Publications 2016 – Københavns Universitet

Publications 2016

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

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


Theme 1

Andersen I, Brønnum-Hansen H., Kriegbaum M., Hougaard CØ, Hansen FK, Diderichsen F. "Increasing illness among people out of labor market - A Danish register-based study." Soc Sci Med. 2016 May; 156:21-8.

Abstract

In spite of decades of very active labor market policies, 25% of Denmark's population in the working ages are still out-of-work. The aim of this study was to investigate whether that is due to consistent or even increasing prevalence of ill health. During the study period, the prevalence of cardiovascular diseases and mental disorders increased among both employed and non-employed people. The increased prevalence for mental disorder was particularly high among people receiving means-tested benefits. Disease incidence was higher among people outside rather than inside the labor market, especially for mental disorders. Employed people with incident diseases had an unsurprisingly increased risk of leaving the labor market. However, a high proportion of people with incident mental disorders received low level means-tested benefits in the three years following this diagnosis, which is concerning. Men treated for mental disorders in 2006 had high excess probability of receiving a cash-benefit, OR = 4.83 (4.53-5.14) for the period 2007-2010. The estimates were similar for women.

See article online.


Baig, Naveed; Kristiansen, Maria. "Intensivsygepleje for muslimske patienter : Intensive nursing care for Muslim patients." in "Intensivsygepleje." red. / Birte Baktoft; Lise Wolder. 1. udg. København K. : Nyt Nordisk Forlag Arnold Busck, 2016. s. 150-158.


Bechshoeft, RL; Reitelseder, S; Højfeldt, GW; Castro-Mejía, JL; Khakimov, B; Bin Ahmad, HF; Kjær, M; Engelsen, SB; Johansen, SMB; Rasmussen, MA; Lassen, AJ; Jensen, T; Beyer, N; Serena, A; Perez-Cueto, FJA; Nielsen, DS; Jespersen, AP and Holm, L. "Counteracting Age-related Loss of Skeletal Muscle Mass: A Randomized Clinical and Ethnological Trial on the Role of Protein Supplementation and Training Load - Rationale, Design and Methods (CALM Intervention Study)." Trials, 17:397, 2016.

Abstract

Aging is associated with decreased muscle mass and functional capacity, which in turn decrease quality of life. The number of citizens over the age of 65 years in the Western world will increase by 50 % over the next four decades, and this demographic shift brings forth new challenges at both societal and individual levels. Only a few longitudinal studies have been reported, but whey protein supplementation seems to improve muscle mass and function, and its combination with heavy strength training appears even more effective. However, heavy resistance training may reduce adherence to training, thereby attenuating the overall benefits of training. We hypothesize that light load resistance training is more efficient when both adherence and physical improvement are considered longitudinally.

See article online


Bybjerg S, Agyemang C, Zwisler AD, Krasnik A, Norredam M. "Cardiovascular disease incidence and survival: Are migrants always worse off?" European Journal of Epidemiology 07/2016;31(7):667-77

Abstract

Studies on cardiovascular disease (CVD) incidence and survival show varying results between different ethnic groups. Our aim was to add a new dimension by exploring the role of migrant status in combination with ethnic background on incidence of-and survival from-CVD and more specifically acute myocardial infarction (AMI) and stroke. Both male and female family-reunified immigrants had significantly lower incidence of CVD, AMI and stroke. All-cause and cause-specific survival after CVD, AMI and stroke was similar or significantly better for migrants compared to Danish-born, regardless of type of migrant (refugee vs. family-reunified) or country of origin. Refugees are disadvantaged in terms of some types of cardiovascular disease compared to Danish-born. Family-reunified migrants on the other hand had lower rates of CVD. All migrants had better survival than Danish-born indicating that migrants may not always be disadvantaged in health.

See article online


Bødker M. "The potentially independent – identifying and realising potential in older people through reablement." Ageing & Society. Accepted 2016.


Christensen CL, Wulff Helge J, Krasnik A, Kriegbaum M, Rasmussen LJ, Hickson ID, Liisberg KB, Oxlund B, Bruun B, Lau SR, Olsen MN, Andersen JS, Heltberg AS, Kuhlman AB, Morville TH, Dohlmann TL, Larsen S, Dela F. "LIFESTAT - Living with statins: An interdisciplinary project on the use of statins as a cholesterol-lowering treatment and for cardiovascular risk reduction." Scand J Public Health. 2016 Jul;44(5):534-9

Abstract

LIFESTAT is an interdisciplinary project that leverages approaches and knowledge from medicine, the humanities and the social sciences to analyze the impact of statin use on health, lifestyle and well-being in cohorts of Danish citizens. The impetus for the study is the fact that 10% of the population in the Scandinavian countries are treated with statins in order to maintain good health and to avoid cardiovascular disease by counteracting high blood levels of cholesterol. The potential benefit of treatment with statins should be considered in light of evidence that statin use has prevalent and unintended side effects (e.g. myalgia, and glucose and exercise intolerance).

See article online


Christensen LKT. "Når institutionen træder ind over dørtærsklen." In Lotz K et al. (ed.): Form til Velfærd. Accepted. Expected publication ultimo 2016.


Christensen LKT. "Selvhjulpenhed som moralsk imperativ. Bag om fænomenet hverdagsrehabilitering." In Oxlund B. (ed.): Aldringens Veje. Accepted.


Handlos LN, Kristiansen M, Norredam M. "Wellbeing or welfare benefits – what are the drivers for migration?" Scandinavian Journal of Public Health. 44(2):117-9, 2016.

Summary
Strong voices in public debates on the rising number of immigrants in Europe are advocating that immigrants who come to European countries, to a large extent, are driven by a quest for maximization of access to welfare benefits [1,2]. This argument is fueling some European immigration policy making, which more or less explicitly assumes that the primary driver behind migrant flows is money. In our research we have explored what drivers lie behind return migration among Bosnian refugees who have residence permits in Denmark and who, therefore, have complete access to welfare services, including healthcare services. The decision-making process that shapes where migrants, and particularly refugees, choose to seek asylum is considerably more complex than it is portrayed in public debates and in some policies currently underway; it cannot simply be concluded that the size of welfare services in a country is a major determining factor. Instead, studies point towards a pursuit for safety, employment opportunities, social networks and overall wellbeing. The cut in welfare services to immigrants that many European countries either consider or are implementing are, therefore, pointless if the aim is to decrease the number of people seeking asylum in their country.

See article online


Jensen T. The Importance of Age Perceptions and Nutritional Science to Early Twentieth-century Institutional Diets. Social History of Medicine. 158-174. 20 June 2016.

Summary

Scholars agree that increased intermingling of science and policy was a characteristic of the nineteenth and twentieth centuries. Within the realm of food this development has been named ‘nutrification’ or the ‘paradigm of nutritionism’. This article investigates this development in early twentieth-century Scandinavia. The thesis is that societal perceptions of age and age-related food habits influenced the pace and degree to which nutritional knowledge was integrated into and affected institutional diets. The analysis is based on dietary regulations for Danish elderly homes. In order to inform discussions around the importance of age perceptions to the nutrification of institutional food, the findings are compared with research on school meals in Norway and Denmark. The analysis concludes that age perceptions greatly influenced the extent to which diets changed in public institutions. As a result, nutrification was a process with unevenly distributed effects among Scandinavian populations.

See article online


Jensen T, Bechschøft RL, Giacalone D, Otto MH, Bin Ahmad, HF, Reitelseder S, Jespersen AP. "Whey protein stories. An experiment in writing a multidisciplinary biography".  Appetite, 285-294. 2016.

Abstract

This is an experimental, dual-purpose article about whey protein and how to conduct interdisciplinary analyses and writings. On the one hand, this article is a multidisciplinary commodity biography, which consists of five descriptions of whey protein written by the five different research groups involved in the interdisciplinary research project CALM(Counteracting Age-related loss of Skeletal Muscle Mass). On the other hand, it is a meta-analysis, which aims to uncover and highlight examples of how the five descriptions contribute to each other with insights into the contextualisation of knowledge, contrasts between the descriptions and the new dimensions they bring to established fields of interest. The meta-analysis also contains a discussion of interdisciplinary study objects and the usefulness of the multidisciplinary commodity biography as a format for interdisciplinary publications.

See article online


Krasnik A. "Categorizations of migrants and ethnic minorities — are they useful for decisions on public health interventions?" Editorial in European Journal of Public Health, DOI: 907. First published online: 15 September 2015.

Decisions regarding population-based preventive interventions require convincing measures of health and risks. Is it justified to initiate special community programs on diabetes prevention among migrants on the basis of a higher prevalence of diabetes than in the non-migrant population? Even as we know that diabetes is not a problem for the majority of the migrants? And that diabetes is also a problem for many non-migrants—however less prevalent? Relative risks and differences in prevalence of risks and diseases between groups are often used to justify such new programs for selected groups and communities based on certain characteristics such as ethnicity, migrant status, family situation or socio-economic position.

See article online


Kristiansen M, Adamsen L, Brinkmann FK, Krasnik A,  Hendriksen C. "Need for strengthened focus on cancer rehabilitation in Danish municipalities" in Danish Medical Journal. 62, 4. 2015.

Danish municipalities have recently been given a mandate to organise cancer rehabilitation services. Knowledge is therefore needed about the services provided and their utilisation. The aim of this national Danish baseline survey was to explore the availability, utilisation, content and organisation of municipal cancer rehabilitation services. Electronic questionnaires were sent to all 98 Danish municipalities in January 2013. The questionnaire consisted of closed-ended and open-ended questions. Descriptive statistics and contents analysis were used. A total of 91 municipalities responded (93% response rate). Of these, 75% reported that they provided cancer rehabilitation services. The number of patients enrolled was below the estimated proportion of patients needing rehabilitation services. Services consisted predominantly of physical training in groups, followed by "stop smoking" courses, dietary advice, physical training guidance, patient education and individual physical training. Inequality in referral by ethnicity, age and gender was reported. Challenges encountered included low patient numbers, inadequate collaboration within and across sectors and lack of evidence-based models for cancer rehabilitation. There is a need for increased capacity and improved alignment between patients' rehabilitation needs and the available services.

See article online


Kristiansen M, Dhami S, Netuveli G, Halken S, Calderón MA, Penagos M, Muraro A, Roberts G, Du Toit G, Kleine-Tebbe J, Larenas-Linnemann D, Lau S, Matricardi PM, Pajno G, Papadopoulos NG, Pfaar O, Ryan D, Santos AF, Timmermanns F, Wahn U, Sheikh A. "Allergen immunotherapy for the prevention of allergy: a systematic review and meta-analysis" in Pediatric Allergy and Immunology. Accepted, 2016.

