

Human cells utilize a variety of complex DNA repair mechanisms in order to combat constant mutagenic and cytotoxic threats from both exogenous and endogenous sources. The RecQ family of DNA helicases, which includes Bloom helicase (BLM), plays an important function in DNA repair by unwinding complementary strands of duplex DNA as well as atypical DNA structures such as Holliday junctions. BLM-deficient cells exhibit increased sensitivity to DNA damaging agents indicating that a selective BLM inhibitor could be useful in potentiating the anticancer activity of these agents. In this work, we describe the medicinal chemistry optimization of the hit molecule following a quantitative high-throughput screen of >355,000 compounds...

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A role for BLM in double strand break repair pathway choice: prevention of CtIP/Mre11 mediated alternative non-homologous end-joining Cell. Grabarz, A., Guirouilh-Barbat, J., Barascu, A., Pennarun, G., Genet, D., Rass, E., Germann, S.M., Bertrand, P., Hickson, I.D. and Lopez, B.S. Cell Rep. 2013 Oct 17;5(1):21-8. 

The choice of the appropriate double-strand break (DSB) repair pathway is essential for the maintenance of genomic stability. Here, we show that the Bloom syndrome gene product, BLM, counteracts CtIP/MRE11-dependent long-range deletions (>200 bp) generated by alternative end-joining (A-EJ). BLM represses A-EJ in an epistatic manner with 53BP1 and RIF1 and is required for ionizing-radiation-induced 53BP1 focus assembly. Conversely, in the absence of 53BP1 or RIF1, BLM promotes formation of A-EJ long deletions, consistent with a role for BLM in DSB end resection. These data highlight a dual role for BLM that influences the DSB repair pathway choice: (1) protection against CtIP/MRE11 long-range deletions associated with A-EJ and (2) promotion of DNA resection. These antagonist roles can be regulated, according to cell-cycle stage, by interacting partners such as 53BP1 and TopIII, to avoid unscheduled resection that might jeopardize genome integrity.

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FBH1 disrupts RAD51 filaments in vitro and modulates homologous recombination in mammalian cells. Simandlova, J., Zagelbaum, J., Payne, M., Chu, W.K., Shevelev, I., Hanada, K., Chatterjee, S., Reid, D.A., Janscak, P., Rothenberg, E. and Hickson, I.D. J. Biol. Chem., 2013 Nov 22;288(47):34168-80. 

Efficient repair of DNA double strand breaks and interstrand cross-links requires the homologous recombination (HR) pathway, a potentially error-free process that utilizes a homologous sequence as a repair template. A key player in HR is RAD51, the eukaryotic ortholog of bacterial RecA protein. RAD51 can polymerize on DNA to form a nucleoprotein filament that facilitates both the search for the homologous DNA sequences and the subsequent DNA strand invasion required to initiate HR. Because of its pivotal role in HR, RAD51 is subject to numerous positive and negative regulatory influences.  We show that FBH1 binds directly to RAD51 and is able to disrupt RAD51 filaments on DNA through its ssDNA translocase function...

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RecQ helicases – conserved guardians of genome integrity. Larsen, N.B. and Hickson, I D. Adv. Exp. Med. Biol. 767, 161-184, 2013. 

The RecQ family of DNA helicases is highly conserved throughout -evolution, and is important for the maintenance of genome stability. In humans, five RecQ family members have been identified: BLM, WRN, RECQ4, RECQ1 and RECQ5. Defects in three of these give rise to Bloom's syndrome (BLM), Werner's syndrome (WRN) and Rothmund-Thomson/RAPADILINO/Baller-Gerold (RECQ4) syndromes. These syndromes are characterised by cancer predisposition and/or premature ageing. In this review, we focus on the roles of BLM and its S. cerevisiae homologue, Sgs1, in genome maintenance. BLM/Sgs1 has been shown to play a critical role in homologous recombination at multiple steps, including end-resection, displacement loop formation, branch migration and double Holliday junction dissolution. In addition, recent evidence has revealed a role for BLM/Sgs1 in the stabilisation and repair of replication forks damaged during a perturbed S-phase. Finally BLM also plays a role in the suppression and/or resolution of ultra-fine anaphase DNA bridges that form between sister-chromatids during mitosis.

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How unfinished business from S-phase affects mitosis and beyond. Mankouri, H.W., Huttner, D. and Hickson, I.D. EMBO J. 32, 2661-2671, 2013. 

The eukaryotic cell cycle is conventionally viewed as comprising several discrete steps, each of which must be completed before the next one is initiated. However, emerging evidence suggests that incompletely replicated, or unresolved, chromosomes from S-phase can persist into mitosis, where they present a potential threat to the faithful segregation of sister chromatids. In this review, we provide an overview of the different classes of loci where this 'unfinished S-phase business' can lead to a variety of cytogenetically distinct DNA structures throughout the various steps of mitosis. Furthermore, we discuss the potential ways in which cells might not only tolerate this inevitable aspect of chromosome biology, but also exploit it to assist in the maintenance of genome stability.

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The dissolution of double Holliday junctions. Bizard, A.H. and Hickson, I.D. (2013) Cold Spring Harbor Perspectives, 2013 (accepted).

Structure-specific endonucleases: guardians of fragile site stability. Minocherhomji, S. and Hickson, I.D. (2013). Trends in Cell Biology, 2013 Dec 19. 

Fragile sites are conserved loci predisposed to form breaks in metaphase chromosomes. The inherent instability of these loci is associated with chromosomal rearrangements in cancers and is a feature of cells from patients with chromosomal instability syndromes. One class of fragile sites, the common fragile sites (CFSs), have previously been shown to recruit several DNA repair proteins after the completion of bulk DNA synthesis in the cell, probably indicative of their inability to complete timely DNA replication. CFS loci are also prone to trigger mitotic non-disjunction of sister chromatids, leading to the formation of ultra-fine anaphase bridges (UFBs) and micronuclei. We discuss recent developments in the CFS field; in particular, the role of DNA structure-specific endonucleases in promoting cleavage at CFSs.

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IL-17A potentiates TNFα-induced secretion from human endothelial cells and alters barrier functions controlling neutrophils rights of passage. Bosteen MH, Tritsaris K, Hansen AJ and Dissing S. Pflügers Archive – European Journal of Physiology, 2013 Sep 27. [Epub ahead of print]. 

Interleukin-17A (IL-17A) is an important pro-inflammatory cytokine that regulates leukocyte mobilization and recruitment. To better understand how IL-17A controls leukocyte trafficking across capillaries in the peripheral blood circulation, we used primary human dermal microvascular endothelial cells (HDMEC) to investigate their secretory potential and barrier function when activated with IL-17A and TNFα. Activation by TNFα and IL-17A causes phosphorylation of p38 as well as IκBα whereby NFκB subsequently becomes phosphorylated, a mechanism that initiates transcription of adhesion molecules such as E-selectin. Members of the neutrophil-specific GRO-family chemokines were significantly up-regulated upon IL-17A stimulation on the mRNA and protein level, whereas all tested non-neutrophil-specific chemokines remained unchanged in comparison...

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IL-27 inhibits lymphatic endothelial cell proliferation by STAT1-regulated gene expression. Nielsen SR, Hammer T, Gibson J, Pepper MS, Nisato RE, Dissing S, Tritsaris K. Microcirculation, 20(6):555-64, 2013. 

OBJECTIVE: IL-27 belongs to the IL-12 family of cytokines and is recognized for its role in Th cell differentiation and as an inhibitor of tumor angiogenesis. The purpose of this study was to investigate the effect of IL-27 on proliferation of lymphatic endothelial cells to gain insight into the interplay between the immune system and development of the lymphatic system. CONCLUSIONS: IL-27 function as an anti-lymphangiogenic regulator in vitro by up-regulating chemokines and interfering with the mitogenic effect of growth factors through STAT1 activation...

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TH17 cell-induction and effects of IL-17A and IL-17F blockade in experimental colitis. Schmidt EGW, Larsen HL, Kristensen NN, Poulsen SS, Pedersen AML, Claesson MH, Pedersen AE. J Inflamm Bowel Dis (IBD) 19 (8): 1567-76, 2013.

BACKGROUND: T helper (TH) 17 cells are believed to play a pivotal role in development of inflammatory bowel disease, and their contribution to intestinal inflammation has been studied in various models of colitis. TH17 cells produce a range of cytokines, some of which are potential targets for immunotherapy. However, blockade of IL-17A alone with secukinumab was not effective in Crohn's disease. In this regard, the pathogenic impact of IL-17A versus IL-17F during intestinal inflammation is still unresolved. CONCLUSIONS: TH17 cell development correlates with colitis progression, and concurrent neutralization of their cytokine products IL-17A and IL-17F ameliorates intestinal inflammation. These findings suggest combined IL-17A and IL-17F blockade as a potential strategy in inflammatory bowel disease therapy...

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Salivary Gland Structure and Functions and Regulation of Saliva Secretion in Health and Disease. Pedersen AML, Sørensen CE, Dynesen AW, Jensen SB. In: Salivary Glands: Anatomy, Functions in Digestion and Role in Disease. Louis Braxton and Simone Quinn (eds). Nova Science Publishers, Inc. New York, Chap. I: 1-43, 2013.

Filaggrin and the oral mucosa. Pedersen AML, Reibel J. In: Filaggrin Molecules in Health and Disease. Thyssen HP, Maibach H (eds.) Springer Verlag Berlin, in press, 2013.

Other biomarkers. Advances in Orofacial Pain Assessment. Alstergren P, Pedersen AML, Jääskeläinen SK. In: Orofacial Pain. IASP. Sessle B. (ed.). In press, 2013.

Diseases causing dry mouth. Pedersen AML. In: Dry Mouth: A Clinical Guide on Causes, Effects and Treatments. Carpenter G. (ed.) Springer Verlag Berlin, Chap. 3. In press, 2013.

Lægemidler til lindring og behandling af mundtørhed. Dynesen AW, Pedersen AML, Jensdottir T, Jensen AB, Jensen SB. Tandlægebladet 117(11): 900-6, 2013.

Lægemidlers anvendelse til den medicinske og psykiatriske patient med relevans for tandlæger. Johansen NB, HL Larsen, Pedersen AML. Tandlægebladet 117 (11): 908-15, 2013

Polyfarmaci. Pedersen AML, Bjerrum L. Tandlægebladet 117 (11): 916-20, 2013.

Helicobacter pylori infection affects mitochondrial function and DNA repair, thus, mediating genetic instability in gastric cells. Machado, A.M., Desler, C., Bøggild, S., Strickertsson, J.A., Friis-Hansen, L., Figueiredo, C., Seruca, R. and Rasmussen. L.J. Mech Ageing Dev. 2013 Oct;134(10):460-6. 

Helicobacter pylori infection is an important factor for the development of atrophic gastritis and gastric carcinogenesis. In this study, we demonstrate that H. pylori infection of gastric adenocarcinoma cells causes mtDNA mutations and a decrease of mtDNA content. Consequently, we show a decrease of respiration coupled ATP turnover and respiratory capacity and accordingly a lower level and activity of complex I of the electron transport chain. Our results suggest that both APE-1 and YB-1 are involved in mtDNA repair during H. pylori infection, furthermore, the results demonstrate that multiple DNA repair activities are involved in protecting mtDNA during infection...

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Genetic screens for the identification of pathogenic gene variants in the cancer predisposition Lynch syndrome. Drost, M., Lützen, A., van Hees, S., Ferreira, D., Calléja, F., Zonneveld, J.B.M., Nielsen, F.C., Rasmussen, L.J. and de Wind, N. Proc. Natl. Acad. Sci. USA. 110:9403-9408. 2013. 

In many individuals suspected of the common cancer predisposition Lynch syndrome, variants of unclear significance (VUS), rather than an obviously pathogenic mutations, are identified in one of the DNA mismatch repair (MMR) genes. The uncertainty of whether such VUS inactivate MMR, and therefore are pathogenic, precludes targeted healthcare for both carriers and their relatives. To facilitate the identification of pathogenic VUS, we have developed an in cellulo genetic screen-based procedure for the large-scale mutagenization, identification, and cataloguing of residues of MMR genes critical for MMR gene function...

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DNA Methylation Changes in Clinical Stages of Oral Cancer Progression and Correlation with DOC2B Promoter. Radhakrishnan, R., Upadhya, R., Aithal, A., Prasada, S., Bhat, S., Jayaprakash, C., Ray, S., Prasad, K.C., Kamath, A., Rasmussen, L.J. and Satyamoorthy, K. Molecular Cancer Research. In press. 2013.

Introducing the hypothome. A way to integrate predicted proteins in interactomes. Desler, C., Zambach, S., Suravajhala, P. and Rasmussen, L.J. Int. J. Bioinf. Res. Appl. In press. 2013.

Enterococcus faecalis causes inflammation, intracellular ROS production, and DNA damage in human gastric cancer cells. Strickertsson, J.A.B., Desler, C., Bertelsen, T.M., Machado, A.M.D., Wadstrøm, T., Winther, O., Rasmussen, L.J. and Friis-Hansen, L. PLoS One. 8(4) e63147. 2013. 

BACKGROUND: Achlorhydria caused by e.g. atrophic gastritis allows for bacterial overgrowth, which induces chronic inflammation and damage to the mucosal cells of infected individuals driving gastric malignancies and cancer. Enterococcus faecalis (E. faecalis) can colonize achlohydric stomachs and we therefore wanted to study the impact of E. faecalis infection on inflammatory response, reactive oxygen species (ROS) formation, mitochondrial respiration, and mitochondrial genetic stability in gastric mucosal cells. CONCLUSIONS: Infection by E. faecalis induced an oxphos-independent intracellular ROS response and damaged the mitochondrial genome in gastric cell culture. Finally the bacteria induced an NF-κB inflammatory response as well as impaired DNA damage response and cell cycle control gene expression...

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DNA damage response, bioenergetics, and neurological disease: the challenge of maintaining brain health in an aging human population. Rasmussen LJ, Shiloh Y, Bergersen LH, Sander M, Bohr VA, Tønjum T. Mech Ageing Dev. Volume 134, Issue 10, October 2013, Pages 427–433. 

Introduction: Genome Dynamics in Neuroscience (GDN) is a series of conferences organized and hosted by leading-edge scientists interested in genome dynamics, genome instability and neuroscience. The fourth conference in the series (GDN4, www.gdn4.com), held in late September 2012 in Oslo, Norway, focused on genome instability in aging and brain disease. GDN4 was an eye-opening and mind-expanding conference, which started with a “wake-up call” to neuroscientists, molecular geneticists, cancer biologists, and other researchers, many of whom have been diligently working to elucidate the molecular mechanisms of human aging and neurodegenerative disease. The wake-up call came in the form of the suggestion that the paradigm underlying modern biomolecular research is based on inaccurate assumptions, and that an improved paradigm, one with potential for much greater success in understanding aging and complex human diseases, must embrace the idea that bioenergetics and epigenetic phenomena are central determinants of human health and disease.

Natural Selection of Mitochondria During Somatic Lifetime Promotes Healthy Aging. Rodell, A., Rasmussen, L.J., Bergersen, L.H., Singh, K.K. and Gjedde. A. Front. Neuroenergetics. 5:7. doi: 10.3389/fnene.2013.00007. 2013. 

Stimulation of mitochondrial biogenesis during life-time challenges both eliminates disadvantageous properties and drives adaptive selection of advantageous phenotypic variations. Intermittent fission and fusion of mitochondria provide specific targets for health promotion by brief temporal stressors, interspersed with periods of recovery and biogenesis. For mitochondria, the mechanisms of selection, variability, and heritability, are complicated by interaction of two independent genomes, including the multiple copies of DNA in each mitochondrion, as well as the shared nuclear genome of each cell. We propose that intermittent purposeful enhancement of mitochondrial biogenesis by stressful episodes with subsequent recovery paradoxically promotes adaptive mitochondrial health and continued healthy aging...

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Functional examination of MLH1, MSH2 and MSH6 intronic mutations identified in Danish colorectal cancer patients. Petersen, S.M., Dandanell, M., Rasmussen, L.J., Gerdes, A.M., Krogh, L.N., Bernstein, I., Okkels, H., Wikman, F., Nielsen, F.C. and Hansen, T.V.O. BMC Med Genet. 14:103. 2013. 

BACKGROUND: Germ-line mutations in the DNA mismatch repair genes MLH1, MSH2, and MSH6 predispose to the development of colorectal cancer (Lynch syndrome or hereditary nonpolyposis colorectal cancer). These mutations include disease-causing frame-shift, nonsense, and splicing mutations as well as large genomic rearrangements. However, a large number of mutations, including missense, silent, and intronic variants, are classified as variants of unknown clinical significance. CONCLUSIONS: In conclusion, we classify five MLH1/MSH2 mutations as pathogenic, whereas four MLH1/MSH2/MSH6 mutations are classified as neutral. This study supports the notion that in silico prediction tools and mini-gene assays are important for the classification of intronic variants, and thereby crucial for the genetic counseling of patients and their family members...

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Application of a five-tiered scheme for standardized classification of 2,392 unique mismatch repair gene variants lodged on the InSiGHT locus-specific database. Thompson, B.A., Spurdle, A.B., Plazzer, J.P., Greenblatt, M., Akagi, K., Al-Mulla, F., Bapat, B., Bernstein, I., Capella, G., du Sart, D., Fabre, A., Farrell, M.P., Farrington, S., Frayling, I., Frebourg, T., Goldgar, D., Heinen, C.D., Holinski-Feder, E., Kohonen-Corish, M., Lagerstedt-Robinson, K., Leung, S.Y., Lindblom, A., Martins, A., Moller, P., Morak, M., Nystrom, M., Peltomaki, P., Pineda, M., Qi, M., Ramesar, R., Rasmussen, L.J., Royer-Pokora, B., Scott, R., Sijmons, R., Tavtigian, S., Tops, C., Weber, T., Wijnen, J., Woods, M., on behalf of InSiGHT, Macrae, F. and Genuardi. M. Nature Genetics 2014 Feb;46(2):107-15 (accepted 2013). 

The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. This large-scale endeavour will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases...

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Relationships between human vitality and mitochondrial respiratory parameters, reactive oxygen species and dNTP levels in peripheral blood mononuclear cells. Maynard, S., Keijzers, G., Gram, M., Desler, C., Bendix, L., Jørgensen, E.B., Molbo, D., Croteau, D.L., Osler, M., Stevsner, T., Rasmussen, L.J., Dela, F., Avlund, K. and Bohr, V.A. Aging (Albany NY). 2013 Nov;5(11):850-64. 

Low vitality (a component of fatigue) in middle-aged and older adults is an important complaint often identified as a symptom of a disease state or side effect of a treatment. We conclude that self-reported persistent low vitality is not associated with specific aspects of mitochondrial oxidative phosphorylation capacity in PBMCs, but may have other underlying cellular dysfunctions that contribute to dNTP imbalance and altered ROS production...

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 Program 1b - Molecular and Cellular: NeurobiologyTil toppen

Decreased sleep spindle density in patients with idiopathic REM sleep behavior disorder and patients with Parkinson's disease. Christensen JA, Kempfner J, Zoetmulder M, Leonthin HL, Arvastson L, Christensen SR, Sorensen HB, Jennum P. Clin Neurophysiol 11: pii: S1388-2457(13)00998-X. doi: 10.1016/j.clinph.2013.08.013. [Epub ahead of print], 2013. 

OBJECTIVE: To determine whether sleep spindles (SS) are potentially a biomarker for Parkinson's disease (PD). CONCLUSIONS: The lower SS density suggests involvement in pre-thalamic fibers involved in SS generation. SS density is a potential early PD biomarker...

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Detection of a sleep disorder predicting Parkinson's disease. Hansen IH, Marcussen M, Christensen JA, Jennum P, Sorensen HB. Conf Proc IEEE Eng Med Biol Soc. 2013: 5793-6, 2013. 

Idiopathic rapid eye-movement (REM) sleep behavior disorder (iRBD) has been found to be a strong early predictor for later development into Parkinson's disease (PD). The feature sets used for classifying subjects were based on the relative powers of the EEG signals in different frequency bands. The classification was based on the fast and classical K-means and Bayesian classifiers. With a subject-specific re-scaling of the feature set and the use of a Bayesian classifier the performance reached 90% in both sensitivity and specificity. For the purpose of reducing the feature count, the features were evaluated with the statistical Smith-Satterthwaite test and by using sequential forward selection a well-performing feature subset was found which contained only five features, while attaining a sensitivity and a specificity of both 80 %...

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Automatic SLEEP staging: From young aduslts to elderly patients using multi-class support vector machine. Kempfner J, Jennum P, Sorensen HB, Christensen JA, Nikolic M. Conf Proc IEEE Eng Med Biol Soc. 2013: 5777-80, 2013. 

Aging is a process that is inevitable, and makes our body vulnerable to age-related diseases. Age is the most consistent factor affecting the sleep structure. This study proposes an automatic sleep stage detector, which can separate wakefulness, rapid-eye-movement (REM) sleep and non-REM (NREM) sleep using only EEG and EOG. The classification of the three sleep stages are achieved by a multi-class support vector machine using the one-versus-rest scheme. It was possible to obtain a high classification accuracy of 0.91. Validation of the sleep stage detector in other sleep disorders, such as apnea and narcolepsy, should be considered in future work...

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SLEEP phenomena as an early biomarker for Parkinsonism. Kempfner J, Jennum P, Nikolic M, Christensen JA, Sorensen HB. Conf Proc IEEE Eng Med Biol Soc. 2013: 5773-6, 2013. 

Idiopathic Rapid-Eye-Movement (REM) sleep Behavior Disorder (iRBD) is one of the most potential biomarkers for Parkinson's Disease (PD) and some atypical PD (AP). The purpose of this study is to investigate the possibility of detecting abnormal high muscle activity during REM sleep in subjects diagnosed with iRBD. This has been achieved by considering the abnormal high muscle activity during REM sleep in iRBD subjects as an outlier detection problem, while exploiting that iRBD muscle activity is more grouped. It was possible to correctly discriminate all iRBD subjects from healthy elderly control subjects and subjects diagnosed with periodic limb movement (PLM) disorder...

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Classification of iRBD and Parkinson's patients using a general data-driven sleep staging model built on EEG. Koch H, Christensen JA, Frandsen R, Arvastson L, Christensen SR, Sorensen HB, Jennum P. Conf Proc IEEE Eng Med Biol Soc. 2013: 4275-8, 2013. 

Sleep analysis is an important diagnostic tool for sleep disorders. This study changes Esbroeck and Westover's [1] latent sleep staging model into a global model. Two features calculated on basis of two latent sleep states classified subjects as "control" or "patient" by a simple clustering algorithm. The mean sleep staging accuracy compared to classical AASM scoring was 72.4% for control subjects and a clustering of the derived features resulted in a sensitivity of 95% and a specificity of 80 %. This study demonstrates that frequency analysis of sleep EEG can be used for data-driven global sleep classification and that topic features separates iRBD and Parkinson's patients from control subjects...

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Classification of iRBD and Parkinson's disease patients based on eye movements during sleep. Christensen JA, Koch H, Frandsen R, Kempfner J, Arvastson L, Christensen SR, Sorensen HB, Jennum P. Conf Proc IEEE Eng Med Biol Soc. 2013: 441-4, 2013. 

Patients suffering from the sleep disorder idiopathic rapid-eye-movement sleep behavior disorder (iRBD) have been observed to be in high risk of developing Parkinson's disease (PD). This study aims at classifying patients suffering from iRBD or PD based on features reflecting eye movements (EMs) during sleep. This study demonstrates in a data-driven approach, that iRBD and PD patients may exhibit abnorm form and/or timely distribution of EMs during sleep...

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Morbidity and mortality in children with obstructive sleep apnoea: a controlled national study. Jennum P, Ibsen R, Kjellberg J. Thorax. 68: 949-54, 2013.

BACKGROUND: Little is known about the diagnostic patterns of obstructive sleep apnoea (OSA) in children. A study was undertaken to evaluate morbidity and mortality in childhood OSA. CONCLUSIONS: Children with OSA have significant morbidities several years before and after their diagnosis...

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Social consequences of sleep disordered breathing on patients and their partners. A controlled national study. Jennum P, Ibsen R, Kjellberg J. Eur Respir J. Eur Respir J. 2014 Jan;43(1):134-44 (Epub 2013 Apr 5.) 

We aimed to evaluate the total costs to patients and their partners of sleep apnoea and obesity hypoventilation syndrome (OHS) and their treatment, as this is poorly described in families. Direct and indirect costs were evaluated for patients and their partners. Sleep apnoea and OHS patients and their partners had higher rates of health-related contact, medication use and unemployment, and lower income levels. Excess yearly direct net health and foregone earnings (indirect costs) were €2174 and €7981 prior to diagnosis, and €3988 and €12,022 after diagnosis for sleep apnoea and OHS, respectively. The comparable annual mean excess health-related costs for spouses were €1965 and €2862 before diagnosis, and €2307 and €3079 after diagnosis, for sleep apnoea and OHS patients, respectively. These socioeconomic consequences were present up to 12 years before first diagnosis, and increased as the disease advanced...

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Sleep transitions in hypocretin-deficient narcolepsy. Sorensen GL, Knudsen S, Jennum P. Sleep. 36: 1173-7, 2013. 

STUDY OBJECTIVES: Narcolepsy is characterized by instability of sleep-wake, tonus, and rapid eye movement (REM) sleep regulation. It is associated with severe hypothalamic hypocretin deficiency, especially in patients with cataplexy (loss of tonus). As the hypocretin neurons coordinate and stabilize the brain's sleep-wake pattern, tonus, and REM flip-flop neuronal centers in animal models, we set out to determine whether hypocretin deficiency and/or cataplexy predicts the unstable sleep-wake and REM sleep pattern of the human phenotype. CONCLUSIONS: In human narcolepsy, hypocretin deficiency and cataplexy are both associated with signs of destabilized sleep-wake and REM sleep control, indicating that the disorder may serve as a human model for the sleep-wake and REM sleep flip-flop switches...

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Health, social and economic consequences of hypersomnia: a controlled national study from a national registry evaluating the societal effect on patients and their partners. Jennum P, Ibsen R, Avlund K, Kjellberg J. Eur J Health Econ. [Epub ahead of print]. PMID: 23757094, 2013. 

Hypersomnia causes significant socioeconomic burden, but there is insufficient information about the time course and the effect on the partner. The aim of this study was to estimate the factual direct and productivity costs of hypersomnia in a controlled study including all national patients and their partners. Direct and productivity costs, including frequencies of primary and sector contacts and procedures, medication, labour supply and social transfer payments were extracted from the national databases. Patients with hypersomnia had significantly higher rates of health-related contact, medication use and socioeconomic cost. Furthermore, they had slightly lower employment rates, and those in employment had a lower income level than control subjects. The annual mean excess health-related cost including social transfers was 3,498 for patients with hypersomnia and 3,851 for their partners. The social and health-related consequences could be identified up to 11 years before the first diagnosis among both the patients and their partners and became more pronounced as the disease advanced. The health effects were present in all age groups and in both genders...

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Comorbidity and mortality of narcolepsy: a controlled retro- and prospective national study. Jennum P, Ibsen R, Knudsen S, Kjellberg J. Sleep. 36: 835-40, 2013. 

STUDY OBJECTIVES: To identify the factual morbidity and mortality of narcolepsy in a controlled design. CONCLUSIONS: Patients with narcolepsy present higher morbidity several years prior to diagnose and even higher thereafter. The mortality rate due to narcolepsy was slightly but not significantly higher...

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Morbidity prior to a diagnosis of sleep-disordered breathing: a controlled national study. Jennum P, Ibsen R, Kjellberg J. J Clin Sleep Med. 9: 103-8, 2013. 

BACKGROUND: Sleep-disordered breathing (SDB) causes burden to the sufferer, the healthcare system, and society. Most studies have focused on cardiovascular diseases (CVDs) after a diagnosis of obstructive sleep apnea (OSA) or obesity hypoventilation syndrome (OHS); however, the overall morbidity prior to an SDB diagnosis has not been evaluated. The aim of this study was to identify morbidity prior to a SDB diagnosis to identify patients at risk for having/developing SDB. CONCLUSIONS: Patients with SDB show significant morbidities several years prior to a diagnosis of OSA or OHS. OSA should be considered in all medical specialties as an important comorbidity. In our study, evidence points to particular emphasis for considering this diagnosis in endocrinology and metabolic specialties...

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Health, social, and economic consequences of neck injuries: a controlled national study evaluating societal effects on patients and their partners. Jennum P, Kjellberg J, Ibsen R, Bendix T. Spine (Phila Pa 1976). 38: 449-57, 2013. 

OBJECTIVE: The aim of this study was to estimate the direct and indirect costs of neck injuries, except fractures, in a national sample of patients and their spouses. CONCLUSION: Neck injuries are associated with major socioeconomic consequences for patients, their spouses, and the society. However, the increased expenses during subsequent years cannot be explained by the injury alone, because these patients already had elevated expenses prior to the injury. This indicates some selection of increased vulnerability for both patients and their spouses...

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Mortality, health, social and economic consequences of amyotrophic lateral sclerosis: a controlled national study. Jennum P, Ibsen R, Pedersen SW, Kjellberg J. J Neurol. 260: 785-93, 2013. 

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that imposes a great burden on the patient, the patient's family and society. We aimed to estimate the factual direct and indirect costs of ALS in a national sample. We conclude that ALS has serious mortality, health and socioeconomic consequences for patients. However, the consequences for spouses are complex; they tend to compensate for the social consequences to patients by increasing their net income after ALS diagnosis...

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The socioeconomic consequences of optic neuritis with and without multiple sclerosis: a controlled national study. Jennum P, Frederiksen JL, Wanscher B, Kjellberg J. Acta Neurol Scand. 127: 242-50, 2013. 

OBJECTIVES: Optic neuritis (ON) often precedes multiple sclerosis (MS). MS is associated with a significant socioeconomic burden. However, the burden of ON with and without MS before and after its diagnosis has never been calculated. CONCLUSIONS: ON, especially if combined with a diagnosis of MS, has a significant socioeconomic consequence for the individual patient and for society. Productivity losses are a far more important economic factor than health sector costs...

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Relationship between cardiac function and resting cerebral blood flow: MRI measurements in healthy elderly subjects. Henriksen OM, Jensen LT, Krabbe K, Larsson HBW, Rostrup E. Clin Physiol Funct Imaging. 2013 Dec 8 doi: 10.1111/cpf.12119. [Epub ahead of print]. 

Although both impaired cardiac function and reduced cerebral blood flow are associated with ageing, current knowledge of the influence of cardiac function on resting cerebral blood flow (CBF) is limited. The aim of this study was to investigate the potential effects of cardiac function on CBF. No effects of cardiac output or cardiac index on CBF or structural signs of brain ageing were observed. Fractional brain flow was also inversely correlated with cerebral white matter lesion grade, although this effect was not significant when adjusted for age. Frequency analysis of heart rate variability showed a gender-related inverse association of increased low-to-high-frequency power ratio with CBF and fractional brain flow. The findings do not support a direct effect of cardiac function on CBF, but demonstrates gender-related differences in cardiac output distribution. We propose fractional brain flow as a novel index that may be a useful marker of adequate brain perfusion in the context of ageing as well as cardiovascular disease...

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Measurement of brain oxygenation changes using dynamic T(1)-weighted imaging. Haddock B, Larsson HBW, Hansen AE, Rostrup E. NeuroImage. 78: 7–15, 2013. 

Magnetic resonance imaging (MRI) has proven useful in evaluating oxygenation in several types of tissue and blood. This study evaluates brain tissue oxygenation changes between normoxia and hyperoxia in healthy subjects using dynamic T1 and T2*-weighted imaging sequences. This study concludes that T1 and T2* responses to FiO2 serve as independent biomarkers of oxygen physiology in the brain with a potential to provide quantitative information on tissue oxygenation...

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Exercise training favors increased insulin-stimulated glucose uptake in skeletal muscle in contrast to adipose tissue: A randomized study using FDG PET imaging. Reichkendler MH, Auerbach P, Rosenkilde M, Christensen AN, Holm S, Petersen MB, Lagerberg A, Larsson HBW, Rostrup E, Mosbech TH, Sjödin A, Kjaer A, Ploug T, Hoejgaard L, Stallknecht BM. Am J Physiol Endocrinol Metab. 305: E496-506, 2013. 

Physical exercise increases peripheral insulin sensitivity, but regional differences are poorly elucidated in humans. We investigated the effect of aerobic exercise training on insulin-stimulated glucose uptake in five individual femoral muscle groups and four different adipose tissue regions, using dynamic (femoral region) and static (abdominal region) 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) PET/CT methodology during steady-state insulin infusion (40 mU·m⁻²·min⁻¹). In conclusion, aerobic exercise training increases insulin-stimulated glucose uptake in skeletal muscle but not in adipose tissue, which demonstrates some interregional differences...

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Sources of variability of resting cerebral blood flow in healthy subjects: a study using ¹³³Xe SPECT measurements. Henriksen OM, Kruuse C, Olesen J, Jensen LT, Larsson HBW, Birk S, Hansen JM, Wienecke T, Rostrup E. J Cereb Blood Flow Metab. 33: 787–92, 2013. 

Measurements of cerebral blood flow (CBF) show large variability among healthy subjects. The aim of the present study was to investigate the relative effect of established factors influencing CBF on the variability of resting CBF. We retrospectively analyzed spontaneous variability in 430 CBF measurements acquired in 152 healthy, young subjects using (133)Xe single-photon emission computed tomography. The present study confirms large between-subject variability in CBF measurements and that gender, Hct, and PETCO₂ explain only a small part of this variability. This implies that a large fraction of CBF variability may be due to unknown factors such as differences in neuron density or metabolism that could be subject for further studies...

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Recommendations to improve imaging and analysis of brain lesion load and atrophy in longitudinal studies of multiple sclerosis. Vrenken H, Jenkinson M, horsfield MA, Battaglini M, Schijndel RA, Rostrup E, Geurts J, Fisher E, Zijdenbos A, Ashburner J, Miller DH, Filippi M, Fazekas F, Rovaris M, Rovira A, Barkhof F, Stefano N. Journal of Neurology. 260: 2458–71, 2013. 

Focal lesions and brain atrophy are the most extensively studied aspects of multiple sclerosis (MS), but the image acquisition and analysis techniques used can be further improved, especially those for studying within-patient changes of lesion load and atrophy longitudinally. Briefly, they are (1) images should be acquired using 3D pulse sequences, with near-isotropic spatial resolution and multiple image contrasts to allow more comprehensive analyses of lesion load and atrophy, across timepoints. Image artifacts need special attention given their effects on image analysis results. (2) Automated image segmentation methods integrating the assessment of lesion load and atrophy are desirable. (3) A standard dataset with benchmark results should be set up to facilitate development, calibration, and objective evaluation of image analysis methods for MS...

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Visual processing speed in old age. Habekost T, Vogel A, Rostrup E, Bundesen C, Kyllingsbaek S, Garde E, Ryberg C, Waldemar G. Scandinavian journal of psychology. 54: 89–94, 2013. 

Mental speed is a common concept in theories of cognitive aging, but it is difficult to get measures of the speed of a particular psychological process that are not confounded by the speed of other processes. We used Bundesen's (1990) Theory of Visual Attention (TVA) to obtain specific estimates of processing speed in the visual system controlled for the influence of response latency and individual variations of the perception threshold. Less dramatic aging effects were found for the perception threshold and the visual apprehension span. In the visual domain, cognitive aging seems to be most clearly related to reductions in processing speed...

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Prognostic value of periodic electroencephalographic discharges for neurological patients with profound disturbances of consciousness. Pedersen GL, Rasmussen SB, Gyllenborg J, Benedek K, Lauritzen M. Clin Neurophysiol. 124: 44-51, 2013. 

OBJECTIVE: To examine if periodic EEG discharges (PDs) predict poor outcome and development of epilepsy in patients with acute brain illnesses irrespective of underlying cerebral pathology. CONCLUSION: PDs predicted poor functional outcome and patients with LPDs-plus had higher risk for later development of epilepsy...

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Lactate Receptor Sites Link Neurotransmission, Neurovascular Coupling, and Brain Energy Metabolism. Lauritzen KH, Morland C, Puchades M, Holm-Hansen S, Hagelin EM, Lauritzen F, Attramadal H, Storm-Mathisen J, Gjedde A, Bergersen LH. Cereb Cortex. 2013 May 21. [Epub ahead of print]. 

The G-protein-coupled lactate receptor, GPR81 (HCA1), is known to promote lipid storage in adipocytes by downregulating cAMP levels. Here, we show that GPR81 is also present in the mammalian brain, including regions of the cerebral neocortex and hippocampus, where it can be activated by physiological concentrations of lactate and by the specific GPR81 agonist 3,5-dihydroxybenzoate to reduce cAMP. The results indicate roles of lactate in brain signaling, including a neuronal glucose and glycogen saving response to the supply of lactate. We propose that lactate, through activation of GPR81 receptors, can act as a volume transmitter that links neuronal activity, cerebral energy metabolism and energy substrate availability...

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Spontaneous calcium waves in Bergman Glia increase with age and hypoxia and may reduce tissue oxygen. Mathiesen C, Brazhe A, Thomsen K, Lauritzen, M. J Cereb Blood Flow Metab. 33: 161-9, 2013. 

Glial calcium (Ca(2+)) waves constitute a means to spread signals between glial cells and to neighboring neurons and blood vessels. These waves occur spontaneously in Bergmann glia (BG) of the mouse cerebellar cortex in vivo. Here, we tested three hypotheses: (1) aging and reduced blood oxygen saturation alters wave activity; (2) glial Ca(2+) waves change cerebral oxygen metabolism; and (3) neuronal and glial wave activity is correlated. We report that the occurrence of spontaneous waves is 20 times more frequent in the cerebellar cortex of aging as compared with adult mice, which correlated with a reduction in resting brain oxygen tension. Finally, although spontaneous Purkinje cell (PC) activity was not associated with increased glia wave activity, spontaneous glial waves did affect intracellular Ca(2+) activity in PCs. The increased wave activity during aging, as well as low resting brain oxygen tension, suggests a relationship between glial waves, brain energy homeostasis, and pathology...

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Multiscale Vision Model Highlights Spontaneous Glial Calcium Waves Recorded by 2-Photon Imaging in Brain Tissue. Brazhe A, Mathiesen C, Lauritzen M. Neuroimage. 68: 192-202, 2013. 

Intercellular glial calcium waves (GCW) constitute a signaling pathway which can be visualized by fluorescence imaging of cytosolic Ca(2+) changes. We demonstrate that the MVM identified and characterized GCWs with much higher sensitivity and detail than pixel thresholding. We conclude that the MVM provides unique possibilities to study spatiotemporally correlated Ca(2+) signaling in brain tissue...

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Increased 20-HETE synthesis explains reduced cerebral blood flow but not impaired neurovascular coupling after cortical spreading depression in rat cerebral cortex. Fordsmann J, Ko R, Choi H, Thomsen K, Witgen B, Mathiesen C, Lønstrup M, Henning Piilgaard, MacVicar B, Lauritzen M. J Neuroscience. 33: 2562-70, 2013. 

Cortical spreading depression (CSD) is associated with release of arachidonic acid, impaired neurovascular coupling, and reduced cerebral blood flow (CBF), caused by cortical vasoconstriction. We tested the hypothesis that the released arachidonic acid is metabolized by the cytochrome P450 enzyme to produce the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE), and that this mechanism explains cortical vasoconstriction and vascular dysfunction after CSD. We suggest that blockade of 20-HETE synthesis may be clinically relevant to ameliorate reduced CBF in patients with migraine and acute brain cortex injuries...

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Integrated measurements of electrical activity, oxygen tension, blood flow and Ca2+-signaling in rodent in vivo. In: Brain Energy Metabolism. Mathiesen C, Lauritzen M. Eds. Hirrlinger J, WaagePetersen, HS, Humana Press, in press, 2013. 

Resume: In order to assess perfusion and metabolic responses in relation to neural function we need to know the cellular signaling network, which types of neurons and astrocytes are involved, and the timing of their activation. We here present the basic electrophysiological indicators of neuronal function, short description of the methods commonly used for recording of electrophysiological signals, examples of data analysis and limitations of the methods. This chapter describes the origin of the extracellularly recorded electrical signal, with special regard to the EEG, local field potentials, and spikes in rodent preparation. We also describe methods for recording of cerebral blood flow (CBF), tissue partial pressure of oxygen (tpO2), and cytosolic calcium transients. We finally give examples where electrophysiology, blood flow, metabolism, and calcium transients have been studied together.