Abstract
There is a need to establish the effectiveness, cost-effectiveness, and safety of allergen immunotherapy (AIT) for the prevention of allergic disease. Two reviewers independently screened nine international biomedical databases. Studies were quantitatively synthesized using random-effects meta-analyses. A total of 32 studies satisfied the inclusion criteria. Overall, meta-analysis found no conclusive evidence that AIT reduced the risk of developing a first allergic disease over the short term (RR = 0.30; 95% CI: 0.04-2.09) and no randomized controlled evidence was found in relation to its longer-term effects for this outcome. There was, however, a reduction in the short-term risk of those with allergic rhinitis developing asthma (RR = 0.40; 95% CI: 0.30-0.54), with this finding being robust to a pre-specified sensitivity analysis. We found inconclusive evidence that this benefit was maintained over the longer term: RR = 0.62; 95% CI: 0.31-1.23. There was evidence that the risk of new sensitization was reduced over the short term, but this was not confirmed in the sensitivity analysis: RR = 0.72; 95% CI: 0.24-2.18. There was no clear evidence of any longer-term reduction in the risk of sensitization: RR = 0.47; 95% CI: 0.08-2.77. AIT appeared to have an acceptable side effect profile. AIT did not result in a statistically significant reduction in the risk of developing a first allergic disease. There was, however, evidence of a reduced short-term risk of developing asthma in those with allergic rhinitis, but it is unclear whether this benefit was maintained over the longer term. We are unable to comment on the cost-effectiveness of AIT.

See article online


Kristiansen M, Sheikh A. "The Health Profile of Muslims in Scotland" in: Muslims in Scotland, P. Hopkins (ed). Edinburgh University Press. Accepted. In press, 2016.


Lassen AJ and Jespersen AP. "Getting old and keeping going: The motivation techniques of active ageing in Denmark" in Lamb, S (ed.): Successful aging? Global perspectives on a contemporary obsession. Rutgers University Press. Accepted, in print. 2017.


Lassen, AJ. "Aktiv aldring imellem hverdag og policy: En etnologisk analyse af hvordan aktiv aldring former det gode ældreliv" in Oxlund, B (ed.) Aldringens veje. Frydenlund. Accepted. 2016.


Lassen, AJ. "Forming old age: Innovation partnerships, activity centers and billiards tables as active ageing technologies" in Majerus, B. (ed.) Framing age: Contested knowledge in science and politics. Routledge. Accepted, in print. 2016.


Lassen AJ and Andersen MC. "What enhancement technologies suggest about the good death" Culture Unbound, 8:2, 2016.

Abstract
The contemporary increase in life expectancy in Western countries has led to an intensified focus on good ageing processes as a way to manage ageing populations. We argue that while qualifications of the ageing process such as active and healthy ageing endeavour to compress morbidity through enhancement techniques, the idea of the good old age also implicitly tells a tale about the ‘good’ death. We explore how current discourses depict old age as an active, engaged and independent life phase and construct a specific idea of the good death as one that is quick and painless. By engaging with literature on ageing, death and enhancement technologies as well as current Danish healthcare initiatives, we examine the paradoxical, contemporary notion of death as natural, quick, painless and controllable. Danish rehabilitation programmes are provided as an example of specific enhancement techniques that through motivation and physical activity orchestrate the good death in a body that has been as healthy as possible for as long as possible. However, when such techniques become a moral injunction rather than a choice, questions arise concerning the relationship between autonomy and death. We argue that the discursive construction of the good death happens in tandem with enhancement techniques that postpone death, and that this postponement of death has increasingly become more of an imperative than an autonomous decision.

See article online


Lidegaard L, Schwennesen N, Williang I and Færch K.  "Barriers and motivators for physical activity among overweight and obese people with type 2 diabetes: patients perspectives" in Diabetic Medicine, early view DOI: 10.1111/dme.13167, 2016

Abstract
To explore barriers to and motivators for physical activity in a group of overweight and obese individuals with dysregulated Type 2 diabetes. Data were collected from the Steno Diabetes Center's outpatient clinic in Denmark. Four focus groups were conducted including 28 individuals with Type 2 diabetes aged 39-71 years. The facilitators used open-ended questions and probes such as images, statements and quotations about physical activity to foster active participation and interaction among participants. Focus groups were recorded on video and the discussions were transcribed and analysed thematically. We identified four main themes: 1) the body as a barrier to physical activity because of functional limitations; 2) logistical challenges, including lack of time and awareness of where to exercise in the local area; 3) being physically active with others, providing a sense of mutual commitment and enjoyment; and 4) goal-setting and self-tracking, which was seen as an opportunity to track physical improvement over time. The findings suggest that, once people are active, a high level of social interaction may help maintain their activity levels. Further research is needed to investigate the effect of combining individually tailored exercise plans with the establishment of customized and locally based exercise communities that offer enjoyment and support. Additionally, it is relevant to explore experiences of using self-tracking technologies to review short- and long-term goals.

See article online


Lokdam N, Kristiansen M, Handlos LN, Norredam M. "Use of healthcare services in the region of origin among patients with an immigrant background in Denmark: a qualitative study of the motives" in BMC Health Services Research. 16(1):99, 2016.

Abstract
In Denmark, immigrants have been found to have a higher use of healthcare services abroad. Since this use may have an impact on both the individual patient and the healthcare system in the country of residence, research into underlying reasons is of increasing relevance. This study therefore investigates what motives patients with an immigrant background have for seeking healthcare services in their region of origin. The study was based on 10 semi-structured interviews with 10 patients who had an immigrant background, primarily originating from Turkey and the Middle East, recruited at a clinic of immigrant medicine in Denmark. The interviews were analysed thematically to elucidate motives for seeking healthcare services abroad, with focus on identifying push and pull factors. Four motives for seeking healthcare in the region of origin were salient in the material: the perception of availability, in terms of quantity and access; familiarity, conceptualised as feeling comfortable within the healthcare system; perception of quality of services; and finally, the perceived need for a second opinion. All motives emerged simultaneously as push factors, motivating immigrants to explore healthcare services abroad, and pull factors, attracting them to their country of origin. Affordability did not emerge as an independent motive but influenced the other factors. The use of healthcare services abroad by patients with an immigrant background constitutes active health-seeking behaviours shaped by a range of factors perceived to be limiting access to high-quality services in Denmark. Further research, including quantitative studies, should be initiated to investigate the importance of these motives among larger, more diverse immigrant groups, consequences for treatment regimes, and the healthcare professionals’ perspective on the use of healthcare in the region of origin among immigrant patients.

See article online


Ludvigsen B. "Når ældre mennesker bliver gamle. Betydningen af velfærdsstaten og medborgerskabet" in Tidsskriftet Antropologi. nr. 73, 2016.

See article online


Ludvigsen B. "Market thinking and home nursing. Perspectives on new socialities in health care in Denmark" in Hadolt, Bernhard & Anita Hardon (eds) New Socialities and Subjectivities in 21st Century Health Care. Amsterdam: Amsterdam University Press. Accepted, in press, 2016.


Ludvigsen B. "Ældre mennesker, medicin og sociale relationer"  in Glasdam, S (red.) Perspektiver på primær sundhedstjeneste – møder mellem mennesker. Nyt Nordisk Forlag Arnold Busck / Schønberg, København. Accepted. Expected publication in 2016.


Mikkelsen HM. "Unthinkable Solitude: Successful Aging in Denmark through the Lacanian Real". Ethos. Volume 44, Issue 4, p. 448–463, December 2016

Abstract

Within recent years, loneliness has been identified as one of the key threats to the well-being of the elderly in the Danish welfare society, and the tendency to view solitary seniors in terms of “loneliness” and “social isolation”—along with the attempts to reintegrate these solitary seniors into society—reveals how solitude is being tied to detrimental states of existence. Based on an ethnographic fieldwork among healthcare workers and solitary elderly men in the rural area of southern Sealand, Denmark, this article lays out the Danish configuration of what has been called the paradigm of “successful aging.” However, not only is the attention to loneliness among Danish eldercare professionals a sign of an inherent fear; at the same time, I will argue, it reveals an inherent inability to conceptualize “solitude” as other than “loneliness.” By employing the concept of the Real—the enigmatic realm within Lacanian psychoanalysis that represents the limit of language—the aim of this article is to uncover how the current discourse on successful aging renders solitude “unthinkable.”

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Norredam M, Sheikh A, Dynnes Svendsen K, Holm Petersen J, Garvey LH, Kristiansen M. "Differences in Hospital Attendance for Anaphylaxis between Immigrants and Non-immigrants: a Cohort Study". Clinical and Experimental Allergy. Accepted, in press. 2016.

Abstract

We investigated variations in hospital attendance for anaphylaxis between immigrants and Danish-born including time- and age- trends. In total 1053 hospital attendances for anaphylaxis were identified: 89 among non-Western immigrants, 9 among Western immigrants and 955 among Danish-born patients. Both male and female non-Western immigrants had a significantly lower risk ratio of hospital attendance for anaphylaxis compared to Danish-born. Compared to Danish-born, non-Western immigrants living in Denmark during the entire follow-up period also showed a decreased risk. Compared to Danish-born, non-Western immigrants who obtained residence permission as children had a decreased risk of hospital attendance for anaphylaxis. This Danish register-based study using nationwide data revealed fewer hospital attendances for anaphylaxis among non-Western immigrants compared to Danish born; however this protection was lost over time.

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Nørtoft  K. "When Anna moved to a nursing home: Empathic movements between self and others in the decision making and process of moving". In: Endter, C. & S. Kienitz (eds.): Alter(n) als soziale und kulturelle Praxis. Ordnungen – Beziehungen – Materialitäten. Bielefeld: Transcript Verlag. 2016.


Nørtoft K. "Motion: fra politik til hverdagspraksis". In: Glasdam, S. & J. W. Jørgensen (eds.): Det Nære Sundhedsvæsen. Munksgaard. 2016.


Nørtoft K. "Alderdommens pædagogisering: samfundsøkonomi, sundhed og individualiserede pædagogiske relationer". In: Oxlund, B. (ed.): Aldringens veje: Sundhed og socialitet i danske livsforløb. Frydenlund. Accepted. 2016


Oxlund B. (ed.): Aldringens veje: Sundhed og socialitet i danske livsforløb. Frydenlund. Accepted, in press. 2016.


Oxlund B. "Unsettling Care and Creolizing Culturally Informed Scripts of Aging: Theoretical Approaches to the Later Life Course in a Migrating World". In: Caring on the move: Ethnographic Explorations of Aging and Migration Across Societies. Edited by Azra Hromadzic and Monica Palmberger. Brooklyn and Oxford: Berghahn Books. Accepted, in press. 2016.


Schwennesen N. "Et omsorgsfuldt (selv)bedrag? Om brug af robotter der imiterer mennesker i ældreplejen". Gerontologi. 32:1, p. 28-33. 2016.

Abstract
This paper discusses the use of care-robots with outset in Sander Burgers documentary from 2015, Alice Cares. The documentary follows three elderly women from the Netherlands who lived with the robot Alice in their home as part of a research project. By using analytical tools from Science and Technology Studies the article explores how care is expressed in the relationship between the women and the robot Alice. The article argues that care and technology are not necessarily oppositional entities, while technology is part of a socio-technical infrastructure that involves both social and technical elements. A willingness to tinker with the technology in order to make it fit with the users situation and experienced problems is of central importance for whether the robot is experienced as careful. Finally it is argued that the three women expresses a tactical engagement with the robot Alice, as they on the one hand take care of it and interact with it as if it was a human being and on the other hand de-emphasize its worth to relatives and care-workers. 

See article online


Schwennesen N, Bødker M, Christensen LKT. "Ageing at home: The configuration of home in a paradigm of ‘ageing in place’". Ageing & Society. Accepted.


Schwennesen N, Henriksen JE and Willaing I. "Patient explanations for non-attendance at type 2 diabetes self-management education: a qualitative study". Scandinavian Journal of Caring Sciences. 30:1, p. 187-92, 2016.

Abstract

In this study, patients cited both individual and organisational factors as explaining non-attendance at type 2 diabetes self-management education. Further studies should take into account the importance of timing and of tailoring schedules and content to individuals’ life situations and resources. As organisational factors are likely to vary across programmes and settings, more case studies are needed to further elucidate the dynamic relationship between individual and organisational factors to explain non-attendance at type 2 diabetes self-management education.

See article online


Vrangbaek K. "Patient involvement in Danish health care" in Journal of Health, Organization and Management. 29, 5, p. 611-24 14. 2015.

Abstract
The paper presents a preliminary framework for analysis of patient involvement in health care. This framework is used to analyze key governance features of patient involvement in Denmark based on previous research papers and reports describing patient involvement in Danish health care. Patient involvement is important in Denmark at the rhetorical level, and many policies and initiatives have been introduced. All three governance forms (voice, choice and co-production) are used. However, there are important barriers and limitations in translating the rhetoric into practice, and potential synergy and negative synergy effects can be identified when pursuing the strategies at the same time. The paper includes implications for the development of patient involvement in health care. This paper fulfills a need to study different types of patient involvement and to develop a theoretical framework for characterizing and analyzing such involvement strategies.

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Weidenbein L, Kristiansen M, Adamsen L, Hjort D, Hendriksen C. Assessment of rehabilitation needs in colorectal cancer treatment: results from a mixed audit and qualitative study in Denmark. Acta Oncologica. Accepted, in press, 2016.

Abstract

This study aimed to explore clinical practices related to identification and documentation of rehabilitation needs among patients with colorectal cancer at Danish hospitals. A retrospective clinical audit was conducted utilizing data from patient files randomly selected at surgical and oncology hospital departments treating colorectal cancer patients. Semi-structured interviews were carried out among clinical nurse specialists. Audit data was analyzed using descriptive statistics, qualitative data using thematic analysis. Documentation of physical, psychological and social rehabilitation needs initially and at end of treatment was evident in 10% of surgical patient trajectories and 35% of oncology trajectories. Physical rehabilitation needs were documented among 90%  of all patients. Referral to municipal rehabilitation services was documented among 5% of all patients. Assessments at surgical departments were shaped by the inherent continuous assessment of rehabilitation needs within standardized fast-track colorectal cancer surgery. In contrast, the implementation of locally developed assessment tools inspired by the distress thermometer (DT) in oncology departments was challenged by a lack of competencies and funding, impeding integration of data into patient files.

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Whyte, SR. "Epilogue: “Successful Aging” and “Desired Interdependence”." In: Lamb S (ed). Successful Aging: Global Perspectives on a Contemporary Obsession. Piscataway: Rutgers University Press. Accepted, with publication date in 2017.


Theme 2

Asmar M, Simonsen L, Asmar A, Holst JJ, Dela F, Bülow J. Journal of Clinical Endocrinology and Metabolism. 101:3155-3162, 2016


Aspinal F, Glasby J, Rostgaard T, Tuntland H, Westendorp RG. "New horizons: Reablement - supporting older people towards independence" in Age and Ageing. Accepted. 

Abstract
As the overwhelming majority of older people prefer to remain in their own homes and communities, innovative service provision aims to promote independence of older people despite incremental age associated frailty. Reablement is one such service intervention that is rapidly being adopted across high-income countries and projected to result in significant cost-savings in public health expenditure by decreasing premature admission to acute care settings and long-term institutionalisation. Although reablement may just seem the right thing to do, studies on the outcomes of this knowledge-based practice are inconsistent-yet there is an emerging evidence and practice base that suggests that reablement improves performance in daily activities. This innovative service however may lead to hidden side effects such as social isolation and a paradoxical increase in hospital admissions. Some of the necessary evaluative research is already underway, the results of which will help fill some of the evidence gaps outlined here.

See article online


Bay B, Mortensen EL, Golombok S, Hohwü L, Obel C, Henriksen TB, Kesmodel US. "Long-awaited pregnancy: intelligence and academic performance in offspring of infertile parents-a cohort study" in Fertility and Sterility. Accepted.

Abstract
To study whether fertility treatment, subfertility, or pregnancy planning are related to long-term intellectual development, a total of 5,032 singletons born from 1990 to 1992 in the Aarhus Birth Cohort were followed up to a mean age of 19 years. These children were born as a result of fertility treatment, had subfertile parents who took more than 12 months before conceiving naturally, had fertile parents who conceived naturally within 12 months, or had parents who reported the pregnancy as unplanned. The children were followed up using questionnaires and information from Danish national registers. In the longest follow-up of cognitive development of children conceived after fertility treatment or by subfertile parents conducted so far, this study did not show any association between pregnancy planning, subfertility, or fertility treatment and cognitive ability or academic performance.

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Blum MR, Wijsman LW, Virgini VS, Bauer DC, den Elzen WP, Jukema JW, Buckley BM, de Craen AJ, Kearney PM, Stott DJ, Gussekloo J, Westendorp RG, Mooijaart SP, Rodondi N; "PROSPER study group. Subclinical Thyroid Dysfunction and Depressive Symptoms among the Elderly: A Prospective Cohort Study" in Neuroendocrinology. 103:291-299, 2016.

Abstract
Subclinical hypothyroidism has been associated with depressive symptoms in cross-sectional studies, but prospective data and data on subclinical hyperthyroidism are scarce. In the Leiden substudy of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), thyroid-stimulating hormone and free T4 levels were measured at baseline and repeated after 6 months in adults aged 70-82 years with pre-existing cardiovascular disease or known cardiovascular risk factors to define persistent thyroid functional status. Main outcome measures were depressive symptoms, assessed with the Geriatric Depression Scale 15 (GDS-15) at baseline and after 3 years. All analyses were adjusted for age, gender and education. In this largest prospective study on the association of persistent subclinical thyroid dysfunction and depression, subclinical hypothyroidism was not associated with increased depressive symptoms among older adults at high cardiovascular risk. Persistent subclinical hyperthyroidism might be associated with increased depressive symptoms, which requires confirmation in a larger prospective study.

See article online


Bach B, Lee C, Mortensen EL, Simonsen E. "How Do DSM-5 Personality Traits Align With Schema Therapy Constructs?" in Journal of Personality Disorders. 30: 502-509, 2016.

Abstract
DSM-5 offers an alternative model of personality pathology that includes 25 traits. Although personality disorders are mostly treated with psychotherapy, the correspondence between DSM-5 traits and concepts in evidence-based psychotherapy has not yet been evaluated adequately. Suitably, schema therapy was developed for treating personality disorders, and it has achieved promising evidence. The authors examined associations between DSM-5 traits and schema therapy constructs in a mixed sample of 662 adults, including 312 clinical participants. Associations were investigated in terms of factor loadings and regression coefficients in relation to five domains, followed by specific correlations among all constructs. The results indicated conceptually coherent associations, and 15 of 25 traits were strongly related to relevant schema therapy constructs. Conclusively, DSM-5 traits may be considered expressions of schema therapy constructs, which psychotherapists might take advantage of in terms of case formulation and targets of treatment. In turn, schema therapy constructs add theoretical understanding to DSM-5 traits.

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Bo S, Bach B, Mortensen EL, & Simonsen E. "Reliability and Hierarchical Structure of DSM-5 Pathological Traits in a Danish Mixed Sample" in Journal of Personality Disorders. 30: 112-129, 2016

Abstract
In this study we assessed the DSM-5 trait model in a large Danish sample (n = 1,119) with respect to reliability of the applied Danish version of the Personality Inventory for DSM-5 (PID-5) self-report form by means of internal consistency and item discrimination. In addition, we tested whether the five-factor structure of the DSM-5 trait model can be replicated in a Danish independent sample using the PID-5 self-report form. Finally, we examined the hierarchical structure of DSM-5 traits. In terms of internal consistency and item discrimination, the applied PID-5 scales were generally found reliable and functional; our data resembled the five-factor structure of previous findings, and we identified a hierarchical structure from one to five factors that was conceptually reasonable and corresponded with existing findings. These results support the new DSM-5 trait model and suggest that it can be generalized to other languages and cultures.

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Broekhuizen K, de Gelder J, Wijsman CA, Wijsman LW, Westendorp RG, Verhagen E, Slagboom PE, de Craen AJ, van Mechelen W, van Heemst D, van der Ouderaa F, Mooijaart SP. "An Internet-Based Physical Activity Intervention to Improve Quality of Life of Inactive Older Adults: A Randomized Controlled Trial" in Journal of Medical Internet Research. 18(4):e74. doi: 10.2196/jmir.4335.

Abstract
The aim of this study was to assess if an Internet-based intervention aimed to increase physical activity was effective in improving quality of life of inactive older adults. The intervention was tested in a randomized controlled trial and was comprised of an Internet program-DirectLife (Philips)-aimed at increasing physical activity using monitoring and feedback by accelerometry and feedback by digital coaching. Participants were inactive 60-70-year-olds and were recruited from the general population. Quality of life and physical activity were measured at baseline and after 3 months using the Research ANd Development 36-item health survey (RAND-36) and wrist-worn triaxial accelerometer, respectively. Our study shows that an Internet-based physical activity program was effective in improving quality of life in 60-70-year-olds after 3 months, particularly in participants that reached their individually targeted increase in daily physical activity.

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Buhmann CB, Nordentoft M, Ekstroem M, Carlsson J, Mortensen EL. "The effect of flexible cognitive behavioral therapy and medical treatment, including antidepressants on PTSD and depression in traumatized refugees - a randomized controlled clinical trial" in British Journal of Psychiatry. 208: 252-259, 2016.

Abstract
Despite the fact that an estimated 30% of populations from areas of conflict have post-traumatic stress disorder (PTSD) very little evidence exists on how best to treat this condition. To estimate treatment effects of flexible cognitive–behavioural therapy (CBT) and antidepressants (sertraline and mianserin) in traumatised refugees, we performed a randomised controlled clinical trial with 2 × 2 factorial design. Participants were refugees with war-related traumatic experiences, post-traumatic stress disorder (PTSD) and without psychotic disorder. Treatment was weekly sessions with a physician and/or psychologist over 6 months. A total of 217 of 280 patients completed treatment (78%). There was no effect on PTSD symptoms, no effect of psychotherapy and no interaction between psychotherapy and medicine. A small but significant effect of treatment with antidepressants was found on depression. In a pragmatic clinical setting, there was no effect of flexible CBT and antidepressants on PTSD, and there was a small-to-moderate effect of antidepressants and psychoeducation on depression in traumatised refugees.

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Bytoft B, Knorr S, Vlachova Z, Jensen RB, Mathiesen ER, Beck-Nielsen H, Gravholt CH, Jensen DM, Clausen TD, Mortensen EL, Damm P. "Long-term Cognitive Implications of Intrauterine Hyperglycemia in Adolescent Offspring of Women With Type 1 Diabetes (the EPICOM Study)" in Diabetes Care. 39: 1356-1363, 2016.