Neurovascular coupling in relation to cortical spreading depression. In: Neurovascular Coupling Methods. Piilgaard H, Lauritzen M. Editor: Schwartz TW, Humana Press, in press 2013.

Unaltered lactate and glucose transporter levels in the MPTP mouse model of Parkinson's disease. Puchades M, Sogn CJ, Maehlen J, Bergersen LH, Gundersen V. J Parkinsons Dis. 2013 Jan 1;3(3):371-85. 

BACKGROUND: Metabolic impairment contributes to development of Parkinson's disease (PD). Mitochondrial dysfunction is involved in degeneration of nigral dopamine neurons. Also, in PD there are alterations in glucose metabolism in nigro-striatal pathways, and increased cerebral lactate levels have been found. DISCUSSION: This is the first study reporting on the distribution of metabolic transporters in PD. Our results suggest that, although there are metabolic impairments in PD, the levels of MCT1, MCT2 and GLUT1 is not changed following dopaminergic neurodegeneration. This is in contrast to findings in other neurodegenerative disease, such as mesial temporal lobe epilepsy, where there are large alterations in MCT levels...

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Lactate Receptor Sites Link Neurotransmission, Neurovascular Coupling, and Brain Energy Metabolism. Lauritzen KH, Morland C, Puchades M, Holm-Hansen S, Hagelin EM, Lauritzen F, Attramadal H, Storm-Mathisen J, Gjedde A, Bergersen LH. Cereb Cortex. 2013 May 21. [Epub ahead of print]. 

The G-protein-coupled lactate receptor, GPR81 (HCA1), is known to promote lipid storage in adipocytes by downregulating cAMP levels. Here, we show that GPR81 is also present in the mammalian brain, including regions of the cerebral neocortex and hippocampus, where it can be activated by physiological concentrations of lactate and by the specific GPR81 agonist 3,5-dihydroxybenzoate to reduce cAMP. The results indicate roles of lactate in brain signaling, including a neuronal glucose and glycogen saving response to the supply of lactate. We propose that lactate, through activation of GPR81 receptors, can act as a volume transmitter that links neuronal activity, cerebral energy metabolism and energy substrate availability...

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Monocarboxylate transporters in temporal lobe epilepsy: roles of lactate and ketogenic diet. Lauritzen F, Eid T, Bergersen LH. Brain Struct Funct. 2013 Nov 19. [Epub ahead of print]. 

Epilepsy is a serious neurological disorder that affects approximately 1 % of the general population, making it one of the most common disorders of the central nervous system. In this review, we will discuss some of the current hypotheses regarding the possible causal relationship between brain energy metabolism and TLE...

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Rapid stimulus-evoked astrocyte Ca2+ elevations and hemodynamic responses in mouse somatosensory cortex in vivo. Lind BL, Brazhe AR, Jessen SB, Tan FC, Lauritzen MJ. Proc Natl Acad Sci U S A. 110: E4678-87, 2013. 

Increased neuron and astrocyte activity triggers increased brain blood flow, but controversy exists over whether stimulation-induced changes in astrocyte activity are rapid and widespread enough to contribute to brain blood flow control. Here, we provide evidence for stimulus-evoked Ca(2+) elevations with rapid onset and short duration in a large proportion of cortical astrocytes in the adult mouse somatosensory cortex. These data establish that a large proportion of cortical astrocytes have brief Ca(2+) responses with a rapid onset in vivo, fast enough to initiate hemodynamic responses or influence synaptic activity...

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DNA damage response, bioenergetics, and neurological disease: the challenge of maintaining brain health in an aging human population. Rasmussen LJ, Shiloh Y, Bergersen LH, Sander M, Bohr VA, Tønjum T. Mech Ageing Dev. 2013 Oct;134(10):427-33. 

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White matter lactate - Does it matter? Rinholm JE, Bergersen LH. Neuroscience. 2013 Oct 12. pii: S0306-4522(13)00846-4. 

About half of the human brain is white matter, characterized by axons covered in myelin, which facilitates the high speed of nerve signals from one brain area to another. During brain development, the oligodendrocytes may use lactate as an alternative source of energy and material for myelin formation. Mature oligodendrocytes, however, can release lactate through the myelin sheath as nutrient for axons. In addition, lactate carries signals as a volume transmitter. Myelin thus seems to serve as a provider of substrates and signals for axons, and not as a mere insulator. We review the fluxes of lactate in white matter and their significance in brain function...

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Natural selection of mitochondria during somatic lifetime promotes healthy aging. Rodell A, Rasmussen LJ, Bergersen LH, Singh KK, Gjedde A. Front Neuroenergetics. 2013 Aug 12;5:7. doi: 0.3389/fnene.2013.00007. eCollection 2013. 

Stimulation of mitochondrial biogenesis during life-time challenges both eliminates disadvantageous properties and drives adaptive selection of advantageous phenotypic variations. We propose that intermittent purposeful enhancement of mitochondrial biogenesis by stressful episodes with subsequent recovery paradoxically promotes adaptive mitochondrial health and continued healthy aging...

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The changing brain--insights into the mechanisms of neural and behavioral adaptation to the environment. Bergersen LH, Bramham CR, Hugdahl K, Sander M, Storm-Mathisen J. Neuroscience. 2013 Sep 5;247:412-22. 

Deep sequencing analysis of the neuropil transcriptome indicates that a large fraction of the synapticproteome is synthesized in situ in axons and dendrites, permitting local regulation (Schuman). Maternal behavior can cause changes in gene expression that stably modify behavior in the offspring (Meaney). Removal of a single sensory channel protein in the vomero-nasal organ can switch off male-specific and switch on female-specific innate behavior of mice in response to environmental stimulation (Dulac). Innate behaviors can be stably transmitted from parent to offspring through generations even when those behaviors cannot be expressed, as illustrated by the elaborate burrowing behavior in a rodent species, in which independent genetic regions regulate distinct modules of the burrowing pattern (Hoekstra). Finally, at the other extreme of the nature-nurture scale, functional magnetic resonance imaging (fMRI) analysis in children and adults identified a brain area specifically involved in reading (Dehaene)...

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Low dopamine D5 receptor density in hippocampus in an animal model of attention-deficit/hyperactivity disorder (ADHD). Medin T, Rinholm JE, Owe SG, Sagvolden T, Gjedde A, Storm-Mathisen J, Bergersen LH. Neuroscience. 2013 Jul9;242:11-20.

A state of low dopaminergic activity has been implicated in attention-deficit/hyperactivity disorder (ADHD). To determine dopamine receptor (DR) density in a well-established animal model for ADHD, we quantified the dopamine D5 receptors in the hippocampus in the spontaneously hypertensive rat. DRs are important for long-term potentiation and long-term depression, hence the deficit may contribute to the learning difficulties in individuals with the diagnosis of ADHD...

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 Program 2 - Molecular and Cellular: Muscle and MatrixTil toppen

Coronary flow reserve predicts cardiopulmonary fitness in patients with coronary artery disease independently of systolic and diastolic function. Snoer, M, Olsen, RH, Monk-Hansen, T, Pedersen, LR, Haugaard, SB, Dela, F, Prescott, E. Echocardiography 2013 Dec [Epub ahead of print]. 

AIMS: Despite revascularization and optimal medical treatment, patients with coronary artery disease (CAD) have reduced exercise capacity. In the absence of coronary artery stenosis, coronary flow reserve (CFR) is a measure of coronary microvascular function, and a marker of future poor outcome in CAD patients. The aim of this study was to examine the relationship among CFR, systolic and diastolic function, peripheral vascular function, and cardiopulmonary fitness in CAD patients. CONCLUSIONS: Coronary flow reserve measured noninvasively predicts cardiopulmonary fitness independently of resting systolic and diastolic function in CAD patients, indicating that cardiac output during maximal exercise is dependent on the ability of the coronary circulation to adapt to the higher metabolic demands of the myocardium...

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Akt and Rac1 signaling are jointly required for insulin-stimulated glucose uptake in skeletal muscle and downregulated in insulin resistance. Sylow, L, Kleinert, M, Pehmoller, C, Prats, C, Chiu, TT, Klip, A, Richter, EA, Jensen, TE. Cell Signal Nov 9;26(2):323-331, 2013. 

Skeletal muscle plays a major role in regulating whole body glucose metabolism. Akt and Rac1 are important regulators of insulin-stimulated glucose uptake in skeletal muscle. Here we delineate how Akt and Rac1 pathways signal to increase glucose transport independently of each other and are simultaneously downregulated in insulin resistant muscle. These findings suggest that Rac1 and Akt regulate insulin-stimulated glucose uptake via distinct parallel pathways, and that insulin-induced Rac1 and Akt signaling are both dysfunctional in insulin resistant muscle. There may thus be multiple treatment targets for improving insulin sensitivity in muscle...

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Combined heart rate- and accelerometer-assessed physical activity energy expenditure and associations with glucose homeostasis markers in a population at high risk of developing diabetes: the ADDITION-PRO study. Hansen, AL, Carstensen, B, Helge, JW, Johansen, NB, Gram, B, Christiansen, JS, Brage, S, Lauritzen, T, Jorgensen, ME, Aadahl, M, Witte, DR. Diabetes Care 36: 3062-3069, 2013. 

OBJECTIVE: Regular physical activity (PA) reduces the risk of developing type 2 diabetes, and different subtypes of dysglycemia have shown different associations with PA. To better understand the associations of PA and glucose homeostasis, we examined the association of objectively measured PA energy expenditure (PAEE) with detailed measures of glucose homeostasis. CONCLUSIONS: Even in an elderly population with low levels of PA, we found higher objectively measured PAEE levels to be associated with a more beneficial glucose metabolic profile. Although our findings are cross-sectional, they indicate that even without high-intensity exercise, increasing the overall level of PAEE slightly in an entire population at risk for developing type 2 diabetes may be a realistic and worthwhile goal to reach in order to achieve beneficial effect in terms of glucose metabolism...

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 An optimized histochemical method to assess skeletal muscle glycogen and lipid stores reveals two metabolically distinct populations of type I muscle fibers. Prats, C, Gomez-Cabello, A, Nordby, P, Andersen, JL, Helge, JW, Dela, F, Baba, O, Ploug, T. PLoS One. 8:e77774, 2013. 

Skeletal muscle energy metabolism has been a research focus of physiologists for more than a century. Here we review the "pros and cons" of previously used histochemical methods and describe an optimized method to ensure the preservation and specificity of detection of both intramyocellular carbohydrate and lipid stores...

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Increased intrinsic mitochondrial function in humans with mitochondrial haplogroup H. Larsen, S, Díez-Sánchez, C, Rabøl, R, Royo, IA, Dela, F, Helge, JW. Biochim Biophys Acta. 2014 Feb;1837(2):226-31 (accepted 2013). 

It has been suggested that human mitochondrial variants influence maximal oxygen uptake (VO2max). We recruited 54 males and determined their mitochondrial haplogroup, mitochondrial oxidative phosphorylation capacity (OXPHOS), mitochondrial content (citrate synthase (CS)) and VO2max. There was no relationship between haplogroups and VO2max. In skeletal muscle from men with mitochondrial haplogroup H, an increased intrinsic mitochondrial function is present...

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The best approach: Homogenization or manual permeabilization of human skeletal muscle fibers for respirometry? Larsen, S, Kraunsøe, R, Gram, M, Gnaiger, E, Helge, JW, Dela, F. Anal Biochem. 2014 Feb 1;446:64-8 (accepted 2013). 

We investigated whether the PBI shredder is useful in preparing a muscle homogenate for measurements of mitochondrial respiratory capacity. The homogenate is compared with the Pfi preparation. Maximal respiratory capacity was significantly reduced in the homogenate compared with the Pfi from human skeletal muscle. A marked cytochrome c response was observed in the homogenate, which was not the case with the Pfi, indicating that the outer mitochondrial membrane was not intact. The mitochondria in the homogenate were more uncoupled compared with the Pfi. Manual permeabilization is an advantageous technique for preparing human skeletal muscle biopsies for respirometry...

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Physical inactivity affects skeletal muscle insulin signaling in a birth weight-dependent manner. Mortensen B, Friedrichsen, M, Andersen, NR, Alibegovic, AC, Højbjerre, L, Sonne, MP, Stallknecht, B, Dela, F, Wojtaszewski, JF, Vaag, A. J Diabetes Complications. 2014 Jan-Feb;28(1):71-8 (accepted in 2013). 

AIMS: We investigated whether physical inactivity could unmask defects in insulin and AMPK signaling in low birth weight (LBW) subjects. CONCLUSIONS: Bed rest-induced insulin resistance is not explained by impaired muscle insulin or AMPK signaling in subjects with or without LBW. Lower muscle insulin signaling in LBW subjects post bed rest despite similar degree of insulin resistance as seen in controls may to some extent support the idea that LBW subjects are at higher risk of developing type 2 diabetes when being physically inactive...

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The association between physical activity, cardiorespiratory fitness and self-rated health. Eriksen, L, Curtis, T, Grønbæk, M, Helge, JW, Tolstrup JS. Prev Med. 57(6): 900-2, 2013. 

OBJECTIVE: To investigate the joint association between self-reported physical activity as well as cardiorespiratory fitness and self-rated health among healthy women and men. CONCLUSION: Although reluctant to conclude on causality, this study suggests that an active lifestyle as well as good cardiorespiratory fitness probably increase self-rated health...

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Muscle strength and physical activity are associated with self-rated health in an adult Danish population. Hansen, AW, Beyer, N, Flensborg-Madsen, T, Grønbæk, M, Helge JW. Prev Med. 57(6):792-8, 2013. 

OBJECTIVE: To describe associations of muscle strength, physical activity and self-rated health. CONCLUSION: The combined score for physical activity level with either HGS or 30s-CS was strongly positively associated with self-related health...

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Effect of lifelong resveratrol supplementation and exercise training on skeletal muscle oxidative capacity in aging mice; impact of PGC-1alpha. Ringholm, S, Olesen, J, Pedersen, JT, Brandt, CT, Halling, JF, Hellsten, Y, Prats, C, Pilegaard, H. Exp Gerontol. 48: 1311-1318, 2013. 

BACKGROUND: The present study tested the hypothesis that lifelong resveratrol (RSV) supplementation counteracts an age-associated decrease in skeletal muscle oxidative capacity through peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and that RSV combined with lifelong exercise training (EX) exerts additive effects through PGC-1α in mice. CONCLUSION: Lifelong EX increased activity/content of oxidative proteins, mtDNA and angiogenic proteins in skeletal muscle through PGC-1α, while RSV supplementation alone had no effect. Combining lifelong EX and RSV supplementation had no additional effect on skeletal muscle oxidative and angiogenic proteins...

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Meal induced gut hormone secretion is altered in aerobically trained compared to sedentary young healthy males. Lund, MT, Taudorf, L, Hartmann, B, Helge, JW, Holst, JJ, Dela, F. Eur J Appl Physiol. 113: 2737-2747, 2013. 

Postprandial insulin release is lower in healthy aerobically trained (T) compared to untrained (UT) individuals. This may be mediated by a lower release of the two incretin hormones [glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] in T. The aim of this study was to assess and compare gut hormone response and satiety changes after a liquid meal intake in young, healthy T and UT males...

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Ethnic differences in leptin and adiponectin levels between Greenlandic Inuit and Danish children. Munch-Andersen, T, Sorensen, K, Aachmann-Andersen, NJ, Aksglaede, L, Juul, A, Helge, JW. Int J Circumpolar Health. 72. 2013.

OBJECTIVE: In a recent study, we found that Greenlandic Inuit children had a more adverse metabolic profile than Danish children. Aerobic fitness and adiposity could only partly account for the differences. Therefore, we set out to evaluate and compare plasma leptin and adiponectin levels in Danish and Inuit children. CONCLUSIONS: In contrast to our hypothesis, plasma leptin was higher in Danish children despite a more healthy metabolic profile compared to Inuit children. As expected, plasma adiponectin was lowest in Inuit children with the most adverse metabolic profile...

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Physical inactivity and muscle oxidative capacity in humans. Gram, M, Dahl, R, Dela, F. Eur J Sport Sci. 2013 Aug 1. [Epub ahead of print]. 

Physical inactivity is associated with a high prevalence of type 2 diabetes and is an independent predictor of mortality. This short review will cover the present literature on the effects of different models of inactivity on muscle oxidative capacity in humans. Furthermore, even though a large body of literature reports the effect of physical training on muscle oxidative capacity, the adaptations that occur with physical inactivity may not always be opposite to that of physical training. Thus, it is concluded that studies on the effect of physical inactivity per se on muscle oxidative capacity in functional human skeletal muscle are warranted...

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Improved glucose tolerance after high-load strength training in patients undergoing dialysis. Molsted, S, Harrison, AP, Eidemak, I, Dela, F, Andersen, JL. Nephron Clin Pract 123: 134-141, 2013. 

BACKGROUND/AIMS: The aim of this controlled study was to investigate the effect of high-load strength training on glucose tolerance in patients undergoing dialysis. CONCLUSION: The conducted strength training was associated with a significant improvement in glucose tolerance in patients with impaired glucose tolerance or type 2 diabetes undergoing dialysis. The effect was apparently not associated with muscle hypertrophy, whereas the muscle fiber type composition was changed...

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Contraction-induced lipolysis is not impaired by inhibition of hormone-sensitive lipase in skeletal muscle. Alsted, TJ, Ploug, T, Prats, C, Serup, AK, Hoeg, L, Schjerling, P, Holm, C, Zimmermann, R, Fledelius, C, Galbo, H, Kiens, B. J Physiol. 591: 5141-5155, 2013. 

In skeletal muscle hormone-sensitive lipase (HSL) has long been accepted to be the principal enzyme responsible for lipolysis of intramyocellular triacylglycerol (IMTG) during contractions. We investigated lipolysis of IMTG in soleus muscles electrically stimulated to contract ex vivo during acute pharmacological inhibition of HSL in rat muscles and in muscles from HSL knockout (HSL-KO) mice. The present study is the first to demonstrate that contraction-induced lipolysis of IMTG occurs in the absence of HSL activity in rat and mouse skeletal muscle. Furthermore, the results suggest that ATGL is activated and plays a major role in lipolysis of IMTG during muscle contractions...

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Glucose-dependent insulinotropic polypeptide has impaired effect on abdominal, subcutaneous adipose tissue metabolism in obese subjects. Asmar, M, Simonsen, L, Arngrim, N, Holst, JJ, Dela, F, Bülow, J. Int J Obes (Lond). 2014 Feb;38(2):259-65 (accepted 2013). 

Objective: Glucose-dependent insulinotropic polypeptide (GIP) appears to have a role in lipid metabolism. Recently, we showed that GIP in combination with hyperinsulinemia and hyperglycemia increases triglyceride uptake in abdominal, subcutaneous adipose tissue in lean humans. It has been suggested that increased GIP secretion in obesity will promote lipid deposition in adipose tissue. In light of the current attempts to employ GIP antagonists in the treatment and prevention of human obesity, the present experiments were performed in order to elucidate whether the adipose tissue lipid metabolism would be enhanced or blunted during a GIP, hyperinsulinemic and hyperglycemic (HI-HG) clamp in obese subjects with either normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). Conclusion: The applied GIP, HI-HG clamp did not induce any changes in TAG uptake in adipose tissue in obese subjects. This may be due to a blunted increase in ATBF. These experiments therefore suggest that GIP does not have a major role in postprandial lipid metabolism in obese subjects...

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Subcellular localization and mechanism of secretion of vascular endothelial growth factor in human skeletal muscle. Hoier, B, Prats, C, Qvortrup, K, Pilegaard, H, Bangsbo, J, Hellsten, Y. FASEB J. 27: 3496-3504, 2013. 

The subcellular distribution and secretion of vascular endothelial growth factor (VEGF) was examined in skeletal muscle of healthy humans. TEM and CM analysis revealed two primary sites of localization of VEGF: in vesicles located in the subsarcolemmal regions and between the contractile elements within the muscle fibers; and in pericytes situated on the skeletal muscle capillaries. This study provides the first evidence in humans for a mechanism by which skeletal muscle fibers can control capillary growth by releasing VEGF from intracellular vesicles during contraction...

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Adverse metabolic risk profiles in Greenlandic Inuit children compared to Danish children. Munch-Andersen, T, Sorensen, K, Andersen, A.L., Aachmann-Andersen, NJ, Aksglaede, L, Juul, A, Helge, JW. Obesity (Sliver Spring). 21: 1226-1231, 2013. 