Abstract
Exposure to maternal diabetes in utero may have a negative impact on the developing brain. The objective was to examine long-term cognitive consequences of intrauterine hyperglycemia in adolescent offspring of women with type 1 diabetes and to ascertain a possible association with maternal HbA1c. Offspring of a prospectively followed cohort of women with type 1 diabetes participated in a follow-up examination at the age of 13-19 years. Cognitive function was evaluated using Reynolds Intellectual Assessment Scales and classified into indices of composite intelligence, verbal and nonverbal intelligence, and composite memory. Frequencies of reading and writing problems and attendance to classes for children with learning difficulties were assessed. Adolescent offspring of women with type 1 diabetes had lower cognitive function compared with a control group, also after adjustment for confounders and potential mediators. These differences may reflect direct harmful effects of maternal diabetes on neurodevelopment in the offspring.

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Christensen GT, Mortensen EL, Christensen K & Osler M. "Intelligence in young adulthood and cause-specific mortality in the Danish Conscription Database – A cohort study of 728.160 men" in Intelligence. 2016.

Abstract
An inverse association has been reported between early life intelligence and all-cause mortality. The aim of this study was to investigate whether this well-established association differed according to the underlying cause of death and across different birth cohorts. The associations between young adult intelligence and mortality from natural and external causes were investigated in the Danish Conscription Database (DCD), which is a cohort of more than 700,000 men born 1939–1959 and followed in Danish registers from young adulthood until late mid-life. Young adult intelligence was inversely related to all-cause mortality with a 28% higher risk of dying during the study period per 1 standard deviation (SD) decrease in intelligence test score. The strength of the observed inverse associations did not vary much across main groups of natural and external causes with the exception of the associations for mortality from respiratory diseases and homicide which were more pronounced compared to the rest. Moreover, for skin cancer mortality, each SD increase in intelligence test score was associated with a small increase in mortality risk. Furthermore, the association between intelligence and mortality was stronger for those born 1950–1959 compared to those born 1939–1949 for almost all natural and external causes of death.

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Christensen K, Nilsson CJ. "Demografi". In: Holm E, Rønholt F (eds.) Geriatri. Munksgaard 2016: 17-27. (book chapter in Danish)

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van Deurzen I, Rod NH, Christensen U, Hansen ÅM, Lund R, Dich N. "Neighborhood perceptions and allostatic load: Evidence from Denmark" in Health and Place.40:1-8, 2016. 

Abstract
An influential argument explaining why living in certain neighborhoods can become harmful to one's health maintains that individuals can perceive certain characteristics of the neighborhood as threatening and the prolonged exposure to a threatening environment could induce chronic stress. Following this line of argumentation, in the present study we test whether subjective perceptions of neighborhood characteristics relate to an objective measure of stress-related physiological functioning, namely allostatic load (AL). We use a large dataset of 5280 respondents living in different regions of Denmark and we account for two alternative mechanisms, i.e., the objective characteristics of the living environment and the socio-economic status of individuals. Our results support the chronic stress mechanisms linking neighborhood quality to health. Heightened perceptions of disorder and pollution were found related to AL and this relationship was particularly robust for women.

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Devantier TA, Nørgaard BL, Poulsen MK, Garde E, Øvrehus KA, Marwan M, Achenbach S, Dey D, Sørensen LH, Videbech P. "White Matter Lesions, Carotid and Coronary Atherosclerosis in Late-Onset Depression and Healthy Controls" in Psychosomatics. 57(4): 369-77, 2016.

Abstract
Cerebral white matter lesions (WMLs) are more common in individuals with late-onset or late-life depression. It has been proposed that carotid atherosclerosis may predispose to WMLs by inducing cerebral hypoperfusion. This hemodynamic effect of carotid atherosclerosis could be important for the formation of WMLs in depression. The case-control study included 29 patients with late-onset major depressive disorder and 27 controls matched for sex, age, and tobacco use. WML volume, carotid intima-media thickness, and coronary plaque volume were assessed using magnetic resonance imaging, ultrasound scan, and coronary computed tomography (CT) angiography, respectively. In older persons aged between 50 and 70 years, WMLs do not seem to be a part of generalized atherosclerotic disease, but seem to be dependent on atherosclerosis in the carotid arteries. Carotid atherosclerosis, however, could not explain the higher WML load observed in the depressed patients, and thus, studies are needed to establish the mechanisms linking depression and WMLs.

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Eriksen L., Grønbæk M., Helge JW, Tolstrup JS. "Cardiorespiratory fitness in 16.025 adults aged 18-91 years and associations with physical activity and sitting time" in Scandinavian Journal of Medical Science in Sports. Accepted, 2016.

Abstract
Our aim was to provide up-to-date cardiorespiratory fitness reference data for adults of all ages and to investigate associations between cardiorespiratory fitness and leisure time physical activity as well as sitting time. In the Danish Health Examination Survey 2007–2008, cardiorespiratory fitness was estimated in 16 025 individuals aged 18–91 years from validated cycle ergometer exercise tests. Level of leisure time physical activity (sedentary, light, moderate, and vigorous) and daily sitting time in hours was obtained from a self-administered questionnaire. Men had 20–33% higher cardiorespiratory fitness than women, depending on age, and cardiorespiratory fitness decreased by 0.26 and 0.23 mL/min/kg per year in men and women, respectively. Cardiorespiratory fitness was higher among participants who reported a high level of physical activity in leisure time compared with participants who were sedentary. Among sedentary or lightly physically active participants, inverse associations between total daily sitting time and cardiorespiratory fitness were found, while there was no association between sitting time and cardiorespiratory fitness among moderately or vigorously physically active participants. These data on cardiorespiratory fitness can serve as useful reference material. Although reluctant to conclude on causality, sitting time might impact cardiorespiratory fitness among individuals with low levels of leisure time physical activity.

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Flensborg-Madsen T, Mortensen EL. "Associations of early developmental milestones with adult intelligence" in Child Development. Accepted.

Abstract
The study investigated whether age at attainment of 20 developmental milestones within the areas of language, walking, eating, dressing, social interaction, and toilet training was associated with adult intelligence. Mothers of 821 children of the Copenhagen Perinatal Cohort recorded 20 developmental milestones at a 3-year examination, and all children were administered the Wechsler Adult Intelligence Scale when they were 20–34 years old. Later attainment of a number of milestones was associated with lower adult IQ with the strongest associations found for those related to language and social interaction. The adjusted full-scale IQ means were 107.0, 101.8, and 100.6 for being able to form a sentence at less than 24 months, at 24 months, and later than 24 months.

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Gaist D, Garde E, Blaabjerg M, Nielsen HH, Krøigård T, Østergaard K, Møller HS, Hjelmborg J, Madsen CG, Iversen P, Kyvik KO, Siebner HR, Ashina M. "Migraine with aura and risk of silent brain infarcts and white matter hyperintensities: an MRI study" in Brain. 139: 2015-2013, 2016.

Abstract
A small number of population-based studies reported an association between migraine with aura and risk of silent brain infarcts and white matter hyperintensities in females. We investigated these relations in a population-based sample of female twins. We contacted female twins ages 30-60 years identified through the population-based Danish Twin Registry. Based on questionnaire responses, twins were invited to participate in a telephone-based interview conducted by physicians. Headache diagnoses were established according to the International Headache Society criteria. Cases with migraine with aura, their co-twins, and unrelated migraine-free twins (controls) were invited to a brain magnetic resonance imaging scan performed at a single centre. Brain scans were assessed for the presence of infarcts, and white matter hyperintensities blinded to headache diagnoses. Comparisons were based on 172 cases, 34 co-twins, and 139 control subjects. We found no evidence of an association between silent brain infarcts, white matter hyperintensities, and migraine with aura.

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Gidaya NB, Lee BK, Burstyn I, Michael Y, Newschaffer CJ, Mortensen EL. "In utero Exposure to β-2-Adrenergic Receptor Agonist Drugs and Risk for Autism Spectrum Disorders" in Pediatrics. 137: Article E20151316, 2016.

Abstract
The purpose of this study was to investigate associations between use of β-2-adrenergic receptor (B2AR) agonist drugs during pregnancy and risk for autism spectrum disorders (ASD). A case-control study was conducted by using Denmark’s health and population registers. Among children born between 1997 and 2006, 5200 cases with ASD admission diagnoses and 52 000 controls without ASD were identified and individually matched on month and year of birth. Conditional logistic regression models were used to estimate odds ratios (OR) and confidence intervals (CI) for any B2AR agonist exposure during pregnancy, preconception, and by trimester. In total, 3.7% of cases and 2.9% of controls were exposed to B2ARs during pregnancy. Use of B2ARs during pregnancy was associated with increased risk of ASD, even after adjustment for maternal asthma and other covariates.The elevated risk was observed with use of B2AR during preconception, first trimester, second trimester, and the third trimester. There was some evidence that longer B2AR within-pregnancy use was associated with the increased risk. B2AR agonist exposure during pregnancy may be associated with an increased risk for ASD. If the effect is real, any intervention must be balanced against benefits of indicated medication use by pregnant women.

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Gow AJ, Mortensen EL. "Social resources and cognitive ageing across 30 years: the Glostrup 1914 Cohort" in Age and Ageing. 45: 480-486, 2016. 

Abstract
To examine associations between social resources and cognitive ageing over 30 years, participants in the Glostrup 1914 Cohort, a year of birth sample, completed a standardised battery of cognitive ability tests every 10 years from age 50 to 80, summarised as general cognitive ability. Participants also provided information concerning a range of social resources, including marital status and living arrangements from age 50, and from age 70, details regarding social support, social contact and loneliness.

Being married, living with others and not feeling lonely were all associated with higher cognitive ability level, while more telephone contact had a negative association. Marital status (at ages 50 and 60) and loneliness at age 70 were the only social resources associated with cognitive change; married individuals and those not feeling lonely experienced less cognitive decline. When the social resources showing significant associations were considered together , loneliness was associated with lower cognitive ability level and greater cognitive decline, while married individuals experienced less decline. In a relatively large cohort followed for up to 30 years, marital status and loneliness were associated with cognitive ability or change. Interventions designed to reduce loneliness in older adults might be supported as one avenue to reduce cognitive ageing.

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Hansen M, Lund MT, Jorgensen AL, Palsoe MK, van Hall G, Helge JW, Dela F. "The effects of diet- and RYGB-induced weight loss on insulin sensitivity in obese patients with and without type 2 diabetes" in Acta Diabetology. 53: 423- 432, 2016.

Abstract
The impact of diet-induced weight loss and weight loss due to RYGB in patients with and without type 2 diabetes was studied. At inclusion (A), after diet-induced weight loss (B), 4 months post-surgery (C) and 18 months post-surgery (D) body composition, hepatic glucose production (HGP), insulin-mediated glucose uptake (GIR), respiratory exchange ratio, hepatic insulin sensitivity and clearance were determined. GLUT4, intramuscular triglycerides (IMTG) and glycogen content were measured in skeletal muscle. Weight loss was 35–40 kg, and approximately one-third of the total improvement in GIR in T2DM was observed after the diet-induced weight loss of only ~6 kg (B). Insulin clearance, visceral fat and fasting plasma insulin also improved significantly after the diet (P < 0.05). Throughout the study, HGP, GLUT4 and glycogen content did not change significantly, but IMTG decreased significantly consistent with significant increases in GIR. Metabolic flexibility and hepatic insulin sensitivity improved after RYGB. Metabolic improvements of RYGB are present already after the diet-induced weight loss prior to surgery. GLUT4 content in skeletal muscle cannot and IMTG content can only partly explain increases in GIR after RYGB.

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Hansen ÅM, Andersen LL, Mendes de Leon CF, Bruunsgaard H, Lund R. "School education, physical performance in late midlife and allostatic load: a retrospective cohort study" in Journal of Epidemiology and Community Health. 70: 748-754, 2016.

Abstract
The mechanisms underlying the social gradient in physical functioning are not fully understood. Cumulative physiological stress may be a pathway. The present study aimed to investigate the association between highest attained school education and physical performance in late midlife, and to determine to what extent cumulative physiological stress mediated these associations. The study is based on data from the Copenhagen Aging and Midlife Biobank. School education was measured as highest examination passed in primary or secondary school. Cumulative stress was operationalised as allostatic load (AL), and measured as the number of biological parameters in which participants scored in the poorest quartile. Physical performance included dynamic muscle performance and muscle strength. Among women, higher school education was associated with better performance in all physical performance tests. Among men, higher school education was associated with better performance only in chair rise and jump height. AL partially mediated the association between school education and physical performance, and accounted only for 2–30% of the total effect among women. Similar results were observed among men for chair rise and jump height. These results might indicate that AL plays a minor role in the association between school education and late midlife dynamic muscle performance in both men and women, and in muscle strength among women.

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Harrsen Bachkati S, Mortensen EL,Brønnum-Hansen H, Holm-Pedersen P. Midlife "Cognitive Ability, Education and Tooth Loss among Old Danes" in Journal of the American Geriatrics Society, Dental and Oral Health. Accepted.

Abstract
To examine the possible influence of cognitive ability and education at age 50 or 60 on number of teeth at age 70, a cognitive ability was assessed using the Wechsler Adult Intelligence Scale at age 50 or 60. Logistic regression analyses revealed that greater cognitive ability and educational attainment had a protective effect against risk of tooth loss. The associations were significant and persisted after adjusting for confounders and a two-way interaction between cognitive ability and education. Higher education level and cognitive ability measured at age 50 or 60 were associated with having more teeth at age 70. Whether these findings are due to the interaction of these factors with oral health, related socioeconomic factors, or other factors remains to be studied.

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Heim N, Rolden H, van Fenema EM, Weverling-Rijnsburger AW, Tuijl JP, Jue P, Oleksik AM, de Craen AJ, Mooijaart SP, Blauw GJ, Westendorp RG, van der Mast RC, van Everdinck IE. "The development, implementation and evaluation of a transitional care programme to improve outcomes of frail older patients after hospitalisation" in Age and Ageing. Accepted.

Abstract
Fragmented healthcare systems are poorly suited to treat the increasing number of older patients with multimorbidity. To report on the development, implementation and evaluation of a regional transitional care programme, aimed at improving the recovery rate of frail hospitalised older patients, a programme was drafted in co-creation with organisations representing older adults, care providers and knowledge institutes. Conducting an action research project, the incidence of adverse outcomes within 3 months after hospital admission, and long-term care expenses (LTCE) were compared between samples in 2010-11 (pre-programme) and 2012-13 (post-programme) in frail and non-frail patients. The programme developed innovations addressed (i) improved risk management; (ii) delivery of integrated, function-oriented care; (iii) specific geriatric interventions; and (iv) optimisation of transfers. By involving stakeholders in designing and developing the transitional care programme, commitment of healthcare providers was secured. Feasible innovations in integrated transitional care for frail older patients after hospitalisation were sustainably implemented from within healthcare organisations.

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Husemoen LL, Ebstrup JF, Mortensen EL, Schwarz P, Skaaby T, Thuesen BH, Jørgensen T, Linneberg A. "Serum 25-hydroxyvitamin D and self-reported mental health status in adult Danes" in Europen Journal of Clinical Nutrition. 70: 78-84, 2016.

Abstract
Vitamin D receptors and vitamin D-metabolising enzymes are present in the brain and in the central nervous system at sites responsible for the regulation of emotions and behaviour. This raises the hypothesis that low vitamin D is related to poor mental health. Our aim was to examine the association between serum 25-hydroxyvitamin D (25(OH)D) and the self-reported symptoms and diagnosis of depression and anxiety in the adult general population. Serum 25(OH)D was measured in three Danish population-based studies, including 5308 adults aged 18–64 years. After 5 years, 2004 participants were re-examined. Symptoms of depression and anxiety were assessed by the Symptom Check List (SCL)-90-R, and self-reported doctor-diagnosed depression and anxiety was recorded by using a questionnaire. Serum 25(OH)D was not associated with SCL average scores for depression and anxiety when analysed by quantile median regression adjusted for sex, age and other potential confounders. Our results suggest that low serum 25(OH)D is not associated with self-reported symptoms/diagnosis of depression and anxiety.

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Højgaard DR, Mortensen EL, Ivarsson T, Hybel K, Skarphedinsson G, Nissen JB, Valderhaug R, Dahl K, Weidle B, Torp NC, Grados M, Lewin AB, Melin KH, Storch EA, Wolters LH, Murphy TK, Sonuga-Barke EJ, Thomsen PH. "Structure and clinical correlates of obsessive-compulsive symptoms in a large sample of children and adolescents: a factor analytic study across five nations" in Eur Child Adolesc Psychiatry. Accepted.

Abstract
The underlying structure of obsessive-compulsive disorder (OCD) remains to be confirmed in child and adolescent populations. In this paper we report the first factor analytic study of individual OCD items from Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). OCD symptoms were assessed using the CY-BOCS symptom checklist in a sample of 854 patients with OCD (7-18 years of age) recruited from clinics in five countries. Pooled data were subjected to exploratory and confirmatory factor analysis (CFA) to identify the optimal factor structure. Various models were tested for age and gender subgroups. Also, the invariance of the solution across age and gender was tested and associations with demographic and clinical factors were explored. A three-factor model provided the best-fit solution. It consisted of the following factors: (1) harm/sexual, (2) symmetry/hoarding, (3) contamination/cleaning. The factor structure was invariant for age and gender across subgroups. Factor one was significantly correlated with anxiety, and factor two with depression and anxiety. Factor three was negatively correlated with tic disorder and attention-deficit/hyperactivity disorder (ADHD). Females had higher scores on factor two than males. The OCD symptom structure in children and adolescents is consistent across age and gender and similar to results from recent child and adolescents although hoarding may not be a separate factor. Our three-factor structure is almost identical to that seen in early studies on adults. Common mental disorders had specific patterns of associations with the different factors.

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Ibrahim-Verbaas CA, Bressler J, Debette S, Schuur M, Smith AV, Bis JC, Davies G, Trompet S, Smith JA, Wolf C, Chibnik LB, Liu Y, Vitart V, Kirin M, Petrovic K, Polasek O, Zgaga L, Fawns-Ritchie C, Hoffmann P, Karjalainen J, Lahti J, Llewellyn DJ, Schmidt CO, Mather KA, Chouraki V, Sun Q, Resnick SM, Rose LM, Oldmeadow C, Stewart M, Smith BH, Gudnason V, Yang Q, Mirza SS, Jukema JW, deJager PL, Harris TB, Liewald DC, Amin N, Coker LH, Stegle O, Lopez OL, Schmidt R, Teumer A, Ford I, Karbalai N, Becker JT, Jonsdottir MK, Au R, Fehrmann RS, Herms S, Nalls M, Zhao W, Turner ST, Yaffe K, Lohman K, van Swieten JC, Kardia SL, Knopman DS, Meeks WM, Heiss G, Holliday EG, Schofield PW, Tanaka T, Stott DJ, Wang J, Ridker P, Gow AJ, Pattie A, Starr JM, Hocking LJ, Armstrong NJ, McLachlan S, Shulman JM, Pilling LC, Eiriksdottir G, Scott RJ, Kochan NA, Palotie A, Hsieh YC, Eriksson JG, Penman A, Gottesman RF, Oostra BA, Yu L, DeStefano AL, Beiser A, Garcia M, Rotter JI, Nöthen MM, Hofman A, Slagboom PE, Westendorp RG, Buckley BM, Wolf PA, Uitterlinden AG, Psaty BM, Grabe HJ, Bandinelli S, Chasman DI, Grodstein F, Räikkönen K, Lambert JC, Porteous DJ; Generation Scotland, Price JF, Sachdev PS, Ferrucci L, Attia JR, Rudan I, Hayward C, Wright AF, Wilson JF, Cichon S, Franke L, Schmidt H, Ding J, de Craen AJ, Fornage M, Bennett DA, Deary IJ, Ikram MA, Launer LJ, Fitzpatrick AL, Seshadri S, van Duijn CM, Mosley TH. "GWAS for executive function and processing speed suggests involvement of the CADM2 gene" in Molecular Psychiatry. 21:189-197, 2016.

Abstract
To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

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Jansen SW, van Heemst D, van der Grond J, Westendorp RG, Oei NY. "Physiological responding to stress in middle-aged males enriched for longevity: a social stress study" in Stress. 19:28-36, 2016.

Abstract
Individuals enriched for familial longevity display a lower prevalence of age-related diseases, such as cardiovascular- and metabolic diseases. Since these diseases are associated with stress and increased cortisol levels, one of the underlying mechanisms that may contribute to healthy longevity might be a more adaptive response to stress. To investigate this, male middle-aged offspring from long-lived families (n = 31) and male non-offspring (with no familial history of longevity) (n = 26) were randomly allocated to the Trier Social Stress Test or a control condition in an experimental design. Physiological (cortisol, blood pressure, heart rate) and subjective responses were measured during the entire procedure. The results showed that Offspring had lower overall cortisol levels compared to Non-offspring regardless of condition, and lower absolute cortisol output (AUCg) during stress compared to Non-Offspring, while the increase (AUCi) did not differ between groups. In addition, systolic blood pressure in Offspring was lower compared to Non-offspring during the entire procedure. At baseline, Offspring had significantly lower systolic blood pressure and reported less subjective stress than Non-offspring and showed a trend towards lower heart rate. Offspring from long-lived families might thus be less stressed prior to potentially stressful events and consequently show overall lower levels in physiological responses. Although attenuated physiological responding cannot be ruled out, lower starting points and a lower peak level in physiological responding when confronted with an actual stressor, might already limit damage due to stress over a lifetime. Lower physiological responding may also contribute to the lower prevalence of cardiovascular diseases and other stress-related diseases in healthy longevity.

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Jorgensen TS, Osler M, Angquist LH, Zimmermann E, Christensen GT, Sorensen TI. "The U-shaped association of body mass index with mortality: Influence of the traits height, intelligence, and education" in Obesity. Accepted. 