OBJECTIVE: During recent decades, the prevalence of metabolic morbidity has increased rapidly in adult Greenlandic Inuit. To what extent this is also reflected in the juvenile Inuit population is unknown. The objective was, therefore, in the comparison with Danish children, to evaluate metabolic profiles in Greenlandic Inuit children from the capital in the southern and from the northern most villages. CONCLUSIONS: Greenlandic Inuit children had adverse metabolic health profile compared to the Danish children, the differences where more pronounced in Inuit children living in Nuuk. The tendencies toward higher prevalence of diabetes and metabolic morbidity in the adult Greenlandic Inuit population may also be present in the Inuit children population...

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Influence of erythropoietin on cognitive performance during experimental hypoglycemia in patients with type 1 diabetes mellitus: a randomized cross-over trial. Kristensen, PL, Pedersen-Bjergaard, U, Kjær, TW, Olsen, NV, Dela, F, Holst, JJ, Faber, J, Tarnow, L, Thorsteinsson, B. PLoS One. 8: e59672, 2013.

INTRODUCTION: The incidence of severe hypoglycemia in type 1 diabetes has not decreased over the past decades. New treatment modalities minimizing the risk of hypoglycemic episodes and attenuating hypoglycemic cognitive dysfunction are needed. We studied if treatment with the neuroprotective hormone erythropoietin (EPO) enhances cognitive function during hypoglycemia. CONCLUSION: In patients with type 1 diabetes and hypoglycemia unawareness, treatment with EPO is associated with a beneficial effect on cognitive function in a complex reaction time task assessing sustained attention/working memory. Hypoglycemic symptoms and hormonal responses were not changed by EPO treatment...

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Adipocyte size and cellular expression of caveolar proteins analyzed by confocal microscopy. Hulstrom, V, Prats, C, Vinten, J. Am J Physiol Cell Physiol. 304: C1168-C1175, 2013. 

Caveolae are abundant in adipocytes and are involved in the regulation of lipid accumulation, which is the main volume determinant of these cells. We have developed and applied a confocal microscopic technique for measuring individual cellular expression of the caveolar proteins cavin-1 and caveolin-1 along with the size of individual adipocytes...

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Impaired mitochondrial function in chronically ischemic human heart. Stride, N, Larsen, S, Hey-Mogensen, M, Hansen, CN, Prats, C, Steinbruchel, D, Kober, L, Dela, F. Am J Physiol Heart Circ Physiol. 304: H1407-H1414, 2013. 

Chronic ischemic heart disease is associated with myocardial hypoperfusion. The resulting hypoxia potentially inflicts damage upon the mitochondria, leading to a compromised energetic state. We hypothesized that mitochondrial respiratory capacity would be diminished in chronic ischemic regions of human myocardium but that these mitochondria would be more resistant to ex vivo ischemia and, second, that ROS generation would be higher in ischemic myocardium. The aim of this study was to test mitochondrial respiratory capacity during hyperoxia and hypoxia, to investigate ROS production, and finally to assess myocardial antioxidant levels...

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Rac1 signaling is required for insulin-stimulated glucose uptake and is dysregulated in insulin-resistant murine and human skeletal muscle. Sylow, L, Jensen, TE, Kleinert, M, Hojlund, K, Kiens, B, Wojtaszewski, J, Prats, C, Schjerling, P, Richter, EA. Diabetes 62: 1865-1875, 2013. 

The actin cytoskeleton-regulating GTPase Rac1 is required for insulin-stimulated GLUT4 translocation in cultured muscle cells. We hypothesized that Rac1 and its downstream target, p21-activated kinase (PAK), are regulators of insulin-stimulated glucose uptake in mouse and human skeletal muscle and are dysregulated in insulin-resistant states. In humans, insulin-stimulated PAK activation was decreased in both acute insulin-resistant (intralipid infusion) and chronic insulin-resistant states (obesity and diabetes). These findings show that Rac1 is a regulator of insulin-stimulated glucose uptake and a novel candidate involved in skeletal muscle insulin resistance...

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Validation of an Internet-Based Long Version of the International Physical Activity Questionnaire in Danish Adults Using Combined Accelerometry and Heart Rate Monitoring. Hansen, AW, Dahl-Petersen, I, Helge, JW, Brage, S, Grønbæk, M, Flensborg-Madsen, T. J Phys Act Health. 2013 Feb 8. Epub ahead of print, accepted. 

BACKGROUND: The International Physical Activity Questionnaire (IPAQ) is commonly used in surveys but reliability and validity has not been established in the Danish population. CONCLUSIONS: This Danish Internet-based version of the long IPAQ had modest validity and reliability when assessing PAEE at population level...

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LKB1 regulates lipid oxidation during exercise independently of AMPK. Jeppesen, J, Maarbjerg, SJ, Jordy, AB, Fritzen, AM, Pehmoller, C, Sylow, L, Serup, AK, Jessen, N, Thorsen, K, Prats, C, Qvortrup, K, Dyck, JR, Hunter, RW, Sakamoto, K, Thomson, DM, Schjerling, P, Wojtaszewski, JF, Richter, EA, Kiens, B. Diabetes. 62: 1490-1499, 2013. 

Lipid metabolism is important for health and insulin action, yet the fundamental process of regulating lipid metabolism during muscle contraction is incompletely understood. Here, we show that liver kinase B1 (LKB1) muscle-specific knockout (LKB1 MKO) mice display decreased fatty acid (FA) oxidation during treadmill exercise...

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Two weeks of metformin treatment enhances mitochondrial respiration in skeletal muscle of AMPK kinase dead but not wild type mice. Kristensen, JM, Larsen, S, Helge, JW, Dela, F, Wojtaszewski, JF. PLoS One. 8: 353533, 2013.

Metformin is used as an anti-diabetic drug. Metformin ameliorates insulin resistance by improving insulin sensitivity in liver and skeletal muscle. We hypothesized that potential effects of in vivo metformin treatment on mitochondrial function and protein expressions in skeletal muscle are dependent upon AMPK signaling. We conclude that two weeks of in vivo metformin treatment enhances mitochondrial respiration in the mitochondrial deficient AMPK KD but not WT mice. The improvement seems to be unrelated to AMPK, and does not involve changes in key mitochondrial proteins...

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Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance. Larsen, S, Stride, N, Hey-Mogensen, M, Hansen, CN, Bang, LE, Bundgaard, H, Nielsen, LB, Helge, JW, Dela, F. J Am Coll Cardiol. 61: 44-53, 2013. 

OBJECTIVES: Glucose tolerance and skeletal muscle coenzyme Q(10) (Q(10)) content, mitochondrial density, and mitochondrial oxidative phosphorylation (OXPHOS) capacity were measured in simvastatin-treated patients (n = 10) and in well-matched control subjects (n = 9). CONCLUSIONS: These simvastatin-treated patients were glucose intolerant. A decreased Q(10) content was accompanied by a decreased maximal OXPHOS capacity in the simvastatin-treated patients. It is plausible that this finding partly explains the muscle pain and exercise intolerance that many patients experience with their statin treatment...

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Rac1 is a novel regulator of contraction-stimulated glucose uptake in skeletal muscle. Sylow, L, Jensen, TE, Kleinert, M, Mouatt, JR, Maarbjerg, SJ, Jeppesen, J, Prats, C, Chiu, TT, Boguslavsky, S, Klip, A, Schjerling, P, Richter, EA. Diabetes. 62: 1139-1151, 2013. 

In skeletal muscle, the actin cytoskeleton-regulating GTPase, Rac1, is necessary for insulin-dependent GLUT4 translocation. Muscle contraction increases glucose transport and represents an alternative signaling pathway to insulin. These are the first data to show that Rac1 is activated during muscle contraction in murine and human skeletal muscle and suggest that Rac1 and possibly the actin cytoskeleton are novel regulators of contraction-stimulated glucose uptake...

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Coronary flow reserve as a link between diastolic and systolic function and exercise capacity in heart failure. Snoer, M, Monk-Hansen, T, Olsen, RH, Pedersen, LR, Nielsen, OW, Rasmusen, H, Dela, F, Prescott, E. Eur Heart J Cardiovasc Imaging 14: 677-683, 2013. 

AIMS: In heart failure, a reduced exercise capacity is the prevailing symptom and an important prognostic marker of future outcome. The purpose of the study was to assess the relation of coronary flow reserve (CFR) to diastolic and systolic function in heart failure and to determine which are the limiting factors for exercise capacity. CONCLUSION: In this group of heart failure patients, VO2 peak was correlated with CFR, E/e', and s' but not with traditional measures of systolic function. CFR remained associated with VO2 peak independently of diastolic and systolic function and is likely to be a limiting factor in functional capacity of heart failure patients...

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Immobilization increases interleukin-6, but not tumour necrosis factor-alpha, release from the leg during exercise in humans. Reihmane, D, Hansen, AV, Gram, M, Kuhlman, AB, Nørregaard, J, Pedersen, HP, Lund, MT, Helge, JW, Dela, F. Exp Physiol 98: 778-783, 2013. 

Data on interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) release during acute exercise are not conclusive, and information is lacking about the impact of physical inactivity. We have now studied the temporal relationship of leg IL-6 and TNF-α release before and during isolated two-legged exercise after 14 days of one-leg immobilization (IM) while the other leg served as the control (CON) leg. In conclusion, prior immobilization enhances release of IL-6 from the leg during exercise at a moderate workload, and the release is already present in the early phase of exercise. Neither immobilization nor exercise had an effect on TNF-α release in the working legs...

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Decreased mitochondrial oxidative phosphorylation capacity in the human heart with left ventricular systolic dysfunction. Stride, N, Larsen, S, Hey-Mogensen, M, Sander, K, Lund, JT, Gustafsson, F, Kober L, Dela, F. Eur J Heart Fail. 15: 150-157, 2013. 

AIMS: Heart failure (HF) with left ventricular systolic dysfunction (LVSD) is associated with a shift in substrate utilization and a compromised energetic state. Whether these changes are connected with mitochondrial dysfunction is not known. We hypothesized that the cardiac phenotype in LVSD could be caused by reduced mitochondrial oxidative phosphorylation (OXPHOS) capacity and reduced mitochondrial creatine kinase (miCK) capacity. The study aim was to test mitochondrial OXPHOS capacity in LVSD myocardium compared with OXPHOS capacity in a comparable patient group without LVSD. stimulation of OXPHOS from octanoyl-l-carnitine titrations elicited ∼40% lower respiration in LVSD compared with CONTROL (P ≤ 0.05). CONCLUSION: Human LVSD is associated with markedly diminished OXPHOS capacity, particularly in MCFA oxidation. This offers a candidate mechanism for a compromised energetic state and decreased reliance on fatty acid utilization in HF...

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Insulin resistance and mitochondrial function in skeletal muscle. Dela, F, Helge, JW. Int J Biochem Cell Biol. 45: 11-15, 2013. 

The mechanism(s) behind the decreased ability of insulin to facilitate glucose uptake in insulin sensitive tissues as seen in type 2 diabetes is not resolved. With the rapidly increasing prevalence of this disease world-wide, and the many complications that follow the disease, large resources are used in the attempt to resolve the mechanisms of insulin resistance. In this context, a dysfunction of mitochondria in the skeletal muscle has been suggested to play a pivotal role. In this review we will present the prevailing view-points and argue for the unlikelihood of this scenario being instrumental in human insulin resistance...

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Increase in IL-6, TNF-alpha, and MMP-9, but not sICAM-1, concentrations depends on exercise duration. Reihmane, D, Jurka, A, Tretjakovs, P, Dela, F. Eur J Appl Physiol. 113: 851-858, 2013. 

It has been suggested that exercise intensity is of importance in the regulation of increase in pro-inflammatory molecules, but there is still a debate about the effect of duration on these molecules. Therefore, the effect of exercise duration on the serum concentrations of interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), soluble form of intercellular adhesion molecule-1 (sICAM-1), and matrix metalloproteinase-9 (MMP-9) was studied in 22 half-marathon (HM) and 18 marathon (M) male amateur runners who completed their exercise task in 1.8 ± 0.2 (mean ± standard deviation) and 3.6 ± 0.4 h, respectively (thus, average speed was 11.7 ± 1.5 and 11.9 ± 1.8 km h(-1), respectively)...

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Ceramide content is higher in type I compared to type II fibers in obesity and type 2 diabetes mellitus. Kristensen, D, Prats, C, Larsen, S, Ara, I, Dela, F, Helge, JW. Acta Diabetol. 50: 705-712, 2013. 

This study investigated fiber-type-specific muscle ceramide content in obese subjects and type 2 diabetes patients. Two substudies, one which compared type 2 diabetes patients to both lean- and obese BMI-matched subjects and the other study which compared lean body-matched post-obese, obese, and control subjects, were performed...

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The incretin effect does not differ in trained and untrained, young, healthy men. Lund MT, Dalby S, Hartmann B, Helge JW, Holst JJ, Dela F. Acta Physiol (Oxf). 2013 Dec 20. Epub ahead of print, accepted. 

AIM: After both oral and intravenous glucose administration, peripheral insulin concentrations are lower in trained compared with untrained humans. Part of this is explained by an adaptation within the β-cell. The insulin secretion rate is higher after oral compared with intravenous glucose administration due to the release of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) enhancing the glucose-induced insulin secretion (the incretin effect). Our aim was to investigate whether GIP or GLP-1 release or the incretin effect was different in trained compared with untrained humans after oral and intravenous glucose administration. CONCLUSION: With no difference in incretin effect and insulin clearance between the two groups, the lower plasma insulin concentrations found in trained compared with untrained, young, healthy men are most likely explained by lower β-cell sensitivity to glucose and enhanced glucose uptake in skeletal muscle in the former group...

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Relationships between human vitality and mitochondrial respiratory parameters, reactive oxygen species production and dNTP levels in peripheral blood mononuclear cells. Maynard S, Keijzers G, Gram M, Desler C, Bendix L, Budtz-Jorgensen E, Molbo D, Croteau DL, Osler M, Stevnsner T, Rasmussen LJ, Dela F, Avlund K, Bohr VA. Aging (Albany NY). 2013 Nov;5(11):850-64. 

Low vitality (a component of fatigue) in middle-aged and older adults is an important complaint often identified as a symptom of a disease state or side effect of a treatment. We found that vitality score had no association with any of the mitochondrial respiration parameters. However, vitality score was inversely associated with cellular ROS production and cellular deoxythymidine triphosphate (dTTP) levels and positively associated with deoxycytidine triphosphate (dCTP) levels. We conclude that self-reported persistent low vitality is not associated with specific aspects of mitochondrial oxidative phosphorylation capacity in PBMCs, but may have other underlying cellular dysfunctions that contribute to dNTP imbalance and altered ROS production...

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Myogenic, matrix, and growth factor mRNA expression in human skeletal muscle: effect of contraction intensity and feeding. Agergaard, J, Reitelseder S, Pedersen, TG, Doessing, S, Schjerling, P, Langberg, H, Miller, BF, Aagaard, P, Kjaer, M, Holm, L. Muscle and Nerve 47: 748-59, 2013. 

INTRODUCTION: We examined short-term (3-hour) and long-term (12-week) training effects after heavy load [HL; 70% 1RM] and light load (LL; 16% 1RM) exercise. CONCLUSIONS: Resistance exercise at LL and HL elevated the expression of genes involved in skeletal muscle hypertrophy, although the greatest response was from HL. However, no long-term effect from either LL or HL resistance exercise was seen on basal levels of the mRNA targets...

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Direct effects of TNF-a on fuel metabolism and cytokine levels in the placebo controlled bilaterally infused human leg: increased insulin sensitivity, increased net protein breakdown and increased IL-6 release. Bach, E, Nielsen, RR, Vendelbo, MH, Møller, AB, Jessen, N, Buhl, M, Hafstrøm, TK, Holm, L, Pedersen, SB, Pilegaard, H, Biensø, RS, Jørgensen, JOL, Møller, N. Diabetes 62: 4023-9, 2013. 

Tumor necrosis factor-α (TNF-α) has widespread metabolic actions. Systemic TNF-α administration, however, generates a complex hormonal and metabolic response. Our study was designed to test whether regional, placebo-controlled TNF-α infusion directly affects insulin resistance and protein breakdown...

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The anabolic potential of dietary protein intake on skeletal muscle is prolonged by prior light-load exercise. Bechshoeft, R, Dideriksen, KJ, Reitelseder, S, Scheike, T, Kjaer, M, Holm, L. Clinical Nutrition 32: 236-244, 2013.

BACKGROUND & AIMS: Hyperaminoacidemia stimulates myofibrillar fractional synthesis rate (myoFSR) transiently in resting skeletal muscle. We investigated whether light-load resistance exercise can extent this responsiveness. CONCLUSIONS: Compared to rest, light-load exercise prolonged the stimulatory effect of dietary protein on muscle biosynthesis providing perspectives for a muscle restorative effect in clinical settings where strenuous activity is intolerable...

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Acute hospitalization of the older patient: changes in muscle strength and functional performance during hospitalization and 30 days after discharge. Bodilsen, AC, Pedersen, MM, Petersen, J, Beyer, N, Andersen, O, Smith, LL, Kehlet, H, Bandholm, T. American Journal of Physical Medicine Rehabilitation 92: 789-96, 2013. 

OBJECTIVE: Acute hospitalization of older patients may be associated with loss of muscle strength and functional performance. The aim of this study was to investigate the effect of acute hospitalization as a result of medical disease on muscle strength and functional performance in older medical patients. CONCLUSIONS: Muscle strength did not change during hospitalization and 30 days after discharge in the acutely admitted older medical patients. Despite a low level of mobility during hospitalization, functional performance improved significantly during hospitalization, without further improvement...

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Tendon and skeletal muscle matrix gene expression and functional responses to immobilisation and rehabilitation in young males: effect of growth hormone administration. Boesen, AP, Dideriksen, K, Couppé, C, Magnusson, SP, Schjerling, P, Boesen, M, Kjaer, M, Langberg, H. Journal of Physiology 591: 6039-52, 2013. 

We examined the effect of growth hormone (GH) on connective tissue of tendon and skeletal muscle during immobilisation and re-training in humans. In conclusion, GH stimulates collagen expression in both skeletal muscle and tendon, abolishes the normal inactivity-related decline in tendon stiffness and LOX, and results in increased tendon CSA and stiffness during rehabilitation. GH has a matrix-stabilising effect during periods of inactivity and rehabilitation in humans...

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The need for transparency and good practices in the qPCR literature. Bustin, SA, Benes, V, Garson, J, Hellemans, J, Huggett, J, Kubista, M, Mueller, R, Nolan, T, Pfaffl, MW, Shipley, G, Wittwer, CT, Schjerling, P, Day, PJ, Vandesompele, J. Nature Methods 10: 1063-7, 2013. 

Two surveys of over 1,700 publications whose authors use quantitative real-time PCR (qPCR) reveal a lack of transparent and comprehensive reporting of essential technical information. Reporting standards are significantly improved in publications that cite the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines, although such publications are still vastly outnumbered by those that do not.

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Differences in tendon properties in elite badminton players with or without patellar tendinopathy. Couppe, C, Kongsgaard, M, Aagaard, P, Bojsen-Moller, J, Vinther, A, Boesen, M, Kjaer, M, Magnusson, SP. Scandinavian Journal of Medicine & Science in Sports 23:e89-95, 2013. 

The aim of this study was to examine the structural and mechanical properties of the patellar tendon in elite male badminton players with and without patellar tendinopathy. Conclusively, the PT group had smaller distal patellar tendon CSA on both the injured (lead extremity) and the uninjured side (non-lead extremity) compared with the CT group. Subsequently, the smaller CSA yielded a greater distal patellar tendon stress in the PT group. Therefore, a small tendon CSA may predispose to the development of tendinopathy...

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Effect of acute exercise on patella tendon protein synthesis and gene expression. Dideriksen, K, Sindby, AK, Krogsgaard, M, Schjerling, P, Holm, L, Langberg, H. Springerplus 2: 109-16, 2013. 

Evidence suggests that habitual loading can result in patellar tendon hypertrophy, especially at the proximal and distal parts of the patellar tendon. The present study investigated how acute exercise affects growth factor production and collagen fractional synthetic rate in patellar tendon tissue from patients undergoing an anterior cruciate ligament reconstruction operation...

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AMPK and insulin action--responses to ageing and high fat diet. Frøsig, C, Jensen, TE, Jeppesen, J, Pehmøller, C, Treebak, JT, Maarbjerg, SJ, Kristensen, JM, Sylow, L, Alsted, TJ, Schjerling, P, Kiens, B, Wojtaszewski, JF, Richter, EA. PLoS One 8:e62338-48, 2013. 

The 5'-AMP-activated protein kinase (AMPK) is considered "a metabolic master-switch" in skeletal muscle reducing ATP- consuming processes whilst stimulating ATP regeneration. Here we hypothesized that mice lacking α2AMPK activity in muscle would be more susceptible to develop insulin resistance associated with ageing alone or in combination with high fat diet. It is concluded that α2AMPK deficiency in mouse skeletal muscle does not cause muscle insulin resistance in young and old mice and does not exacerbate obesity-induced insulin resistance in old mice suggesting that decreased α2AMPK activity does not increase susceptibility for insulin resistance in skeletal muscle...

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Local administration of insulin-like growth factor-I (IGF-I) stimulates tendon collagen synthesis in humans. Hansen, M, Boesen, A, Holm, L, Flyvbjerg, A, Langberg, H, Kjaer, M. Scandinavian Journal of Medicine & Science in Sports 23: 614-619, 2013. 

Collagen is the predominant structural protein in tendons and ligaments, and can be controlled by hormonal changes. In animals, injections of insulin-like growth factor I (IGF-I) has been shown to increase collagen synthesis in tendons and ligaments and to improve structural tissue healing, but the effect of local IGF-I administration on tendon collagen synthesis in human has not been studied. The purpose of this study was to study whether local injections of IGF-I would have a stimulating effect on tendon collagen synthesis...

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Impact of oral contraceptive use and menstrual phases on patellar tendon morphology, biochemical composition and biomechanical properties in female athletes. Hansen, M, Couppe, C, Hansen, CE, Skovgaard, D, Kovanen, V, Larsen, JO, Aagaard, P, Magnusson, SP, Kjær, M. Journal of Applied Physiology, 114: 998-1008, 2013. 

Sex differences exist with regards to ligament and tendon injuries. Lower collagen synthesis has been observed in exercising women vs. men, and in users of oral contraceptives (OC) vs. nonusers, but it is unknown if OC will influence tendon biomechanics of women undergoing regular training. The results indicate that long-term OC use or menstrual phases does not influence structure or mechanical properties of the patellar tendon in female team handball athletes...

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Micromechanical properties and composition of ruptured human Achilles tendon. Hansen, P, Kovanen, V, Hølmich, P, Krogsgaard, M, Hansson, P, Dahl, M, Hall, M, Aagaard, P, Kjaer, M, Magnusson, SP. American Journal of Sports Medicine 41: 437-443, 2013. 

HYPOTHESIS: Ruptured human Achilles tendon displays inferior biomechanical properties and altered collagen composition compared with noninjured tendon. CONCLUSION: These data imply that there may be a mechanical weakening of the tendon and that a reduced collagen content may be related to the pathophysiological characteristics of Achilles tendon rupture...

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Expression of extracellular matrix components and related growth factors in human tendon and muscle after acute exercise. Heinemeier, KM, Bjerrum, SS, Schjerling, P, Kjaer, M. Scandinavian Journal of Medicine & Science in Sports 23: e150-61, 2013. 

Acute kicking exercise induces collagen synthesis in both tendon and muscle in humans, but it is not known if this relates to increased collagen transcription and if other matrix genes are regulated. In conclusion, the relatively robust changes in matrix components and related growth factors in muscle indicate a stimulation of extracellular matrix even with moderate exercise. However, in tendon tissue, this exercise model does not appear to induce any anabolic response on the transcriptional level...

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Lack of tissue renewal in human adult Achilles tendon is revealed by nuclear bomb 14C. Heinemeier, KM, Schjerling, P, Heinemeier, J, Magnusson, SP, Kjaer, M. FASEB Journal 27: 2074-9, 2013. 

Tendons are often injured and heal poorly. With the purpose of determining life-long turnover of human tendon tissue, we used the (14)C bomb-pulse method. This method takes advantage of the dramatic increase in atmospheric levels of (14)C, produced by nuclear bomb tests in 1955-1963, which is reflected in all living organisms. We found that Achilles tendon tissue retained levels of (14)C corresponding to atmospheric levels several decades before tissue sampling, demonstrating a very limited tissue turnover. Our observation provides a fundamental premise for understanding tendon function and pathology, and likely explains the poor regenerative capacity of tendon tissue...

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Bone blood flow and metabolism in humans: Effect of muscular exercise and other physiological perturbations. Heinonen, I, Kemppainen, J, Kaskinoro, K, Langberg, H, Knuuti, J, Boushel, R, Kjaer, M, Kalliokoski, K. Journal of Bone Mineral Research 28: 1068-1074, 2013. 

Human bone blood flow and metabolism during physical exercise remains poorly characterized. In the present study we measured femoral bone blood flow and glucose uptake in young healthy subjects by positron emission tomography in three separate protocols. In conclusion, resting femoral bone blood flow increases by physical exercise, but appears to level off with increasing exercise intensities. Moreover, although moderate systemic hypoxia does not change bone blood flow at rest or during exercise, intra-arterially administered adenosine during resting conditions is capable of markedly enhancing bone blood flow in humans. Finally, bone glucose uptake also increases substantially in response to exercise...

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Extensive monitoring through multiple blood samples in professional soccer players. Heisterberg, MF, Fahrenkrug, J, Krustrup, P, Storskov, A, Kjær, M, Andersen, JL. Journal of Strength and Conditioning Research. 27: 1260-71, 2013. 

The aim of this study was to make a comprehensive gathering of consecutive detailed blood samples from professional soccer players and to analyze different blood parameters in relation to seasonal changes in training and match exposure. We suggest that regular analyses of blood samples could be an important initiative to optimize training adaptation, training load, and game participation, but sampling has to be regular, and a database has to be built for each individual player...

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In vitro tendon tissue development from human fibroblasts demonstrates collagen fibril diameter growth associated with a rise in mechanical strength. Herchenhan, A, Bayer, ML, Svensson, RB, Magnusson, SP, Kjaer, M. Developmental Dynamics 242: 2-8, 2013. 

BACKGROUND: Collagen-rich tendons and ligaments are important for joint stability and force transmission, but the capacity to form new tendon is poorly understood. In the present study, we investigated mechanical strength, fibril size, and structure during development of tendon-like tissue from adult human tenocytes (termed tendon constructs) in vitro over 5 weeks in 3D tissue culture. CONCLUSIONS: The present study demonstrates that 3D tendon constructs can be formed by isolated human tendon fibroblasts, and when these constructs are subjected to static self-generated tension, the fibrils will grow in size and strength approaching that of adult human tendon in vivo...

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Determination of steady state protein breakdown rate in vivo by the disappearance of protein-bound tracer-labeled amino acids: a method applicable in humans. Holm, L, O’Rouke, B, Ebenstein, D, Toth, MJ, Bechshoeft, R, Holstein-Rathlou, NH, Kjaer, M, Matthews, DE. American Journal of Physiology 304: E895-907, 2013. 

A method to determine the rate of protein breakdown in individual proteins was developed and tested in rats and confirmed in humans, using administration of deuterium oxide and incorporation of the deuterium into alanine that was subsequently incorporated into body proteins...

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Four days of muscle disuse impairs single fiber contractile function in young and old healthy men. Hvid, LG, Suetta, C, Aagaard, P, Kjaer, M, Frandsen, U, Ortenblad, N. Experimental Gerontology 48: 154-161, 2013. 

The purpose of the study was to investigate the effects of 4 days of disuse (knee brace) on contractile function of isolated vastus lateralis fibers (n=486) from 11 young (24.3±0.9 yrs) and 11 old (67.2±1.0 yrs) healthy men having comparable levels of physical activity...

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Expression and inhibition of matrix metalloproteinase (MMP)-8, MMP-9 and MMP-12 in early colonic anastomotic repair. Krarup, PM, Eld, M, Heinemeier, K, Jorgensen, LN, Hansen, MB, Ågren, MS. International Journal of Colorectal Disease 28: 1151-9, 2013. 

PURPOSE: Submucosal collagen is paramount for colonic anastomotic integrity. Matrix metalloproteinases (MMPs) mediate collagen degradation that increases the risk of wound dehiscence. Although broad-spectrum MMP inhibitors are beneficial for anastomotic strength, they can cause adverse reactions. Knowledge of specific MMPs responsible for the weakening of anastomoses can be used to optimise MMP inhibition therapy. We aimed to quantify transcript and protein levels of multiple MMPs in colonic anastomoses and evaluate the effect of inhibiting the MMPs that displayed the highest expression levels on anastomotic repair. CONCLUSION: The present findings justify the concept of selective MMP inhibition to enhance anastomotic strength in colon...

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Contraction and AICAR stimulate IL-6 vesicle depletion from skeletal muscle fibers in vivo. Lauritzen, HP, Brandauer, J, Schjerling, P, Koh, HJ, Treebak, JT, Hirshman, MF, Galbo, H, Goodyear, LJ. Diabetes 62:3081-92, 2013. 

Recent studies suggest that interleukin 6 (IL-6) is released from contracting skeletal muscles; however, the cellular origin, secretion kinetics, and signaling mechanisms regulating IL-6 secretion are unknown. In conclusion, resting skeletal muscles contain IL-6-positive vesicles that are expressed throughout myofibers...

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Automated image segmentation of haematoxylin and eosin stained skeletal muscle cross-sections. Liu, F, Mackey, AL, Srikuea, R, Esser, KA and Yang, L. Journal of Microscopy 252: 275-85, 2013. 

The ability to accurately and efficiently quantify muscle morphology is essential to determine the physiological relevance of a variety of muscle conditions including growth, atrophy and repair. Our proposed automatic segmentation algorithm for haematoxylin and eosin stained skeletal muscle cross-sections consists of two major steps: (1) A learning-based seed detection method to find the geometric centres of the muscle fibres, and (2) a colour gradient repulsive balloon snake deformable model that adopts colour gradient in Luv colour space...

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Morphological adaptation of muscle collagen and receptor of advanced glycation end product (RAGE) in osteoarthritis patients with 12 weeks of resistance training: influence of anti-inflammatory or glucosamine treatment. Mattiello-Sverzut, AC, Petersen, SG, Kjaer, M and Mackey, AL. Rheumatology International 33: 2215-24, 2013. 

The aim of this study was to investigate the effect of 12-week resistance training on morphological presence of collagen and RAGE (receptor for advanced glycation end products) in skeletal muscle of patients with knee osteoarthritis (OA). These findings suggest a basement membrane remodelling in favour of a strengthened extracellular matrix surrounding individual muscle fibres after 12 weeks of resistance training...

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The heat shock protein response following eccentric exercise in human skeletal muscle is unaffected by local NSAID infusion. Mikkelsen, UR, Paulsen, G, Schjerling, P, Helmark, IC, Langberg, H, Kjær, M, Heinemeier, KM. European Journal of Applied Physiology 113: 1883-93, 2013. 

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely consumed in relation to pain and injuries in skeletal muscle, but may adversely affect muscle adaptation probably via inhibition of prostaglandin synthesis. Induction of heat shock proteins (HSP) represents an important adaptive response in muscle subjected to stress, and in several cell types including cardiac myocytes prostaglandins are important in induction of the HSP response. This study aimed to determine the influence of NSAIDs on the HSP response to eccentric exercise in human skeletal muscle...

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The effect of acute exercise on collagen turnover in human tendons: influence of prior immobilization period. Moerch, L, Pingel, J, Boesen, M, Kjaer, M, Langberg, H. European Journal of Applied Physiology 113: 449-455, 2013.

Mechanical loading of human tendon stimulates collagen synthesis, but the relationship between acute loading responses and training status of the tendon is not clear. We tested the effect of prolonged load deprivation on the acute loading-induced collagen turnover in human tendons, by applying the same absolute load to a relative untrained Achilles tendon (2-week immobilization period prior to acute loading) and a habitually loaded contra-lateral Achilles tendon, respectively, within the same individuals...

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Resistance exercise, but not endurance exercise, induces IKKβ phosphorylation in human skeletal muscle of training-accustomed individuals. Møller, AB, Vendelbo, MH, Rahbek, SK, Clasen, BF, Schjerling, P, Vissing, K, Jessen, N. Pflugers Archive 465: 1785-95, 2013. 

The mammalian target of rapamycin complex 1 (mTORC1) is considered an important role in the muscular adaptations to exercise. In the present study, we extended this investigation by examining IκB kinase complex (IKK), TSC1, MAPK, and upstream Akt activators, along with gene expression of selected cytokines, in skeletal muscles from these subjects. In conclusion, resistance exercise, but not endurance exercise, increases IKKβ phosphorylation in trained human subjects, which support the idea that IKKβ can influence the activation of mTORC1 in human skeletal muscle...

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The Effects of High-Load Strength Training With Protein- or Nonprotein-Containing Nutritional Supplementation in Patients Undergoing Dialysis. Molsted, S, Harrison, AP, Eidemak, I, Andersen, JL. Journal of Renal Nutrition 23: 132-40, 2013. 

OBJECTIVE: The aim of this study was to investigate the effects of high-load strength training and protein intake in patients undergoing dialysis with a focus on muscle strength, physical performance, and muscle morphology. CONCLUSIONS: High-load strength training is associated with improvements in muscle strength and power, physical performance, and quality of life. The effects were surprisingly not associated with muscle hypertrophy, and the results did not reveal any additional benefit of combining the training with protein intake. The positive results in muscle strength and physical performance have clinically relevant implications in the treatment of patients undergoing dialysis...

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Type VI collagen turnover-related peptides-novel serological biomarkers of muscle mass and anabolic response to loading in young men. Nedergaard, A, Sun, S, Karsdal, MA, Henriksen, K, Kjaer, M, Lou, Y, He, Y, Zheng, Q, Suetta, C. Journal of Cachexia Sarcopenia Muscle, 4: 267-275, 2013. 

BACKGROUND: Immobilization-induced loss of muscle mass is a complex phenomenon with several parallels to sarcopenic and cachectic muscle loss. Muscle is a large organ with a protein turnover that is orders of magnitude larger than most other tissues. Thus, we hypothesize that muscle loss and regain is reflected by peptide biomarkers derived from type VI collagen processing released in the circulation. CONCLUSION: While we cannot rule out the possibility that these biomarkers in part stem from other tissues, our results strongly indicate that these markers represent novel biomarkers of muscle mass or change in muscle mass in young men...

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Twenty-four-hour mobility during acute hospitalization in older medical patients. Pedersen, MM, Bodilsen, AC, Petersen, J, Beyer, N, Andersen, O, Lawson-Smith, L, Kehlet, H, Bandholm, T. Journal of Gerontology A Biol Sci Med Sci 68:331-7, 2013. 

BACKGROUND: Inactivity during hospitalization in older medical patients may lead to functional decline. This study quantified 24-hour mobility, validated the accelerometers used, and assessed the daily level of basic mobility in acutely admitted older medical patients during their hospitalization. CONCLUSIONS: Older acutely hospitalized medical patients with walking ability spent 17h/d of their in-hospital time in bed, and the level of in-hospital mobility seemed to depend on the patients' level of basic mobility. The accelerometers were valid in assessing mobility in older medical patients...

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No inflammatory gene-expression response to acute exercise in human Achilles tendinopathy. Pingel, J, Fredberg, U, Mikkelsen, LR, Schjerling, P, Heinemeier, KM, Kjaer, M, Harisson, A, Langberg, H. European Journal of Applied Physiology 113: 2101-9, 2013. 

The purpose of the present study was to elucidate whether inflammatory signalling responses after acute mechanical loading were more pronounced in tendinopathic versus healthy regions of human tendon and if treatment with non-steroidal anti-inflammatory medications (NSAID's) reduces this response. In contrast to the hypothesis, inflammatory signalling was not exaggerated in tendinopathic tendon 2 h after acute mechanical loading...

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Differentially Activated Macrophages Orchestrate Myogenic Precursor Cell Fate During Human Skeletal Muscle Regeneration. Saclier, M, Yacoub-Youssef, H, Mackey, AL, Arnold, L, Ardjoune, H, Magnan, M, Sailhan, F, Chelly, J, Pavlath, GK, Mounier, R, Kjaer, M, Chazaud, B. Stem Cells 31: 384-96, 2013.

Macrophages (MPs) exert either beneficial or deleterious effects on tissue repair, depending on their activation/polarization state. They are crucial for adult skeletal muscle repair, notably by acting on myogenic precursor cells. Here, we explored both in vitro and in vivo, in human, the interactions of differentially activated MPs with myogenic precursor cells (MPCs) during adult myogenesis and skeletal muscle regeneration...

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Sex hormones and skeletal muscle weakness. Sipilä, S, Narici, M, Kjaer, M, Pöllänen, E, Atkinson, RA, Hansen, M, Kovanen, V. Biogerontology 14: 231-245, 2013. 

Human ageing is accompanied with deterioration in endocrine functions the most notable and well characterized of which being the decrease in the production of sex hormones. Current research literature suggests that low sex hormone concentration may be among the key mechanism for sarcopenia and muscle weakness...

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Suetta, C, Frandsen, U, Mackey, AL, Jensen, L, Hvid, LG, Ageing is associated with diminished muscle re-growth and myogenic precursor cell expansion early after immobility-induced atrophy in human skeletal muscle. Bayer, ML, Petersson, SJ, Schrøder, HD, Andersen, JL, Aagaard, P, Schjerling, P, Kjaer, M. Journal of Physiology 591: 3789-804, 2013. 

Recovery of skeletal muscle mass from immobilisation-induced atrophy is faster in young than older individuals, yet the cellular mechanisms remain unknown. We examined the cellular and molecular regulation of muscle recovery in young and older human subjects subsequent to 2 weeks of immobility-induced muscle atrophy. In conclusion, the diminished muscle re-growth after immobilisation in elderly humans was associated with a lesser response in satellite cell proliferation in combination with an age-specific regulation of myostatin. In contrast, expression of local growth factors did not seem to explain the age-related difference in muscle mass recovery...

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Physical function and sef-efficacy – important aspects of health-related quality of life in individuals with osteoarthritis. Sunden, A, Ekdahl, C, Magnusson, SP, Johnsson, B, Lundvik Gyllensten, A. European Journal of Physiotherapy, 15: 151-159, 2013. 

Objectives: The aim of the present study was to investigate the associations between health-related quality of life (HRQL), physical function and self-efficacy (the sense of being able to perform specific tasks), in individuals with X-ray-verified hip OA. The aim was also to determine factors explaining good perceived HRQL. Conclusion: The results of the current study indicated that good physical ability and good self-efficacy are important for HRQL in subjects with hip OA. This knowledge ought to influence future rehabilitation strategies. The treatment strategies for individuals with OA ought to be directed not only to the symptoms of the disease, but also to the individual's possibilities of gaining perceived control over the consequences of the disease including the HRQL...

 

Fracture mechanics of collagen fibrils: Influence of natural cross-links. Svensson, RB, Mulder, H, Kovanen, V, Magnusson, SP. Biophysical Journal 104: 2476-2484, 2013. 

Tendons are important load-bearing structures, which are frequently injured in both sports and work. To improve our understanding of how molecular bonds translate into tendon mechanics, we used an atomic force microscopy technique to measure the mechanical behavior of individual collagen fibrils loaded to failure. We found a characteristic three-phase stress-strain behavior in the human collagen fibrils...

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Metabonomic response to milk proteins after a single bout of heavy resistance exercise elucidated by 1H nuclear magnetic resonance spectroscopy. Yde, CC, Ditlev, DB, Reitelseder, S, Bertram, HC. Metabolites 3: 33-46, 2013. 

In the present study, proton NMR-based metabonomics was applied on femoral arterial plasma samples collected from young male subjects (milk protein n = 12 in a crossover design; non-caloric control n = 8) at different time intervals (70, 220, 370 min) after heavy resistance training and intake of either a whey or calcium caseinate protein drink in order to elucidate the impact of the protein source on post-exercise metabolism, which is important for muscle hypertrophy. In conclusion, no difference in the effects on low-molecular weight metabolites as measured by proton NMR-based metabonomics was found between the two protein sources..

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Positive muscle protein net balance and differential regulation of atrogene expression after resistance exercise and milk protein supplementation. Reitelseder S, Agergaard, J, Doessing, S, Helmark, IC, Schjerling, P, van Hall, G, Kjaer, M, Holm, L. European Journal of Nutrition 2014 Feb;53(1):321-33 (accepted 2013). 