Abstract
The U-shaped association between body mass index (BMI) and mortality may depend on other traits with permanent health effects. Whether the association between BMI and mortality depends on levels of health-related traits known to be inversely associated with mortality throughout adult life such as height, intelligence, and education was investigated. The study was based on a cohort of young men with data on weight, height, intelligence test score, and education from the Danish Conscription Database. In total, 346,500 men born 1939 to 1959 were followed until December 2013. The association between BMI and mortality was analyzed using Cox-regression models including interactions between BMI and height, intelligence, and education, respectively. BMI and mortality showed the U-shaped association from the start of the follow-up period, and it persisted through the subsequent 56 years. As expected, the mortality was inversely associated with height, intelligence, and education, but the U shape of the association between BMI and mortality was unaffected by the levels of these traits except at higher BMI values, where the slopes were steeper for men with higher levels of height, intelligence, and education. High and low BMI was associated with higher mortality throughout life regardless of the levels of height, intelligence, and education.

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Kasenburg N, Liptrot M, Reislev NL, Ørting SN, Nielsen M, Garde E, Feragen A. "Training shortest-path tractography: Automatic learning of spatial priors" in Neuroimage. 130:63-76, 2016. 

Abstract
Tractography is the standard tool for automatic delineation of white matter tracts from diffusion weighted images. However, the output of tractography often requires post-processing to remove false positives and ensure a robust delineation of the studied tract, and this demands expert prior knowledge. Here we demonstrate how such prior knowledge, or indeed any prior spatial information, can be automatically incorporated into a shortest-path tractography approach to produce more robust results. We describe how such a prior can be automatically generated (learned) from a population, and we demonstrate that our framework also retains support for conventional interactive constraints such as waypoint regions. We apply our approach to the open access, high quality Human Connectome Project data, as well as a dataset acquired on a typical clinical scanner. Our results show that the use of a learned prior substantially increases the overlap of tractography output with a reference atlas on both populations, and this is confirmed by visual inspection. Furthermore, we demonstrate how a prior learned on the high quality dataset significantly increases the overlap with the reference for the more typical yet lower quality data acquired on a clinical scanner. We hope that such automatic incorporation of prior knowledge and the obviation of expert interactive tract delineation on every subject, will improve the feasibility of large clinical tractography studies.

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Knudsen GM, Jensen PS, Erritzoe D, Baaré WF, Ettrup A, Fisher PM, Gillings N, Hansen HD, Hansen LK, Hasselbalch SG, Henningsson S, Herth MM, Holst KK, Iversen P, Kessing LV, Macoveanu J, Madsen KS, Mortensen EL, Nielsen FÅ, Paulson OB, Siebner HR, Stenbæk DS, Svarer C, Jernigan TL, Strother SC, Frokjaer VG. "The Center for Integrated Molecular Brain Imaging (Cimbi) database" in Neuroimage. 124, S1: 1213-1219, 2016.

Abstract
We here describe a multimodality neuroimaging containing data from healthy volunteers and patients, acquired within the Lundbeck Foundation Center for Integrated Molecular Brain Imaging (Cimbi) in Copenhagen, Denmark. The data is of particular relevance for neurobiological research questions related to the serotonergic transmitter system with its normative data on the serotonergic subtype receptors 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 and the 5-HT transporter (5-HTT), but can easily serve other purposes. The Cimbi database and Cimbi biobank were formally established in 2008 with the purpose to store the wealth of Cimbi-acquired data in a highly structured and standardized manner in accordance with the regulations issued by the Danish Data Protection Agency as well as to provide a quality-controlled resource for future hypothesis-generating and hypothesis-driven studies. The Cimbi database currently comprises a total of 1100 PET and 1000 structural and functional MRI scans and it holds a multitude of additional data, such as genetic and biochemical data, and scores from 17 self-reported questionnaires and from 11 neuropsychological paper/computer tests. The database associated Cimbi biobank currently contains blood and in some instances saliva samples from about 500 healthy volunteers and 300 patients with e.g., major depression, dementia, substance abuse, obesity, and impulsive aggression. Data continue to be added to the Cimbi database and biobank.

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Koopman JJ, van Bodegom D, Ziem JB, Westendorp RG. "An Emerging Epidemic of Noncommunicable Diseases in Developing Populations Due to a Triple Evolutionary Mismatch" in Am J Trop Medical Hygiene. 94:1189-1192, 2016.

Abstract
With their transition from adverse to affluent environments, developing populations experience a rapid increase in the number of individuals with noncommunicable diseases. Here, we emphasize that developing populations are more susceptible than western populations to acquire these chronic diseases, because their genetic, cultural, and epigenetic characteristics do not match with the eagerly awaited affluent environments. In regard to this, there is an urgent need for public health organizations to reorganize current environments in developing populations so as to fit their inherited characteristics. Unfortunately, this need is neglected as an essential part of the Sustainable Development Goals that form the core of the United Nations' Post-2015 Development Agenda. Only through global collaborative efforts can the environments in developing populations be reorganized and, thereby, the emerging epidemic of noncommunicable diseases be stalled.

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Koopman JJ, Pijpe J, Böhringer S, van Bodegom D, Eriksson UK, Sanchez-Faddeev  H, Ziem JB, Zwaan B, Slagboom PE, de Knijff P, Westendorp RG. "Genetic variants determining survival and fertility in an adverse African environment: a population-based large-scale candidate gene association study" in Aging (Albany NY). 8:1364-83, 2016.

Abstract
Human survival probability and fertility decline strongly with age. These life history traits have been shaped by evolution. However, research has failed to uncover a consistent genetic determination of variation in survival and fertility. As an explanation, such genetic determinants have been selected in adverse environments, in which humans have lived during most of their history, but are almost exclusively studied in populations in modern affluent environments. Here, we present a large-scale candidate gene association study in a rural African population living in an adverse environment. In 4387 individuals, we studied 4052 SNPs in 148 genes that have previously been identified as possible determinants of survival or fertility in animals or humans. We studied their associations with survival comparing newborns, middle-age adults, and old individuals. In women, we assessed their associations with reported and observed numbers of children. We found no statistically significant associations of these SNPs with survival between the three age groups nor with women's reported and observed fertility. Population stratification was unlikely to explain these results. Apart from a lack of power, we hypothesise that genetic heterogeneity of complex phenotypes and gene-environment interactions prevent the identification of genetic variants explaining variation in survival and fertility in humans.

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Koopman JJ, Rozing MP, Kramer A, Abad JM, Finne P, Heaf JG, Hoitsma AJ, De Meester JM, Palsson R, Postorino M, Ravani P, Wanner C, Jager KJ, van Bodegom D, Westendorp RG. "Calculating the Rate of Senescence From Mortality Data: An Analysis of Data From the ERA-EDTA Registry" in Journals of Gerontology Series  A Biological Science and Medical  Science. 71: 468-474, 20116. 

Abstract
The rate of senescence can be inferred from the acceleration by which mortality rates increase over age. Such a senescence rate is generally estimated from parameters of a mathematical model fitted to these mortality rates. However, such models have limitations and underlying assumptions. Notably, they do not fit mortality rates at young and old ages. Therefore, we developed a method to calculate senescence rates from the acceleration of mortality directly without modeling the mortality rates. We applied the different methods to age group–specific mortality data from the European Renal Association—European Dialysis and Transplant Association Registry, including patients with end-stage renal disease on dialysis, who are known to suffer from increased senescence rates ( n = 302,455), and patients with a functioning kidney transplant ( n = 74,490). From age 20 to 70, senescence rates were comparable when calculated with or without a model. However, when using non-modeled mortality rates, senescence rates were yielded at young and old ages that remained concealed when using modeled mortality rates. At young ages senescence rates were negative, while senescence rates declined at old ages. In conclusion, the rate of senescence can be calculated directly from non-modeled mortality rates, overcoming the disadvantages of an indirect estimation based on modeled mortality rates.

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Kusumastuti S, Derks MG, Tellier S, Di Nucci E, Lund R, Mortensen EL, Westendorp RG. "Successful ageing: A study of the literature using citation network analysis" in Maturitas. Accepted. 

Abstract
This novel, hypothesis-free and quantitative analysis of citation networks explores the literature on successful ageing. From 1902 through 2015, two distinct clusters of citation networks were identified. The first cluster focused on the perspective of older persons themselves and the importance of coping strategies and psycho-social engagement. The second cluster focused on objective measurements as determined by researchers and pointed to different domains of functioning.These different points of view help to explain the disability paradox, as successful ageing lies in the eyes of the beholder. In the current literature two mutually exclusive concepts of successful ageing are circulating that depend on whether the individual himself or an outsider judges the situation. These different points of view help to explain the disability paradox, as successful ageing lies in the eyes of the beholder.

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Lucas SJE, Helge JW, Schütz UHW, Goldman RF, Cotter JD. "Moving in Extreme Environments - Extreme loading: Carriage versus distance" in Extreme Physiology and Medicine. Accepted.

Abstract
This review addresses human capacity for movement in the context of extreme loading and with it the combined effects of metabolic, biomechanical and gravitational stress on the human body. This topic encompasses extreme duration, as occurs in ultra-endurance competitions and expeditions , to the more gravitationally limited load carriage. Juxtaposed to these circumstances is the extreme metabolic and mechanical unloading associated with space travel, prolonged bedrest and sedentary lifestyle, which may be at least as problematic, and are therefore included as a reference, e.g. when considering exposure, dangers and (mal)adaptations. We describe adaptation patterns that are often U or J shaped and that over time minimal or no load carriage decreases the global load carrying capacity and eventually leads to severe adverse effects and manifest disease under minimal absolute but high relative loads. We advocate that further understanding of load carrying capacity and the inherent mechanisms leading to adverse effects may advantageously be studied in this perspective. With improved access to insightful and portable technologies, there are some exciting possibilities to explore these questions in this context.

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Lund MT, Hansen M, Wimmelmann C, Taudorf L, Helge JW, Mortensen EL, Dela F. "Gastric bypass patients increase cardio-pulmonary fitness due to weight loss not increased physical activity after surgery" in Scandinavian Journal of Medical Science in Sports. Accepted 2016.

Abstract
Roux-en-Y gastric bypass (RYGB) leads to a major weight loss in obese patients. However, given that most patients remain obese after the weight loss, regular exercise should be part of a healthier lifestyle. The primary aim of this study was to investigate the cardiopulmonary fitness in obese patients before and after RYGB. Thirty-four patients had body composition and cardiopulmonary fitness (VO2max ) assessed and completed questionnaires regarding physical activity and function twice before RYGB (time points A and B) and 4 and 18 months after surgery (time points C and D). Weight loss was 37 ± 2 kg during the study period. VO2max increased (A: 21 ± 1 vs D: 29 mL/min/kg, P < 0.001), but absolute VO2max decreased (A: 2713 ± 126 vs 2609 ± 187 mL/min, P = 0.02) and VO2max per kilogram fat free mass did not change. Self-perceived limitations to perform exercise decreased and self-perceived physical fitness increased after RYGB. Self-reported low- and high-intensity physical activity did not change. With weight loss, self-rated fitness level increased and the limitations to perform exercise decreased in RYGB patients. Nevertheless, as shown by the lower absolute VO2max , RYGB patients do not adopt new exercise habits following surgery. 