PURPOSE: Resistance exercise and amino acid availability are positive regulators of muscle protein net balance (NB). However, anabolic responses to resistance exercise and protein supplementation deserve further elucidation. The purpose was to compare intakes of whey, caseinate (both: 0.30 g/kg lean body mass), or a non-caloric control after heavy resistance exercise on protein turnover and mRNA expressions of forkhead homeobox type O (FOXO) isoforms, muscle RING finger 1 (MuRF1), and Atrogin1 in young healthy males. CONCLUSIONS: Whey and caseinate were equally superior to control in the 6-h recovery period and displayed temporal differences with whey having a fast and superior effect in the early part of the recovery period. Effects on mRNA expressions indicate different regulatory mechanisms on the ubiquitin ligases MuRF1 and Atrogin1 in recovery from heavy resistance exercise...

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Chronic alterations in growth hormone/insulin-like growth factor-I signalling lead to changes in mouse tendon structure. Nielsen, RH, Clausen, NM, Schjerling, P, Larsen, JO, Martinussen, T, List, EO, Kopchick, JJ, Kjaer, M, Heinemeier, KM. Matrix Biology. Sep 28 2013. 

The growth hormone/insulin-like growth factor-I (GH/IGF-I) axis is an important stimulator of collagen synthesis in connective tissue, but the effect of chronically altered GH/IGF-I levels on connective tissue of the muscle-tendon unit is not known. In conclusion, chronic manipulation of the GH/IGF-I axis influenced both morphology and mRNA levels of selected genes in the muscle-tendon unit of mice. Whereas only moderate structural changes were observed with up-regulation of GH/IGF-I axis, disruption of the GH receptor had pronounced effects upon tendon ultra-structure...

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Accuracy of MRI technique in measuring tendon cross-sectional area. Couppe, C, Svensson, RB, Sødring-Elbrønd, V, Hansen, P, Kjaer, M, Magnusson, SP. Clinical Physiology Functional Imaging. Sep 20 2013. 

Magnetic resonance imaging (MRI) has commonly been applied to determine tendon cross-sectional area (CSA) and length either to measure structural changes or to normalize mechanical measurements to stress and strain. The purpose of this study was to compare tendon CSA measured by MRI with that measured in vitro with the mould casting technique...

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Differential regulation of the satellite cell density of type I and II fibres with lifelong endurance running in old men. Mackey, AL, Karlsen, A, Couppe ,C, Mikkelsen, UR, Nielsen, RH, Magnusson, SP, Kjaer, M. Acta Physiologica, 2014 Mar;210(3):612-27 (accepted 2013). 

AIM: To investigate the influence of lifelong endurance running on the satellite cell pool of type I and type II fibres in healthy human skeletal muscle. CONCLUSION: Lifelong endurance training (i) does not deplete the satellite cell pool and (ii) is associated with a similar density of satellite cells in type I and II fibres despite a failure to preserve the equal fibre type distribution of satellite cells observed in young individuals. Taken together, these data reveal a differential regulation of satellite cell content between fibre types, in young and old healthy men with dramatically different training histories...

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Life-long endurance exercise in humans: Circulating levels of inflammatory markers and leg muscle size. Mikkelsen, UR, Couppe, C, Karlsen, A, Grosset, JF, Schjerling, P, Mackey, A, Hedegaard, H, Magnusson, SP, Kjaer, M. Mechanisms in Ageing and Development, accepted 2013. 

Human aging is associated with a loss of skeletal muscle and an increase in circulating inflammatory markers. It is unknown whether endurance training (Tr) can prevent these changes. Most importantly, life-long endurance exercise was associated with a lower level of the inflammatory markers CRP and IL-6 (p<0.05), and with a greater thigh muscle area (p<0.05), compared to age-matched untrained counterparts. These findings in a limited group of individuals suggest that regular physical endurance activity may play a role in reducing some markers of systemic inflammation, even within the normal range, and in maintaining muscle mass with aging...

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Effect of growth hormone on aging connective tissue in muscle and tendon – gene expression, morphology, and function following immobilization and rehabilitation. Boesen, AP, Dideriksen, K, Couppe, C, Magnusson, SP, Schjerling, P, Aagaard, P, Boesen, M, Kjaer, M, Langberg, H. Journal of Applied Physiology, 2014 Jan 15;116(2):192-203 (accepted 2013). 

It is unknown whether loss in musculotendinous tissue during inactivity can be counteracted by growth hormone (GH), and whether GH accelerate rehabilitation in aging individuals. In conclusion, in elderly humans, GH seems to have a matrix stabilizing effect during inactivity and rehabilitation by stimulating collagen expression in the musculotendinous tissue and increasing tendon CSA and stiffness...

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The influence of physical activity during youth on structural and functional properties of the Achilles tendon. Lenskjold, A, Kongsgaard, M, Larsen, JO, Nielsen, RH, Kovanen, V, Aagaard, P, Kjaer, M, Magnusson, SP. Scandinavian Journal of Medicind and Science in Sports, Nov 14 2013. 

Achilles tendinopathy is a highly prevalent sports injury. Animal studies show a growth response in tendons in response to loading in the immature phase but not after puberty maturation. The aim of this investigation was to examine the structural and material properties in long distance runners who were either physically active (HAY) or inactive (LAY) in young age. The data suggest that high or low activity during youth did not appreciably influence the mechanical, structural, or biochemical properties of the Achilles tendon in adult long distance runners...

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Increase in tendon protein synthesis in response to insulin-like growth factor I (IGF-I) is preserved in elderly men. Nielsen, RH, Holm, L, Malmgaard-Clausen, NM, Reitelseder, S, Heinemeier, KM, Kjaer, M. Journal of Applied Physiology 2014 Jan 1;116(1):42-6 (accepted 2013). 

Insulin-like growth factor-I (IGF-I) is known to be an anabolic factor in tendon, and the systemic levels are reduced with aging. The purpose of this study was to investigate the in vivo IGF-I stimulation of tendon protein synthesis in elderly compared with young men.In conclusion, local IGF-I stimulated tendon protein synthesis in both young and old men, despite lower systemic IGF-I levels in the old group. This could indicate that the changed phenotype in aging tendon is not caused by decreased fibroblast function...

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Release of tensile strain on engineered human tendon tissue disturbs cell adhesions, changes matrix architecture, and induces an inflammatory phenotype. Beyer, ML, Schjerling, P, Herchenhan, A, Gullberg, D, Zeltz, C, Heinemeier, KM, Christensen, L, Krogsgaard, M, Kjaer, M. PLoS One 2014 Jan 21;9(1):e86078 (accepted 2013). 

Mechanical loading of tendon cells results in an upregulation of mechanotransduction signaling pathways, cell-matrix adhesion and collagen synthesis, but whether unloading removes these responses is unclear. We investigated the response to tension release, with regard to matrix proteins, pro-inflammatory mediators and tendon phenotypic specific molecules, in an in vitro model where tendon-like tissue was engineered from human tendon cells...

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Træthed. I: Søvn, Ed: P.Jennum. pp 219-226, Munkgaard, 2013. Avlund, K, Waller, L, Kjaer, M.

Ældre patienter bør tilbydes fysisk træning tidligt efter kirurgi. Beyer, N, Suetta, C. Ugeskr Læger 175: 2421-24, 2013.

Værktøjer til systematisk identifikation af nedsat fysisk funktionsniveau hos ældre borgere. Beyer, N. Sundhedsstyrelsen 2013.

Influence of Amino Acids, Dietary Protein, and Physical Activity on Muscle Mass Development in Humans. Dideriksen, K, Reitelseder, S, Holm, L. Nutrients 5: 852-876, 2013. 

Ingestion of protein is crucial for maintenance of a variety of body functions and within the scope of this review we will specifically focus on the regulation of skeletal muscle mass. In the ageing population, physical training may counteract the development of "anabolic resistance" and restore the beneficial effect of protein feeding. Presently, our knowledge is based on measures obtained in standardized experimental settings or during long-term intervention periods. However, to improve coherence between these types of data and to further improve our knowledge of the effects of protein ingestion, other investigative approaches than those presently used are requested...

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What is the impact of inflammation on the critical interplay between mechanical signaling and biochemical changes in tendon matrix? Kjaer, M, Bayer, ML, Eliasson, P, Heinemeier, KM. Journal of Applied Physiology 115: 879-83, 2013. 

Mechanical loading can influence tendon collagen homeostasis in animal models, while the dynamics of the human adult tendon core tissue are more debatable. Currently available data indicate that human tendon adaptation to loading may happen primarily in the outer tendon region...

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Idrætsmedicin. Kjaer, M. I: Bispebjerg Hospital’s 100 års Jubilæumsbog, pp 267-278, 2013.

Commentaries on viewpoint: On the hysteresis in the human Achilles tendon. Lichtwark, GA, Cresswell, AG, Ker, RF, Reeves, ND, Maganaris, CN, Magnusson, SP, Svensson, RB, Couppe, C, Hershenhan, A, Eliasson, P, Nordez, A, Fouré, A, Cornu, C, Arampatzis, A, Morey-Klapsing, G, Mademli, L, Karamanidis, K, Vagula, MC, Nelatury, SR. Journal of Applied Physiology 114: 518-520, 2013.

Does an NSAID a Day Keep Satellite Cells at Bay? Mackey, AL. Journal of Applied Physiology 115: 900-8, 2013. 

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely consumed by athletes worldwide, despite growing evidence for a negative influence on the adaptation of skeletal muscle to exercise, at least in young healthy individuals. This review focuses on the potential of NSAIDs to alter the activity of satellite cells, the muscle stem cell responsible for repair and maintenance of skeletal muscle...

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 Program 3 - Body and LifeTil toppen

Neonatal chemokine levels and risk of autism spectrum disorders: Findings from a Danish historic birth cohort follow-up study.Abdallah MW, Larsen N, Grove J, Bonefeld-Jørgensen EC, Nørgaard-Pedersen B, Hougaard DM, Mortensen EL. Cytokine. 61: 370-376, 2013. 

A potential role of chemokines in the pathophysiology of Autism Spectrum Disorders (ASDs) has been previously suggested. In a recent study we examined levels of three inflammatory chemokines (MCP-1, MIP-1α and RANTES) in samples of amniotic fluid of children diagnosed later in life with ASD and controls frequency-matched to cases on gender and year of birth. In this follow-up study, levels of the same chemokines were analyzed postnatally in dried blood spot samples from the same subjects utilizing the Danish Newborn Screening Biobank...

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Amniotic Fluid Inflammatory Cytokines: Potential Markers of Immunologic Dysfunction in Autism Spectrum Disorders. Abdallah MW, Larsen N, Grove J, Nørgaard-Pedersen B, Thorsen P, Mortensen EL, Hougaard DM. World J Biol Psychiatry. 7: 528-538, 2013. 

OBJECTIVES: The aim of the study was to analyze cytokine profiles in amniotic fluid (AF) samples of children developing autism spectrum disorders (ASD) and controls, adjusting for maternal autoimmune disorders and maternal infections during pregnancy. CONCLUSIONS: AF samples of individuals with ASD or OCPD showed differential cytokine profiles compared to frequency-matched controls. Further studies to examine the specificity of the reported cytokine profiles in ASD and OCPD are required...

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Neonatal Levels of Neurotrophic Factors and Risk of Autism Spectrum Disorders. Abdallah MW, Mortensen EL, Greaves-Lord K, Larsen N, Bonefeld-Jørgensen EC, Nørgaard-Pedersen B, Hougaard DM, Grove J. Acta Psychiatr Scand 128:61-69, 2013. 

OBJECTIVE: To examine levels of 3 neurotrophic factors (NTFs): Brain derived neurotrophic factor (BDNF), Neurotrophin-4 (NT-4), and transforming growth factor-β (TGF-β) in dried blood spot samples of neonates diagnosed with autism spectrum disorders (ASD) later in life and frequency-matched controls. CONCLUSION: Results cautiously indicate decreased NTFs levels during neonatal period in ASD. This may contribute to the pathophysiology of ASD through impairments of neuroplasticity. Further research is required to confirm our results and to examine the potential therapeutic effects of NTFs in ASD...

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Intakes of calcium, vitamin D, and dairy servings and dental plaque in older Danish adults. Adegboye AR, Christensen LB, Holm-Pedersen P, Avlund K, Boucher BJ, Heitmann BL. Nutrition Journal 12: 61, 2013. 

BACKGROUND: To investigate whether intakes of calcium and dairy-servings within-recommendations were associated with plaque score when allowing for vitamin D intakes. CONCLUSION: Intakes of calcium dairy-servings within-recommendations were inversely associated with plaque, among those with higher, but not lower, vitamin D intakes. Due to the cross-sectional nature of the study, it is not possible to infer that this association is causal...

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Fatigue in older populations. Avlund K. Fatigue 1: 43-63, 2013. 

The aim of this paper is to give an overview of research on general fatigue, mobility-related fatigue, and fatigability in older adults, with a focus on fatigue as an early indicator of the aging process...

Copenhagen Aging and Midlife Biobank (CAMB). An introduction. Avlund K, Osler M, Mortensen EL, Christensen U, Bruunsgaard H, Holm-Pedersen P, Fiehn N, Hansen ÅM, Bachkati SB, Meincke RH, Jepsen E, Molbo D, Lund R. J Aging Health, 2014 Feb;26(1):5-20

Assisted Reproduction and Child Neurodevelopment Outcomes – a Systematic Review. Bay B, Mortensen EL, Kesmodel US. Fertil Steril. 2013 Sep;100(3):844-53. 

OBJECTIVE: To systematically review the existing literature on neurodevelopmental outcomes in children born after medically assisted reproduction compared with those of children born after spontaneous conception. CONCLUSION(S): It may tentatively be concluded that the neurodevelopment of children born after fertility treatment is overall comparable to that in children born after spontaneous conception...

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Fertility Treatment and the Risk of Childhood and Adolescent Mental Disorders: a register-based cohort study. Bay B, Mortensen EL, Kesmodel US. BMJ, 2013 Jul 5;347:f3978.

OBJECTIVE: To assess the mental health of children born after fertility treatment by comparing their risk of mental disorders with that of spontaneously conceived children. CONCLUSIONS: There was a small increase in the incidence of mental disorders in children born after ovulation induction/intrauterine insemination. Children born after in vitro fertilisation/intracytoplasmic sperm injection were found to have overall risk comparable with children conceived spontaneously...

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Frailty and depression in older adults: A high-risk clinical population. Brown PJ, Liu X, Fieo R, Rantanen T, Sned JR, Rutherford R, Devanand DP, Roose SP, Avlund K. Am J Geriatr Psychiatry. 2013 Aug 20. pii: S1064-7481(13)00228-5.

OBJECTIVE: To identify salient characteristics of frailty that increase risk of death in depressed elders. CONCLUSION: The confluence of specific characteristics of frailty (fatigue and slow gait speed) and depressive illness is associated with an increased risk of death in older adults; this association is particularly strong in older depressed women. Future research should investigate whether multimodal interventions targeting depressive illness, mobility deficits, and fatigue can decrease mortality and improve quality of life in older depressed individuals with characteristics of the syndrome of frailty...

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Addressing social inequality in aging by the Danish Occupational Social Class Measurement. Christensen U, Krølner R, Nilsson CJ, Lyngbye PW, Hougaard CØ, Nygaard E, Thielen K, Avlund K, Holstein BE, Lund R. J Aging Health, 2014 Feb;26(1):106-27 (accepted 2013). 

OBJECTIVE: To present the Danish Occupational Social Class (DOSC) measurement as a measure of socioeconomic position (SEP) applicable in a late midlife population, and to analyze associations of this measure with three aging-related outcomes in midlife, adjusting for education. DISCUSSION: The DOSC measure was associated with aging-related outcomes in a midlife Danish population, and is, thus, well suited for future epidemiological research on social inequalities in health and aging...

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How do musculoskeletal pain, avoidant coping and sickness absence relate to each other? Findings from a prospective cohort study. Christensen U, Schmidt L, Thielen K, Nygaard E, Lund R. J Rehab Med, accepted 2013.

Cognitive function in adult offspring of women with gestational diabetes – the role of glucose and other factors. Clausen T, Mortensen EL, Smidt L, Mathiesen E, Hansen T, Jensen D, Damm P. S One. 2013 Jun 28;8(6):e67107. 

OBJECTIVE: We aimed to evaluate cognitive function in adult offspring of women with diet-treated gestational diabetes and to study potential associations with maternal glucose values. CONCLUSIONS: Lower cognitive test scores in adult offspring of women with diet-treated gestational diabetes were explained by well known predictors of cognitive function, but not by maternal hyperglycaemia during pregnancy. We find it reassuring that mild intrauterine hyperglycaemia does not seem to have adverse effect on offspring cognitive function...

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Trait aggression and trait impulsivity are not related to frontal cortex 5-HT2A receptor binding in healthy individuals. da Cunha-Bang SA, Stenbæk DS, Holst KK, Licht CL, Jensen PS, Frokjaer VF, Mortensen EL, Knudsen GM. Psychiatry Res 212, 125-131, 2013. 

Numerous studies indicate that the serotonergic (5-HT) transmitter system is involved in the regulation of impulsive aggression and there is from post-mortem, in vivo imaging and genetic studies evidence that the 5-HT2A receptor may be involved.Contrary to our hypothesis, results revealed no significant associations between 5-HT2AR and the AQ or BIS-11 total scores...

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Fatigue, general health and ischemic heart disease in older adults. Ekmann A, Petersen I, Mänty M, Christensen K, Avlund K. J Gerontol Med Sci 68: 279-85, 2013. 

BACKGROUNDS: Fatigue has been shown to predict ischemic heart disease (IHD) and mortality in nonsmoking middle-aged men free of cardiovascular disease. The aim of this study was to investigate the predictive value of fatigue for IHD and general health in nondisabled individuals free of cardiovascular disease and older than 70 years. CONCLUSION: We concluded that fatigue in nondisabled older adults free of cardiovascular disease is an early predictor for development of subsequent poor general health and IHD...

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Analytic versus systemic group therapy for women with a history of child sexual abuse: one-year follow-up of a randomized controlled trial. Elkjaer H, Kristensen E, Mortensen EL, Poulsen S, Lau M. Psychology and Psychotherapy: 013 Sep 7. doi: 10.1111/papt.12011. [Epub ahead of print]. 

OBJECTIVE: This randomized prospective study examines durability of improvement in general symptomatology, psychosocial functioning and interpersonal problems, and compares the long-term efficacy of analytic and systemic group psychotherapy in women 1 year after completion of treatment for childhood sexual abuse. CONCLUSION: The findings stress the importance of long-term follow-up data in effect studies. Different trajectories were associated with the two treatments, but improvement in the two treatment groups did not differ significantly at the 1-year follow-up. Implications of the difference in trajectories for treatment planning are discussed...

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The impact of virtual admission on self-efficacy in patients with chronic obstructive pulmonary disease (COPD) – a randomized clinical trial. Emme C, Mortensen EL, Rydahl-Hansen S, Østergaard B, Schou L, Jakobsen AS, Phanareth K. J Clin Nurs. 2014 Jan 30. doi: 10.1111/jocn.12553. [Epub ahead of print]. 

AIMS AND OBJECTIVES: To investigate how virtual admission during acute exacerbation influences self-efficacy in patients with chronic obstructive pulmonary disease, compared with conventional hospital admission. CONCLUSIONS: The results of the study suggest that there is no difference between self-efficacy in chronic obstructive pulmonary disease patients undergoing virtual admission, compared with conventional hospital admission. However, the anticipated sample size could not be reached, which prompts caution regarding interpretation of the findings...

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Predictors of intelligence at the afe of 5: Family, pregnancy and birth characteristics, postnatal influences, and postnatal growth. Eriksen HF, Kesmodel U, Underbjerg M, Kilburn TR, Bertrand J, Mortensen EL. PLoS One. 2013 Nov 13;8(11):e79200. 

Parental education and maternal intelligence are well-known predictors of child IQ. However, the literature regarding other factors that may contribute to individual differences in IQ is inconclusive. The aim of this study was to examine the contribution of a number of variables whose predictive status remain unclarified, in a sample of basically healthy children with a low rate of pre- and postnatal complications...

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Relation of Frontal D2/3 Binding Potentials to Cognition: A Study of Antipsychotic-Naive Schizophrenia Patients. Fagerlund B, Pinborg LH, Mortensen EL, Friberg L, Baaré WFC, Gade A, Svarer C, Glenthøj BY. Int J Neuropsychopharmacol. 16: 23-26, 2013. 

Studies of in vivo dopamine receptors in schizophrenia have mostly focused on D(2) receptors in striatal areas or on D(1) receptors in cortex. The objective was to examine this relation in the frontal cortex in first-episode, drug-naive schizophrenia patients. The main findings indicated a relation between D(2/3) receptor binding in the frontal cortex and set shifting, planning and attention, but also support a differential involvement of cortical dopamine D(2/3) receptor binding in at least some cognitive functions, perhaps particularly attention, in schizophrenia patients compared to healthy people...

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A register based study of long-term healthcare use before and after psychotherapy. Fenger M, Mortensen EL, Poulsen S, Lau M. Nord J Psychiatry. 2013 Nov 25. [Epub ahead of print]. 

Aim: To investigate long-term changes in utilization of public healthcare services for patients referred to psychotherapeutic treatment. Conclusion: Over a long-term period, patients who completed psychotherapeutic treatment increased utilization of healthcare services. Studies are needed to clarify how and why psychotherapeutic treatment does not necessarily lead to a reduction in the utilization of healthcare services for the average patient and to evaluate other potential interventions for patients with mental problems and include efficiency studies in this evaluation...

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Improving a measure of mobility-related fatigue (the Mob-T Scale) by establishing item intensity. Fieo R, Mortensen EL, Rantanen T, Avlund K. J Am Geriatr Soc 61:429-433, 2013. 

OBJECTIVES: To improve the construct validity of self-reported fatigue by establishing a formal hierarchy of scale items and to determine whether such a hierarchy could be maintained across time (aged 75-80), sex, and nationality. CONCLUSION: Establishing a formal hierarchy at age 75 allowed which tasks were most debilitating to be identified more clearly and the individual's "distance" from these tasks to be gauged. Because it was possible to confirm that the item hierarchy was maintained across time (aged 75-80), researchers or clinicians can be more confident that performance over time is the result of real change and has less to do with measurement error...

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Early motor developmental milestones and level of neuroticism in young adulthood. A 23-year follow-up study of the Copenhagen Perinatal Cohort. Flensborg-Madsen T, Sørensen HJ, Revsbech R, Mortensen EL. Psychol Med 43: 1293-1301, 2013. 

BACKGROUND: Studies investigating early developmental factors in relation to psychopathology have mainly focused on schizophrenia. The personality dimension of neuroticism seems to be a general risk factor for psychopathology, but evidence on associations between early developmental precursors and personality traits is almost non-existent. This study is therefore the first to investigate associations between early motor developmental milestones and neuroticism in adulthood. CONCLUSIONS: The findings are the first of their kind and suggest that delays in early motor development may not only characterize psychopathological disorders such as schizophrenia, but may also be associated with the personality dimension of neuroticism in adulthood...

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Occupational characteristics and cognitive aging in the Glostrup 1914 Cohort. Gow AJ, Avlund K, Mortensen EL. J Gerontol B Psychol Sci Soc Sci. 2014 Mar;69(2):228-36. 

Objectives. The effect of occupational characteristics on cognitive change over 20 years was examined. Discussion. Notwithstanding the reversal of the effect of occupational intellectual challenge on cognitive ability level after accounting for pre-exiting cognitive differences, there was no evidence for long-term effects of occupational characteristics on cognitive change in old age...

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Local administration of insulin-like growth factor-I (IGF-I) stimulates tendon collagen synthesis in humans. Hansen M, Boesen A, Holm L, Flyvbjerg A, Langberg H, Kjaer M. Scand J Med Sci Sports. 23: 614-9 , 2013. 

Collagen is the predominant structural protein in tendons and ligaments, and can be controlled by hormonal changes. The purpose of this study was to study whether local injections of IGF-I would have a stimulating effect on tendon collagen synthesis. In conclusion, local IGF-I administration can directly enhance tendon collagen synthesis both within and around the human tendon tissue...

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Social gradient in allostatic load among danish men and women in late midlife. Hansen, Å.M., Lund, R., Bruunsgaard, H., Rod, N.H., Garde, A.H., Molbo, D., & Avlund, K. J Aging Health. 2014 Feb;26(1):72-87. 

OBJECTIVE: The objective of the present study is to describe the prevalence of allostatic load (AL) among Danish men and women in late midlife, and if there is a social gradient in AL. DISCUSSION: AL may be a potential biomarker for early aging in countries with a strong social welfare system. It is important for intervention studies to be aware of this type of biological vulnerability already present in late midlife...

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Social class differences in physical functions in middle-aged men and women. Hansen ÅM, Andersen LL, Skotte J, Christensen U, Mortensen OS, Molbo D, Lund R, Nilsson CJ, Avlund K. J Aging Health. 2014 Feb;26(1):88-105.

OBJECTIVE: The objective of the present study is to analyze gender differences and social class gradients in physical functions; and to study whether the social class gradients in physical functions in midlife differed between men and women. DISCUSSION: Including measures of vigorous physical functioning may add to the existing knowledge on development of functional limitation and poorer functional health later in life...

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Personality in Adults Who Were Born Very Preterm. Hertz CL, Mathiasen R, Hansen BM, Mortensen EL, Greisen G. PLoS One. 2013 Jun 26;8(6):e66881. Print 2013.

AIM: To investigate the personality in very preterm individuals (VPT; gestational age, GA.

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Physical performance as long-term predictor of onset of ADL disability: A nine-year longitudinal study among community-living older women. Idland G, Pettersen R, Avlund K, Bergland A. Arch Gerontol Geriatr 56: 501-506, 2013.

Disability in ADL of aging women is an important public health concern. We assessed whether three physical performance-based measurements could predict ADL disability 9 years later. In conclusion all the three performance measurements were related to onset of ADL disability, with walking speed having the strongest predictive value. Systematic screening based on walking speed measurements of non-disabled older women might help health professionals to identify those at risk of ADL disability and introduce preventive measures in time...

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Health, social and economic consequences of hypersomnia: a controlled national study from a national registry evaluating the societal effect on patients and their partners. Jennum P, Ibsen R, Avlund K, Kjellberg J. Eur J Health Econ. 2013 Jun 12. [Epub ahead of print]. 

Hypersomnia causes significant socioeconomic burden, but there is insufficient information about the time course and the effect on the partner. The aim of this study was to estimate the factual direct and productivity costs of hypersomnia in a controlled study including all national patients and their partners...

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Heterogeneity of treatment changes after psychodynamic therapy within a one year follow-up: A replication study. Jensen HJ, Mortensen EL, Lotz M. Scand J Psychol, in press, 2013.

SCL-90-R Symptom Profiles and Outcome of Short-Term Psychodynamic Group Therapy. Jensen HJ, Mortensen EL, Lotz M. ISRN Psychiatry, Article 540134, 7 p, 2013. 

Background. Psychodynamic group psychotherapy may not be an optimal treatment for anxiety and agoraphobic symptoms. We explore remission of SCL-90-R Global Severity Index (GSI) and target symptoms in 39 sessions of psychodynamic group therapy. Conclusions. The negative results as associated with the SCL-90-R phobic anxiety scale and the phobic anxiety target symptom group are largely in agreement with recent studies. In contrast, whatever the diagnoses, patients with interpersonal sensitivity target symptom may be especially suited for psychodynamic group therapy...

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Profile of cognitive deficits and associations with depressive symptoms and intelligence in chronic early-onset schizophrenia patients. Jepsen JR, Fagerlund B, Pagsberg AK, Christensen AM, Nordentoft M, Mortensen EL. Scand J Psychol 54, 363-370, 2013. Doi: 10.1111/sjop.12062. 

Cognitive deficits in several domains have been demonstrated in early-onset schizophrenia patients but their profile and relation to depressive symptoms and intelligence need further characterization. The purpose was to characterize the profile of cognitive deficits in chronic, early-onset schizophrenia patients, assess the potential associations with depressive symptom severity, and examine whether cognitive deficits within several domains reflect intelligence impairments...

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Does Binge Drinking During Early Pregnancy Increase the Risk of Psychomotor Deficits? Kesmodel US, Bay B, Wimberley T, Eriksen HLF, Mortensen EL. Alcohol Clin Exp Res 37:1203-1212, 2013. 

BACKGROUND: The potential effects of binge drinking during pregnancy on child motor function have only been assessed in a few, small studies. We aimed to examine the effects of binge alcohol consumption during early pregnancy, including number of binge episodes and timing of binge drinking, on child motor function at age 5. CONCLUSIONS: In this study, we found no systematic association between isolated episodes of binge drinking during early pregnancy and child motor function at age 5...

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Does the association between broken partnership and first time myocardial infarction vary with time after break-up? Kriegbaum M, Andersen PK, Osler M, Christensen U, Lund R. Int J Epidemiol. 2013 Dec;42(6):1811-9. 

BACKGROUND: Marriage is associated with lower risk of coronary heart disease, but it is unknown if the association depends on time since break-up with a partner. In this study we included both married and unmarried couples to study if the association between broken partnership (BP) and first time incident myocardial infarction (MI) changes with time since BP. CONCLUSIONS: We found both a short-term elevated risk of first time MI following BP and a weaker long-term elevated risk, in both men and women...

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Childhood Socioeconomic Position, young adult intelligence and fillings of prescribed medicine for the prevention of cardiovascular disease in middle-aged men. Kriegbaum M, Kildemoes, HW, Rasmussen JN, Hendriksen C, Vass M, Mortensen EL, Osler M. BMJ Open, in press, 2013. 

OBJECTIVES: To explore the relationship between childhood socioeconomic position (SEP) and filling of medicine prescriptions for prevention of cardiovascular diseases (CVDs), with young adult intelligence (IQ) as a potential mediator. CONCLUSIONS: Low childhood SEP was related to more frequent initiation of and poorer refill persistency for statins. IQ in young adulthood explained most of the association between childhood SEP and initiation of statins, but had no impact on refill persistency...

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Association between frailty and dementia: A population-based study. Kulmala J, Nykänen I, Mänty M, Hartikainen S. Gerontology 2014;60(1):16-21 (accepted 2013). 

BACKGROUND: Frailty is commonly considered as a syndrome with several symptoms, including weight loss, exhaustion, weakness, slow walking speed and physical inactivity. It has been suggested that cognitive impairment should be included in the frailty index, however the association between frailty and cognition has not yet been fully established. CONCLUSION: Frailty is strongly associated with cognitive impairment and clinically diagnosed dementia among persons aged 76 and older. It is possible that cognitive impairment is a clinical feature of frailty and therefore should be included in the frailty definition...

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Face and content validation of a measure of social relations. Lund R ,Nielsen LS, Schmidt L, Henriksen PE, Avlund K, Christensen U. J Aging Health in press, 2013.

Negative aspects of close social relations and 10-year incident ischaemic heart disease hospitalization among middle-aged Danes. Lund R, Rod NH, Thielen K, Nilsson CJ, Christensen U. Eur J Prev Cardiol. 2013 Apr 4. [Epub ahead of print]. 

BACKGROUND: Little is known about the association between negative aspects of close social relations and development of ischaemic heart disease (IHD). We aim to address if the experience of worries/demands and conflicts with close social relations are related to risk of first-time hospitalization with IHD and whether emotional support can buffer this effect. CONCLUSIONS: Negative aspects of close social relations are associated with higher risk of incident IHD hospitalization except for conflicts with partner. We found no clear evidence of a buffering effect of emotional support...

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Improving personality facet scores with multidimensional computer adaptive testing: An illustration with the NEO PI-R. Makransky G, Mortensen EL, Glas CAW. Assessment 30:3-13, 2013. 

Narrowly defined personality facet scores are commonly reported and used for making decisions in clinical and organizational settings. This article investigates the possibility of increasing the precision of the NEO PI-R facet scores by scoring items with multidimensional item response theory and by efficiently administering and scoring items with multidimensional computer adaptive testing (MCAT). Results indicate that the NEO PI-R could be substantially shorter without attenuating precision when the MCAT methodology is used...

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Intelligence in early adulthood and mortality from natural and unnatural causes in middle-aged Danish men. Meincke RH, Mortensen EL, Avlund K, Rosthøj S, Sørensen HJ, Osler M. J Epidemiol Community Health. 2014 Feb;68(2):130-6 (accepted 2013). 

BACKGROUND: High intelligence early in life has consistently been associated with decreased mortality, but the mechanisms are still not fully understood. In this cohort study, we examined the association between intelligence in early adulthood and later mortality from natural and unnatural causes taking birth weight, parental socioeconomic position, participants' own education and body mass index into account. CONCLUSIONS: In men, intelligence in early adulthood was inversely associated with midlife mortality from natural and unnatural causes. The associations remained after adjustments for a range of covariates...

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A prospective cohort study of quality of life and ischemic heart disease. Mikkelsen SS, Mortensen EL, Flensborg-Madsen T. Scand J Public Health. 2014 Feb;42(1):60-6 (accepted 2013). 

AIMS: To examine the role of self-rated quality of life, as a whole, on the risk of developing ischemic heart disease. CONCLUSIONS: Among women, the risk for ischemic heart disease was two to four times greater for those who rated their quality of life as poor or good, than for women with the most positive rating. For men, the association was not statistically significant...

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The effect of acute exercise on collagen turnover in human tendons: influence of prior immobilization period. Moerch L, Pingel J, Boesen M, Kjaer M, Langberg H. Eur J Appl Physiol 113: 449-55, 2013. 

Mechanical loading of human tendon stimulates collagen synthesis, but the relationship between acute loading responses and training status of the tendon is not clear. We tested the effect of prolonged load deprivation on the acute loading-induced collagen turnover in human tendons, by applying the same absolute load to a relative untrained Achilles tendon (2-week immobilization period prior to acute loading) and a habitually loaded contra-lateral Achilles tendon, respectively, within the same individuals.The present study indicates that 2 weeks of tendon load deprivation is not sufficient to affect the normal adaptive response to loading determined as increased collagen synthesis of peritendinous Achilles tendon tissue in humans...

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Personality in late midlife. Associations with demographic factors and cognitive ability. Mortensen EL, Flensborg-Madsen T, Molbo D, Christensen U, Osler M, Avlund K, Lund, R. J Aging Health. 2014 Feb;26(1):21-36 (accepted 2013). 

OBJECTIVES: To analyze associations in late midlife between sex, age, education and social class, and the Big Five personality traits; to analyze associations between personality traits and cognitive ability in late midlife; and to evaluate how these associations are influenced by demographic factors. DISCUSSION: Robust sex, educational, and social class differences in personality may contribute to late midlife social gradients in health and early aging. Demographic factors did not fully explain correlations between personality and cognitive ability or cohort differences in personality...

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The relationship between cognitive ability and demographic factors in late midlife. Mortensen EL, Flensborg-Madsen T, Molbo D, Fagerlund B, Christensen U, Lund R, Osler M, Avlund K. J Aging Health. 2014 Feb;26(1):37-53 (accepted 2013). 

OBJECTIVE: The aim of the article is to analyze associations between sex, age, education, and social class and cognitive ability in late midlife and to evaluate differences in cognitive ability among the three Copenhagen Aging and Midlife Biobank (CAMB) cohorts. DISCUSSION: Late-midlife cognitive ability is associated with a number of demographic factors, and demographic differences may contribute to individual differences in health and early aging. In analyses of cognitive ability, the three CAMB cohorts can be combined provided the relevant demographic variables are included as covariates...

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Smoking and drinking as risk indicators for tooth loss in middle-aged Danes. Morse DE, Avlund K, Christensen LB, Fiehn NE, Molbo D, Holmstrup P, Kongstad J, Mortensen EL, Holm-Pedersen P. J Aging Health. 2014 Feb;26(1):54-71 (accepted 2013). 

OBJECTIVES: To investigate tobacco and alcohol consumption as risk indicators for missing teeth in late middle-aged Danes. DISCUSSION: Our findings suggest that smoking is positively associated, while alcoholic beverage consumption is inversely related to tooth loss in middle-aged Danes...

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Indoor mobility-related fatigue and muscle strength in nonagenarians: a prospective longitudinal study. Mänty M, Ekmann A, Thinggaard M, Christensen K, Avlund K. Aging Clin Exp Res. 2014 Feb;26(1):39-46 (accepted 2013).

BACKGROUND AND AIMS: Mobility-related fatigue is an important indicator of functional decline in old age, however, very little is known about fatigue in the oldest old population segment. The aim of this study was to examine the association between indoor mobility-related fatigue and muscle strength decline in nonagenarians. CONCLUSIONS: Indoor mobility-related fatigue in advanced later life should not merely be considered as an unpleasant symptom, but rather an indicator of physical impairment, and consequently declined physiological reserve...

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Musculoskeletal pain and physical functioning in the oldest old. Mänty M, Thinggaard M, Christensen K, Avlund K. Eur J Pain. 2014 Apr;18(4):522-9 (accepted 2013). 

BACKGROUND: Little is known about the impact of pain on physical functioning among the oldest-old subjects. In this study, we first examined the associations between the number of painful sites and measures of physical functioning reflecting different stages of the disablement process (physical impairment, functional limitation and disability) among nonagenarians (more than ninety years old persons). Second, we described the effect of painful sites on disability during a 2-year follow-up period. CONCLUSIONS: The findings of this study suggest that musculoskeletal pain in nonagenarians is highly prevalent and is associated with poor physical performance and disability...

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Does a history of physical exposures at work affect hand-grip strength in midlife? A retrospective cohort study in Denmark. Møller A, Reventlow S, Hansen ÅM, Andersen LL, Siersma V, Lund R, Avlund K, Andersen JH, Mortensen OS. Scand J Work Environ Health 2013;39(6):599-608. 

OBJECTIVE: The aim of this cohort study was to examine associations between physical exposures throughout working life and hand-grip strength (HGS) in midlife. CONCLUSION: A history of physical exposures at work explained only a minor part of the variation in HGS, though exposure to kneeling throughout working life was associated with a slightly higher HGS among men. Exposure to lifting and standing/walking was not associated with HGS...

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”Social ulighed og gamle mennesker”. Nilsson CJ, Hendriksen C, Vass M. Månedsskrift for Almen Praksis 2013, 91, 937 – 945 (in Danish).

Education and risk of coronary heart disease: assessment of mediation by behavioral risk factors using the additive hazards model. Nordahl H, Rod NH, Frederiksen BL, Andersen I, Lange T, Diderichsen F, Prescott E, Overvad K, Osler M. Eur J Epidemiol 28: 149-57, 2013. 

Educational-related gradients in coronary heart disease (CHD) and mediation by behavioral risk factors are plausible given previous research; however this has not been comprehensively addressed in absolute measures. This study confirms previous claims based on the Cox proportional hazards model that behavioral risk factors partially mediates the effect of education on CHD, and the results seems not to be particularly model dependent...

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Clinically significant changes in the emotional condition of relatives of patients with severe traumatic brain injury during sub-acute rehabilitation. Norup A, Kristensen KS, Poulsen I, Nielsen CL, Mortensen EL. J Rehabil Med 45, 820-826. 

OBJECTIVE: To investigate clinically significant change in the emotional condition of relatives of patients with severe traumatic brain injury during sub-acute rehabilitation. CONCLUSION: Of the relatives who reported scores above cut-off values on the anxiety and depression scales at patient's admission, approximately 40% experienced CSC in anxiety and depression during the patient's rehabilitation. Relatives of patients experiencing improvement during inpatient rehabilitation are more likely to experience CSC in anxiety...

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Neuropsychological intervention in the acute phase: a pilot study of emotional wellbeing of relatives of patients with severe brain injury. Norup A, Siert L, Mortensen EL. J Rehabil Med 2013 Sep;45(8):827-34. 

OBJECTIVE: This pilot study investigated the effects of acute neuropsychological intervention for relatives of patients with severe brain injury. CONCLUSION: Any effects of the acute neuropsychological intervention were limited. Further research is needed to explore the effects of different interventions in more homo-genous and larger groups of relatives...

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Longitudinal Trajectories of Health Related Quality of Life in Danish Family Members of Individuals with Severe Brain Injury. Norup A, Snipes DJ, Siert L, Mortensen,EL, Perrin PB, Arango-Lasprilla JC. Australian Journal of Rehabilitation Counselling, 2, 71-83, 2013. 