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Lund MT, Kristensen M, Hansen M, Tveskov L, Floyd AK, Stockel M, Vainer B, Poulsen SS, Helge JW, Prats C, Dela F (2016). "Hepatic mitochondrial oxidative phosphorylation is normal in obese patients with and without type 2 diabetes" in Journal of Physiology. 594: 4351-4358, 2016.

Abstract
Hepatic insulin resistance in patients with obesity or type 2 diabetes has been suggested to result from hepatic mitochondrial dysfunction. High-resolution respirometry (HRR) can be used to assess oxidative phosphorylation by measuring the mitochondrial oxygen consumption rate in the individual complexes of the mitochondria. By using HRR, the present study demonstrates no difference in hepatic mitochondrial oxidative phosphorylation among subjects with obesity with or without type 2 diabetes and non-obese controls. Furthermore, the amount of mitochondria, assessed by the citrate synthase activity, is not different between the three groups. Together the present findings indicate that hepatic mitochondrial oxidative phosphorylation capacity is not impaired in patients with obesity or type 2 diabetes.

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Meincke RH, Hansen ÅM, Mortensen LH, Osler M, Mortensen EL. "Intelligence in early adulthood and midlife physical performance in men: The mediating roles of education and physical activity" in Intelligence. 58: 62–68, 2016.

Abstract
The objective of this study was to examine whether associations between intelligence in early adulthood and midlife physical performance in men were mediated by education and leisure-time physical activity. Intelligence correlated positively with later education and negatively with physical activity. We found higher early adult intelligence to be associated with better midlife physical performance for five of the seven measures. Education mediated the association between intelligence and chair-rise and jump height with mediated proportions of 32.4% and 28.4%, respectively. No significant mediating effects of education were seen for sagittal flexibility, postural balance, handgrip strength, or muscle force in the abdomen or lower back. Physical activity was positively associated with physical performance, but because intelligence in early adulthood was inversely associated with physical activity, the indirect effects through physical activity were negative. Overall, education and leisure-time physical activity were not strong mediators of the association between early adult intelligence and midlife physical performance.

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Meincke RH, Osler M, Mortensen EL, Hansen ÅM. "Is Intelligence in Early Adulthood Associated With Midlife Physical Performance Among Danish Males?" in Journal of Aging and Health. 28: 530-545, 2016.

Abstract
Insights into the causes of variances in physical performance are important to prevent mobility limitations in old age. We examined associations between intelligence in early adulthood and midlife physical performance. Data from the Copenhagen Aging and Midlife Biobank were analyzed using linear regression. In total, 2,848 male cohort members had intelligence scores from conscription and physical performance measures from midlife. In adjusted models, a 1 SD increase in intelligence resulted in 1.10 more chair-rises (p < .001), a 1.03 cm higher jump (p < .001), a 3.69% smaller balance area (p < .001), a 0.71 kg increase in handgrip strength (p < .001), and a 5.03 N increase in back force (p < .001). Results for flexibility and abdominal force were not significant. Discussion: Public health interventions should focus on addressing people with different cognitive abilities and bear in mind that prevention of mobility limitations might need to start early in life.

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Mora-Rodríguez R, Sanchez-Roncero A, Fernández-Elías VE, Guadalupe-Grau A, Ortega JF, Dela F, Helge JW. "Aerobic Exercise Training Increases Muscle Water Content in Obese Middle-Age Men" in Medicine and Science in Sports and Exercise. 48: 822-828, 2016.

Abstract
The objective of this study is to determine whether muscle water content expands with training in deconditioned middle-age men and the effects of this expansion in other muscle metabolites. Eighteen obese untrained metabolic syndrome men completed a 4-month aerobic cycling training program. Body weight and fat mass were reduced -1.9% and -5.4%, respectively, whereas leg fat free mass increased with training. Cardiorespiratory fitness, exercise maximal fat oxidation, and maximal cycling power improved with training (11%, 33%, and 10%, respectively). After 4 months of training, H2Omuscle increased, whereas muscle protein concentration decreased. Citrate synthase activity increased by 31%. Muscle glycogen concentration increased by 14% although without reaching statistical significance when expressed as per kilogram of wet weight (P = 0.15). Our findings suggest that aerobic cycling training increases quadriceps muscle water although reduces muscle protein concentration in obese metabolic syndrome men. Reduced protein concentration coexists with increased leg lean mass suggestive of a water dilution effect that however does not impair increased cycling leg power with training.

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Mygind E, Wulf K, Rosenkilde M, and Helge JW. "Prediction of performance in Vasaloppet through long lasting ski-ergometer and rollerski tests" in International Journal of Sports and Exercise Medicine, Accepted.

Abstract
The main purpose was to investigate if long lasting cross-country (c-c) test procedures could predict performance time in ‘Vasaloppet’ and secondly the effect of a 16 weeks training period on a 90 min double poling performance test. 24 moderate trained c-c skiers participated in the study and completed Vasaloppet. A long lasting (90 minutes) upper-body ski-ergometer test was significantly associated with performance in Vasaloppet pre and post three months training period. The distance in ski-ergometer tests improved significantly from 18.0 ± 0.6 to 19.2 ± 0.7 km/h from pre to post after three months training. A long lasting (120 minutes) Rollerski test was significantly associated with racing time in Vasaloppet pre and post three months training period The total body fat percentage was significantly reduced, while trunk and total lean body mass increased significantly. Long lasting ski-ergometer and Rollerski field tests correlate strongly with performance in Vasaloppet and therefore might be useful test tools for recreational skiers who wish to participate in long lasting c-c competitions.

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Mysyuk Y, Westendorp RG, Lindenberg J. "How older persons explain why they became victims of abuse" in Age and Ageing. Accepted. 

Abstract
Elder abuse greatly impacts the quality of life of older individuals. A qualitative study on the perceptions and experiences of victims of elder abuse was conducted using in-depth semi-structured interviews. The main causes of abuse identified by older victims themselves were mutual dependency between victim and perpetrator, power and control imbalances, loneliness and a marginalised social position of older persons. Effects of abuse included negative feelings, physical and psychological distress, a change of personal norms and values, changed perspectives on money and low self-efficacy. These differential effects depended upon the types of abuse experienced and the relationship with the perpetrator. Coping strategies mentioned by victims were seeking informal or professional help and using self-help strategies. older victims perceive abuse differently depending on the expected acceptability of the type(s) of abuse experienced and the anticipated stigma associated with the perpetrator involved. The effects and chosen coping strategies are influenced by these considerations and therewith also influence their help-seeking behaviour. Healthcare professionals are encouraged to use these findings in practice to prevent, detect and intervene in elder abuse.

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Mysyuk Y, Westendorp RG, Lindenberg J. "Older persons' definitions and explanations of elder abuse in the Netherlands" in Journal of Elder Abuse & Neglect. 28:95-113, 2016. 

Abstract
In this article we explore older persons' definitions of and explanations for elder abuse in the Netherlands by means of interviews with older persons. A qualitative study was conducted based on semistructured interviews with 35 older persons who had no experience with abuse. Our findings show that older persons participating in our study define elder abuse foremost as physical violence that is performed intentionally. The study participants explain elder abuse as a result of the dependency and vulnerability of older persons, of changing norms and values, and of changes in the position of older persons in society, which result in disrespect toward older persons and a lack of social control and responsibility. The older persons' explanations for the occurrence of abuse mainly focus on societal changes; older persons seem to regard elder abuse primarily as a societal problem. This understanding of, and explanation for, elder abuse may influence their detection and reporting behavior, as they may tend to acknowledge only severe cases of intentional physical violence that leave clear and therefore physically detectable evidence.

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NCD Risk Factor Collaboration (NCD-RisC),  including Mortensen, EL. "Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants" in Lancet.387 (10026): 1377-1396, 2016. 

Abstract
Underweight and severe and morbid obesity are associated with highly elevated risks of adverse health outcomes. We estimated trends in mean body-mass index (BMI), which characterises its population distribution, and in the prevalences of a complete set of BMI categories for adults in all countries. We analysed, with use of a consistent protocol, population-based studies that had measured height and weight in adults aged 18 years and older. We applied a Bayesian hierarchical model to these data to estimate trends from 1975 to 2014 in mean BMI and in the prevalences of BMI categories (<18·5 kg/m2 [underweight], 18·5 kg/m2 to <20 kg/m2, 20 kg/m2 to <25 kg/m2, 25 kg/m2 to <30 kg/m2, 30 kg/m2 to <35 kg/m2, 35 kg/m2 to <40 kg/m2, ≥40 kg/m2 [morbid obesity]), by sex in 200 countries and territories, organised in 21 regions. We calculated the posterior probability of meeting the target of halting by 2025 the rise in obesity at its 2010 levels, if post-2000 trends continue. If post-2000 trends continue, the probability of meeting the global obesity target is virtually zero. Rather, if these trends continue, by 2025, global obesity prevalence will reach 18% in men and surpass 21% in women; severe obesity will surpass 6% in men and 9% in women. Nonetheless, underweight remains prevalent in the world's poorest regions, especially in south Asia.

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NCD Risk Factor Collaboration (NCD-RisC), including Mortensen EL. "A century of trends in adult human height" in Elife. Accepted. 

Abstract
Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3–19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8–144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.

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Niederseer D, Steidle-Kloc E, Mayr M, Müller EE, Cadamuro J, Patsch W, Dela F, Müller, E, Niebauer, J. "Effects of a 12-week alpine skiing intervention on endothelial progenitor cells, peripheral arterial tone and endothelial biomarkers in the elderly" in International Journal of Cardiology. 214: 343-347, 2016.

Abstract
Endothelial dysfunction occurs early during atherogenesis and it can be normalized by exercise training. Unfortunately, patients' compliance with exercise prescription remains low, often because the given choices do not appeal to them. In Alpine regions, skiing is a popular mode of exercise, and therefore we set out to assess whether it can induce antiatherogenic effects. The study shows that skiing induces several beneficial effects on markers of atherogenesis including EPCs, peripheral arterial tone and homocysteine. Our findings suggest that recreational alpine skiing may serve as a further mode of preventive exercise training, which might result in improved compliance with current recommendations.

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Ogliari G, Smit RA, van der Spoel E, Mari D, Torresani E, Felicetta I, Lucchi TA, Rossi PD, van Heemst D, de Craen AJ, Westendorp RG. "Thyroid Status and Mortality Risk in Older Adults With Normal Thyrotropin: Sex Differences in the Milan Geriatrics 75+ Cohort Study" in J Gerontol A Biol Sci Med Sci. Accepted.

Abstract
Thresholds of optimal thyroid status in old age are controversial. We investigated the longitudinal association between thyroid parameters and 10-year all-cause mortality risk in older outpatients with normal thyrotropin (TSH) and modification by sex and age. Baseline TSH, free thyroxine (fT4), and free triiodothyronine (fT3) were assessed in the Milan Geriatrics 75+ Cohort Study. 324 men and 609 women older than 75 years had normal TSH. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for the associations between thyroid parameters and mortality risk using Cox regression. Sex-stratified analyses were adjusted for sociodemographic factors and comorbidities. Among older outpatients with normal TSH, higher TSH and lower fT4 were associated with decreased mortality risk in men but not in women. When assessing thyroid status, sex and age should be taken into account.