Scant research has examined health-related quality of life (HRQoL) in family members of patients with severe brain injury, even less has been done in Scandinavian countries, and none has examined this construct longitudinally. The current study therefore used multilevel modelling to investigate the trajectories of HRQoL in 94 Danish family members of patients with severe brain injury at five time points, beginning at the patient's stay in a neuro intensive care unit through one year after injury...

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Excluding the typical Patients in Thirty Years of Pharmacotherapy Efficacy Trials for Obsessive Compulsive Disorder. Odlaug B, Weinhandl E, Mancebo MC, Mortensen EL, Eisen KL, Rasmussen SA, Schreiber LRN, Grant JE. Ann Clin Psychiatry, in press, 2013. 

BACKGROUND: Over the past 30 years, clinical trials have resulted in several successful pharmacotherapies for obsessive-compulsive disorder (OCD), yet patients in clinical settings often report inadequate response. This study compares clinical characteristics of treatment-seeking OCD patients to the inclusion/exclusion criteria used in pharmacotherapy trials. CONCLUSIONS: The majority of treatment-seeking individuals with OCD would not qualify for OCD treatment studies due to comorbid psychiatric disorders, and failure to meet OCD severity threshold criteria. This illustrates the need to include a more community-representative sample of OCD patients in clinical trials examining pharmacotherapy efficacy...

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Child Behavioural Problems and Body Size among 2-6 Year Old Children Predisposed to Overweight. Results from the “Healthy Start” Study. Olsen NJ, Pedersen J, Händel MN, Stougaard M, Mortensen EL, Heitmann BL. PLoS One. 2013 Nov 8;8(11):e78974. 

OBJECTIVE: Psychological adversities among young children may be associated with childhood overweight and obesity. We examined if an increased level of child behavioural problems was associated with body size among a selected group of 2-6 year old children, who were all predisposed to develop overweight. CONCLUSION: The results suggested a threshold effect between SDQ-TD score and BMI z-score, where BMI z-score was associated with childhood behavioural problems only for those with the highest scores of SDQ-TD. No significant association between PSB score and BMI z-score was found...

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Socioeconomic position early in life, cognitive development and cognitive change from young adulthood to middle-age. Osler M, Avlund K, Mortensen EL. Eur J Public Health 23: 974-980, 2013. 

BACKGROUND: We examine the influence of social circumstances early in life on changes in cognitive function from young adulthood to middle age, and we explore the impact of birth characteristics, childhood activities, education and adult social class on the expected relationship. CONCLUSION: Adverse social circumstances early in life were associated with lower cognitive function at ages 12, 18 and 57 years, as well as with a decline between these ages. Educational status at age 18 years and adult social class seemed to account for most of the associations, whereas childhood activities were independent predictors that did not explain the social inequality...

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Mobility decline in old age. Rantakokko M, Mänty M, Rantanen T. Exerc Sport Sci Revf. 41: 19-25, 2013. 

Mobility is important for community independence. With increasing age, underlying pathologies, genetic vulnerabilities, physiological and sensory impairments, and environmental barriers increase the risk for mobility decline. Understanding how mobility declines is paramount to finding ways to promote mobility in old age.

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Health care service use before and after a natural disaster in survivors with and without PTSD: A prospective and retrospective cohort study. Rosendal S, Mortensen EL, Andersen H, Heir T. Psychiatr Services, in press, 2013. 

Objective This study used a questionnaire to identify individuals who met criteria for posttraumatic stress disorder (PTSD) ten months after surviving a disaster and compared their use of health care services before and after the disaster with that of survivors who did not meet criteria for PTSD. Conclusions Postdisaster health care service utilization was predicted by predisaster health care service utilization and was hardly affected by the onset of PTSD itself. Associations between PTSD and subsequent health problems must be interpreted with caution...

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The effects of low to moderate alcohol consumption and binge drinking in early pregnancy on behaviour in five-year-old children. A prospective cohort study on 1628 children. Skogerbø Å, Kesmodel US, Denny CH, Kjaersgaard MIS, Wimberley T, Landrø NI, Mortensen EL. BJOG 120: 1042-1050, 2013.

OBJECTIVE: To examine the effects of low to moderate maternal alcohol consumption and binge drinking in early pregnancy on behaviour in children at the age of 5 years. CONCLUSION: This study observed no consistent effects of low to moderate alcohol consumption or binge drinking in early pregnancy on offspring behaviour at the age of 5 years...

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Treatment of traumatized refugees with Sertraline versus Venlafaxine in combination with psychotherapy – study protocol for a randomized clinical trial. Sonne C, Carlsson J, Elklit A, Mortensen EL, Ekstroem,M. Trials. 2013 May 11;14:137. 

BACKGROUND: The pharmacological treatments of choice today for post-traumatic stress disorder are antidepressants from the subgroup selective serotonin reuptake inhibitors, especially sertraline. The evidence for the use of selective serotonin reuptake inhibitors in the treatment of complex post-traumatic stress disorder in traumatized refugees is very limited. Venlafaxine is a dual-action antidepressant that works on several pathways in the brain. It influences areas in the brain which are responsible for the enhanced anxiety and hyper-arousal experienced by traumatized refugees and which some studies have found to be enlarged among patients suffering from post-traumatic stress disorder. DISCUSSION: This study is expected to bring forward new knowledge on treatment and clinical evaluation of traumatized refugees and the results are expected to be used in reference programs and clinical guidelines...

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Premorbid teacher-rated social functioning predicts adult schizophrenia-spectrum disorder: A High-risk prospective investigation. Tsuji T, Kline E, Sorensen H, Mortensen E, Michelsen N, Ekstrom M, Mednick S, Schiffman J. Schizophr Res 151: 270-3, 2013. 

Social functioning deficits are a core component of schizophrenia spectrum disorders, and may emerge years prior to the onset of diagnosable illness. The current study prospectively examines the relation between teacher-rated childhood social dysfunction and later mental illness among participants who were at genetic high-risk for schizophrenia and controls (n=244)...

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On the well-being of adult expremies in Denmark. Ulrich M, Mortensen EL, Jensen C, Kamper J. Acta Paediatr 102, 602-606, 2013. 

AIM: To study health, well-being in daily life, educational level and socio-economic status in adulthood in moderately premature infants and the relationship to gender and socio-economic status at birth. CONCLUSION: Moderately premature infants, born before the era of intensive care, at the age of 32 years with regard to health, quality of life, education and social status proved to fare as well as their term counterparts...

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Psychological predictors of mental health and health-related quality of life after bariatric surgery: A review of the recent research. Wimmelmann CL, Dela F, Mortensen EL. Obes Res Clin Pract in press, 2013. 

Background: Improvement of mental health and health-related quality of life (HRQOL) is an important success criterion for bariatric surgery. In general, mental health and HRQOL improve after surgery, but some patients experience negative psychological reactions postoperatively and the influence of pre-surgical psychological factors on mental wellbeing after surgery is unclear. The aim of the current article therefore is to review recent research investigating psychological predictors of mental health and HRQOL outcome. Conclusion: Certain psychological factors appear to be important for mental health and HRQOL after bariatric surgery. However, the literature is extremely sparse and further research is highly needed...

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Psychological predictors of weight loss after bariatric surgery: A review of the recent research. Wimmelmann CL, Dela F, Mortensen EL. Obes Res Clin Pract: Received 13 May 2013; received in revised form 9 September 2013; accepted 16 September 2013. Published online 14 October 2013. 

Background: Morbid obesity is the fastest growing BMI group in the U.S. and the prevalence of morbid obesity worldwide has never been higher. Bariatric surgery is the most effective treatment for severe forms of obesity especially with regard to a sustained long-term weight loss. Psychological factors are thought to play an important role for maintaining the surgical weight loss. However, results from prior research examining preoperative psychological predictors of weight loss outcome are inconsistent. The aim of this article was to review more recent literature on psychological predictors of surgical weight loss. Conclusion: In general, recent research remains inconsistent, but the findings suggest that pre-surgical cognitive function, personality, mental health, composite psychological variables and binge eating may predict post-surgical weight loss to the extent that these factors influence post-operative eating behaviour...

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CAMB – En ressource for fremtidig aldringsforskning. VILLUM FONDENs og VELUXFONDENs årsskrift 2012. Avlund K. 2013

CAMB – A resource for future aging research. THE VILLUM FOUNDATION AND THE VELUX FOUNDATION’S annual yearbook. Avlund K. 2013

Disability in old age – the relationship with oral health. Avlund K. In: Holm-Pedersen P, Walls A, Ship J. Textbook of Geriatric Dentistry, 3rd edition. In press, 2013. Publication Date: June 9, 2014.

Træthed som led i aldringsprocessen: En indikator på sårbarhed? Avlund K, Waller L, Kjær M. I: Jennum P (ed). Søvn. Munksgaard Danmark. Kapitel 20, 219-226, 2013.

Palliativ Indsats for KOL-patienter: En deskriptiv Undersøgelse af Danske KOL patienters Sygdomsforløb og behov for palliativ Indsats. Marie Gade Husted, Nicolai Kirkegaard, Margit Kriegbaum, Helle Timm, Peter Lange. Danmarks Lungeforening, København

Sundhed og sociale netværk. Lund R, Nilsson CJ. I: Grit Niklasson (ed.) Sundhed, Menneske og Samfund. Samfundslitteratur 2013: 271-293. (in Danish)

“Forebyggelse og rehabilitering i et aldrende samfund”. Hansen EB, Nilsson CJ. Ugeskrift for Læger 2013, 12, 796 (in Danish).

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”Social ulighed og gamle mennesker”. Nilsson CJ, Hendriksen C, Vass M. Månedsskrift for Almen Praksis 2013, 91, 937 – 945 (in Danish). 

Ældre er lige så forskellige som andre patienter, og skal behandles individuelt. Gruppen er imidlertid karakteriseret af en stigende social og helbredsmæssig sårbarhed, og den sociale ulighed i sundhed er til stede højt op i alderen. Almen praksis har en central rolle over for et progredierende funktionstab samt ved de risikofyldte sektorovergange. Artiklen beskriver den eksisterende viden på området og anviser handlemuligheder for den praktiserende læge, der kender sine ældre patienter.

 Program 4 - Society and CultureTil toppen

Ældre Migranters sundhed – en ny udfordring for sundhedsvæsenet. I: Ældre med anden etnisk baggrund – viden og inspiration til indsats[ Elderly migrants Health – a new challenge for the Health Care system. In: Elderly with a different ethnic background – knowledge and inspiration for action]. Kessing LL, Krasnik A. Ældreforum [Ageforum], Oktober 2013; S.38-41.

Migrants use of healthcare in their country of origin in Lunt N, Hanefeld J, Horsfall D (eds). Nielsen SS, Handlos LN. Elgar Handbook on Medical Tourism and Patient Mobiliy. London, Edward Elgar, 2014. (chapter submitted in 2013, book will be published in 2014)

Adherence to preventive statin therapy according to socioeconomic position. Wallach-Kildemoes H, Andersen M, Diderichsen F, Lange T. Eur J Clin Pharmacol. 2013 Aug;69(8):1553-63. doi: 10.1007/s00228-013-1488-6. 

AIM: To explore whether long-term adherence to preventive statin therapy depends on socioeconomic position (SEP). CONCLUSION: Adherence to preventive statin therapy in Denmark decreases with decreasing income-especially in men aged 40-64 years...

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Ulighed i sundhed og forebyggelse af hjertekar sygdom med stationer [Inequalities in health and prevention of cardiovascular disease with statins]. Wallach-Kildemoes H, Andersen M, Diderichsen F, Lange T, Krasnik A. Månedsskrift for Almen Praksis [Journal for General Practice], 2013

Childhood Socioeconomic Position, young adult intelligence and fillings of prescribed medicine for the prevention of cardiovascular disease in middle-aged men. Kriegbaum M, Wallach-Kildemoes H, Norgaard Rasmussen J, Hendriksen C, Vass M, Lykke Mortensen E, Osler M. BMJ Open. 2014 Jan 17;4(1):e004178. 

OBJECTIVES: To explore the relationship between childhood socioeconomic position (SEP) and filling of medicine prescriptions for prevention of cardiovascular diseases (CVDs), with young adult intelligence (IQ) as a potential mediator. CONCLUSIONS: Low childhood SEP was related to more frequent initiation of and poorer refill persistency for statins. IQ in young adulthood explained most of the association between childhood SEP and initiation of statins, but had no impact on refill persistency...

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Sociale relationer her og hisset: minder og forbundethed blandt slægtninge efter livets afslutning [Social relationships here and the beyond: memories and connectedness among relatives after the end of life], pp. 55-72. Ludvigsen B, Steffen V. In Hanne O. Mogensen and Olwig, K.F. (ed.), Familie og Slægtskab Antropologiske perspektiver [Family and Relationship Anthropological Perspectives], 2013. Frederiksberg: Samfundslitteratur.

Informeret samtykke i kliniske forsøg: teknikaliteter, tillid og tætte relationer [Informed consent in clinical trials: technicalities, trust and close relationships]. Wadmann S. Etikk i Praksis [Ethics in Practice], 2013 7(2):31-46.

Beyond the therapeutic misconception: Research, care and moral friction. Wadmann S, Hoeyer K. BioSocieties (2014) 9, 3–23 (accepted 2013). 

In research ethics regulation, health care and research are depicted as serving distinct goals, and policies are in place to prevent what is seen as patients’ misconceived understanding of research as health care. On the basis of ethnographic research in four Danish hospitals in conjunction with a cardiovascular drug trial in patients with chronic disease, we argue that the objectives of health care and research often merge in mutually constitutive practices. We conclude that the presentation of the research-care tension as an ethical dilemma is misleading and even part of the problem that must be dealt with by those involved...


Positionings in healthcare: diabetes training for Arabic-speaking immigrants. Ahlmark N, Whyte SR, Curtis T, Tjørnhøj-Thomsen T. Health Education, Vol. 114 Iss: 2, pp.133 - 151. 

The purpose of this study is to explore how healthcare professionals in Denmark perceived and enacted their role as diabetes trainers for Arabic-speaking immigrants in three new local authority settings. The paper used positioning theory, which is a dynamic alternative to the more static concept of role in that it seeks to capture the variable, situationally specific, multiple and shifting character of social interaction, as the analytical tool to examine how people situationally produce and explain behaviour of themselves and others...

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The publics of the New Public Health: life conditions and ‘lifestyle diseases’ in Uganda. Whyte SR. In: Ruth J. Prince and Rebecca Marsland (eds.) Making Public Health in Africa: Ethnographic and Historical Perspectives. Athens, OH: Ohio University Press. 2013

The visibility of non-communicable diseases in northern Uganda. Whyte SR, Park SJ, Odong G, Ojara M, Lamwaka A. African Health Sciences. Accepted.

 Program 5 - Health Promotion and Innovation Til toppen

A Question of Location – Life with Fatigue after Stroke, Andersen, M, PhD Thesis, 2013. 

This thesis treats the experiences of fatigue after stroke. Based on a qualitative fieldwork conducted among people who have had a stroke, it explores how they experience fatigue. This is done by way of an ethnological examination of how the informants locate fatigue in their everyday lives. By approaching their location as both place and practice, it is illustrated how a stroke may dislocate and relocate the experience of fatigue and how a new location of fatigue calls for new meaningful contexts in everyday life.

”Et rigtigt menneske” – folkloristiske fortolkninger af en kvindes fortællinger om arbejds- og familieliv i et livshistorisk perspektiv. Blaakilde, AL. Pp. 202-228 in Folkloristikens aktuella utmaninger. Red. Owe Ronström, Georg Drakos og Jonas Engman. Gotland University Press. 2013

Introduction. Mobility and Migration in Later Life. Blaakilde, AL and Nilsson, G. Pp. 9-26 in Blaakilde and Nilsson (Eds.): Nordic Seniors on the Move. Mobility and Migration in later life. Lund Studies in Arts and Cultural Sciences Vol 4. December 2013.

A Challenge to the Danish Welfare-State: How International Retirement Migration and Transnational Health-Promotion Clash with National Policies. Blaakilde, AL. Pp. 1977-204 in Blaakilde and Nilsson (Eds.): Nordic Seniors on the Move. Mobility and Migration in later life. Lund Studies in Arts and Cultural Sciences Vol 4. December 2013.

Unsettling successful ageing. A history and queering of the concept of successful ageing in ageing research, Bülow, M.H., PhD Thesis, 2013. 

The main part of this project investigates the history of the concept of ‘successful ageing’, tracing its reception within ageing research since Rowe and Kahn’s seminal article in 1987. As part of an expanding research field – and touching upon several key ideas and debates about ageing and the role of ageing research – the history of ‘successful ageing’ contains several issues relevant to the broader field of ageing research and biomedicine. Another important part of the project engages more directly with ethical and normative issues within ageing research, particularly addressing norms of embodied subjecthood, and the subject of frailty and vulnerability...

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Good old brains. How notions of human enhancement and concerns about the ageing societies interact in neuroscience. Bülow, M.H. (accepted). Rehmann-Sutter, C., Eilers, M. & Grüber, K. (eds.). The Human Enhancement Debate and Disability. New Bodies for a Better Life? Palgrave Macmillan.

Compliance with physical exercise: Using a multidisciplinary approach within a dose-dependent exercise study of moderately overweight men. Gram, AS , Bønnelycke, J , Rosenkilde Larsen, M , Reichkendler, M , Auerbach, P , Sjödin, A , Ploug, T , Jespersen, A & Stallknecht, B. Scand J Public Health. 2014 Feb;42(1):38-44. 

AIMS: Sixty-one healthy, sedentary, moderately overweight young men participated in a randomised controlled trial to examine the effects of two different doses of endurance exercise on health behaviour and exercise compliance. CONCLUSIONS: A multidisciplinary approach provided explanations for similar effects of two different doses of exercise. This could not have been determined via either qualitative or quantitative methodology alone. The preconditions of the TBP were fulfilled, and it represents a methodological model to explain the high degree of compliance and motivation to exercise...

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Careful science? Bodywork and care practices in randomised clinical trials. Jespersen, A , Bønnelycke, J & Eriksen, HH. Sociology of Health and Illness , vol 35, nr. 8., 2013. 

Concern about obesity has prompted numerous public health campaigns that urge people to be more physically active. The campaigns often include normative statements and attempt to impose restrictions on individuals' lives without considering the complexities of daily life. We suggest that broadening the focus to reflect everyday practices would foster better targeted public health campaigns. This article is based on our participation in FINE, a multidisciplinary Danish research project. The core methodology of FINE was a randomised controlled trial in which 61 moderately overweight men were put into different exercise groups. In this article we analyse the scientific work of the trial as representing entangled processes of bodywork, where data are extracted and objectified bodies are manipulated and care practices address the emotional, social and mundane aspects of the participants' everyday lives. Care practices are an inherent part of producing scientific facts but they are removed from the recognised results of scientific practice and thus from common public health recommendations. However, knowledge about the strategic use of care practices in lifestyle interventions is important for public health initiatives and future efforts should incorporate this aspect.

Innovating for ‘active ageing’ in a public-private innovation partnership: Creating doable problems and alignment. Lassen, A.J., Bønnelycke, J and Otto, L. Technological Forecasting and Social Change. Accepted 2013. 

By focusing on different constructions of the elderly and how these definitions are aligned within a Danish public–private innovation partnership called No Age, the article examines how various understandings of ‘the elderly’, ‘active ageing’ and ‘health’ clash and entangle in innovation work. The ambition of No Age is to create welfare technologies for elderly people. The authors were invited to contribute ethnographic insights to the partnership. We argue that the No Age's innovation process creates doable problems by co-producing technological solutions, their users and the health issues the products are designed to address. Furthermore, we argue that the specific constellation and alignment of actors in such a partnership define how and what kinds of users are constituted, as the target groups and success criteria for the development of welfare technologies are shaped throughout the innovation process rather than decided at the beginning. This has implications for the role of ethnographers as providers of user-insights in health-related innovation projects.

Billiards, rhythms, collectives – Billiards at a Danish activity centre as a culturally specific form of active ageing. Lassen, A.J. Ethnologia Europaea. Accepted 2013.

Negotiating a healthy body in old age: preventive home visits and biopolitics. Otto, L. International Journal of Ageing & Later Life. 2013, Vol. 8 Issue 1.

 AndetTil toppen

The Meaning of Ageing. Otto, L. Anmeldelse af Åsa Alftberg: Vad är det att åldras? En etnologisk studie av åldrande, kropp och materialitet Arv. 2013:1 , 4 s.