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Ogliari G, Smit RA, Westendorp RG, Jukema JW, de Craen AJ, Sabayan B. "Visit-to-visit blood pressure variability and future functional decline in old age" in Journal of Hypertension.34:1544-50., 2016.

Abstract
Higher blood pressure variability (BPV), independent of mean blood pressure (BP), has been associated with adverse health outcomes. We investigated the association between visit-to-visit BPV and functional decline in older adults at high cardiovascular risk. In PROspective Study of Pravastatin in the Elderly at Risk, 4745 participants with mean age of 75.2 years and high cardiovascular risk were followed for a mean of 3.2 years. BP was measured in every 3 months during the first 18 months. BPV was defined as the intraindividual SD of measurements across these visits. Functional status in basic and instrumental activities of daily living was measured using the Barthel (ADL) and Lawton (IADL) scales, first at 18 months and then during follow-up until 48 months. Functional decline was calculated over this period. Higher visit-to-visit SBPV but not DBPV was associated with steeper functional decline in older adults at high cardiovascular risk. Higher SBPV is a novel risk factor for functional decline.

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Pedersen JM, Budtz-Jørgensen E, Mortensen EL, Bruunsgaard H, Osler M, Sørensen TI, Rod NH, Lund R. "Late midlife C-reactive protein and interleukin-6 in middle aged danish men in relation to body size history within and across generations" in Obesity. 24:461-468, 2016. 

Abstract
The aim was to estimate the effects of ponderal index at birth and body mass index (BMI) in early adulthood on C-reactive protein (CRP) and interleukin-6 (IL-6) and to quantify the effects through subsequent measures of body size. In a subanalysis, the contributions of maternal BMI to the inflammatory status of offspring were investigated. The study was based on 2,986 Danish males from the Copenhagen Aging and Midlife Biobank. Path analysis was employed to estimate direct and indirect effects. A 10% higher maternal BMI was associated with 7% higher CRP and 3% higher IL-6 among offspring. A 10% higher ponderal index at birth was associated with 4% lower CRP in late midlife; this effect was only partially mediated by later growth. A 10% higher BMI in early adulthood was associated with 8% higher CRP and 4% higher IL-6 in late midlife. The findings suggest that weight gain in adulthood is associated with low-grade inflammation in late midlife. Ponderal index at birth is associated with CRP in later life independently of adult BMI. The findings additionally suggest that preventing weight gain in early adulthood would be beneficial for inflammatory status in later life.

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Pedersen JM, Lund R, Andersen I, Clark AJ, Prescott E, Rod NH. "Psychosocial risk factors for the metabolic syndrome: A prospective cohort study" in International Journal of Cardiology. 215:41-46, 2016.

Abstract
We aim to estimate the effect of a comprehensive range of psychosocial factors on the risk of developing metabolic syndrome in men and women. The study population consisted of 3621 men and women from the Copenhagen City Heart Study who were free of metabolic syndrome at baseline and re-examined after 10 years. We found major life events in adult life and major life events at work, lacking a confidant and dissatisfaction with social network to be risk factors for developing the metabolic syndrome in women, while vital exhaustion and intake of sleep medications may play a more important role in men.

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Ponce-González JG, Ara, I, Larsen S,  Guerra B, Calbet JAL, Helge JW. "Biogenesis regulating proteins in human skeletal muscle and obesity. Effect of regional muscle location but not adiposity on mitochondrial biogenesis regulating proteins" in European Journal of Applied Physiology.  116: 11- 18, 2016.

Abstract
The aim of this study was to determine if the expression of the mitochondrial biogenesis-regulating proteins SIRT1, SIRT3 and PGC-1alpha in human skeletal muscle is influenced by adiposity. Twenty-nine male subjects were recruited into three groups: control, obese and post-obese. Intentionally, groups were matched by age, aerobic capacity and in addition the control and post-obese groups also by BMI. The study shows that PGC-1alpha, SIRT1 and SIRT3 protein expression in basal conditions was not altered in humans with different levels of adiposity but similar aerobic capacity. The expression of PGC-1alpha, SIRT1 and SIRT3 was higher in vastus lateralis than in deltoid muscle, indicating that local rather than systemic factors prevail in regulating the level of expression of these proteins.

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Puvill T, Lindenberg J, Slaets JP, de Craen AJ, Westendorp RG. "How is Change in Physical Health Status Reflected by Reports of Nurses and Older People Themselves?" in Journal of Gerontology Series A Biological Science and Medical Science.  Accepted. 

Abstract
We investigated how older people’s change in self-ratings, in comparison to their retrospective appreciation and change in nurse ratings, reflect functional decline and mortality risk. Functional decline was reflected by all reports of change in health. When incongruent, change in nurse-ratings reflected functional decline better than change in self-ratings but retrospective appreciation reflected functional decline best. Mortality risk was only reflected by retrospective appreciation. Retrospective appreciation of health by older people is superior to change in self-ratings and nurse-ratings in reflecting change in physical health, possibly because similar norms and values are applied in the assessment. The nurse’s norms, like the norms of older people, may shift with the ageing of the researched cohort. Asking people to retrospectively appreciate their change in health is a valuable addition to usual enquiries in practice and research.

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Rakhshan P, Sørensen H, DeVylder J, Mittal V, Mortensen EL, Michelsen NM, Ekstrøm M, Pitts SC, Mednick SA, Schiffman J. "Childhood pegboard task predicts adult-onset psychosis-spectrum disorder among a genetic high-risk sample" in Schizophrenia Research. Accepted.

Abstract
Motor abnormalities have been established as a core aspect of psychosis-spectrum disorders, with numerous studies identifying deficits prior to clinical symptom presentation. Additional research is needed to pinpoint standardized motor assessments associated with psychosis-spectrum disorders prior to illness onset to enhance prediction and understanding of etiology. With a long history of findings among people with diagnosable psychosis-spectrum disorders, but little research conducted during the premorbid phase, pegboard tasks are a viable and understudied measure of premorbid for psychosis motor functioning. In the current study, examining data from the Copenhagen Perinatal Cohort, the Simultaneous Pegs Test was performed with children at genetic high risk for psychosis and controls. Findings suggest that children who eventually developed a psychosis-spectrum disorder were less likely to successfully complete the task within time limit relative to controls. Additionally, children who eventually developed a psychosis-spectrum disorder took significantly longer to complete the task relative to controls. As pegboard performance is thought to tap both diffuse and specific brain networks, findings suggest that pegboard tests may be useful premorbid measures of motor functioning among those on a trajectory towards a psychosis-spectrum disorder.

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Rasmussen MU, Amris K, Rydahl-Hansen S, Danneskiold-Samsoe B, Mortensen EL, Christensen R, H Sjölund B. "Are the changes in observed functioning after multi-disciplinary rehabilitation of patients with fibromyalgia associated with changes in pain self-efficacy?" in Disabilty and Rehabilitation. Accepted.

Abstract
The objective was to examine the hypothesis that change in pain self-efficacy is associated with observed and self-reported activity, pain intensity, catastrophizing, and quality of life after multi-disciplinary rehabilitation of fibromyalgia patients. This was done via an in-depth analyses of secondary outcomes of a randomized-controlled trial. The subjects were Women with fibromyalgia. The main hypothesis was falsified, as there was no association between pain self-efficacy and actual performance of activity. The relation to functioning may be limited to perceived, cognitive-emotional aspects, as indicated by the weak to moderate correlations to the self-reported measures. This result has implications for rehabilitation. Improvement in observed activity post multi-disciplinary rehabilitation was not associated with change in pain self-efficacy. Patients performed better after rehabilitation, but did not perceive to have improved their capacity. The relationship between pain self-efficacy and functioning may be limited to cognitive-emotional aspects rather than actual activity. Both observational and self-reported measures should be included in evaluating outcomes of rehabilitation for patients with fibromyalgia.

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Rasmussen MU, Rydahl-Hansen S, Amris K, Samsoe, BD, Mortensen EL. "The adaptation of a Danish version of the Pain Self-Efficacy Questionnaire: Reliability and construct validity and in a population of patients with fibromyalgia in Denmark" in Scandinavian Journal of Caring Sciences. 30: 202-210, 2016.   

Abstract
The aim of this study was to translate, culturally adapt and evaluate the psychometric properties of the Pain Self-Efficacy Questionnaire (PSEQ) in a population of patients with fibromyalgia in Denmark. The study sample included 102 patients diagnosed with fibromyalgia referred to a specialist clinic. The PSEQ was translated and adapted to a Danish setting using a standard stepwise forward-backward translation procedure, followed by initial testing and focus group interview. Reliability was examined by analysing internal consistency and test-retest agreement. Construct validity was examined by investigating dimensionality, targeting, local independence, category functioning and differential item functioning (DIF). Reliability was high: Cronbach's alpha 0.88, test-retest correlation 0.93, intraclass correlation coefficient (ICC) 0.89 and item-total correlations 0.44-0.70. Factor analyses and item response (IRT) models indicated unidimensionality, and the PSEQ-DK was well targeted to the sample. High interitem correlation was observed between two items, indicating local dependence, and item misfit and DIF were observed for a few items. However, the overall fit of the scale to a single-factor model and IRT models supported acceptable construct validity. The PSEQ-DK showed acceptable psychometric properties and can therefore represent a reliable and valid measure for evaluating self-efficacy in patients with fibromyalgia in Denmark.

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Ratzer R, Iversen P, Börnsen L, Dyrby TB, Romme Christensen J, Ammitzbøll C, Madsen CG, Garde E, Lyksborg M, Andersen B, Hyldstrup L, Sørensen PS, Siebner HR, Sellebjerg F. "Monthly oral methylprednisolone pulse treatment in progressive multiple sclerosis" in Multiple Sclerosis. 22(7):926-934, 2016.

Abstract
To evaluate the effect of monthly oral methylprednisolone pulse treatment on intrathecal inflammation in progressive MS, 15 primary progressive and 15 secondary progressive MS patients received oral methylprednisolone pulse treatment for 60 weeks in this open-label phase 2A study. Primary outcome was changes in CSF concentrations of osteopontin. Secondary outcomes were other CSF biomarkers of inflammation, axonal damage and demyelination; clinical scores; magnetic resonance imaging measures of disease activity, magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI); motor evoked potentials; and bone density scans. We found no change in the CSF concentration of osteopontin, but we observed significant improvement in clinical scores, MTR, DTI and some secondary CSF outcome measures. Adverse events were well-known side effects to methylprednisolone. Monthly methylprednisolone pulse treatment was safe, but had no effect on the primary outcome. However, improvements in secondary clinical and MRI outcome measures suggest that this treatment regimen may have a beneficial effect in progressive MS.

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Reinisch JM, Mortensen EL, & Sanders SA. "Prenatal Exposure to Progesterone Affects Sexual Orientation in Humans" in Archives of Sexual Behavior. Accepted.

Abstract
Prenatal sex hormone levels affect physical and behavioral sexual differentiation in animals and humans. Although prenatal hormones are theorized to influence sexual orientation in humans, evidence is sparse. Sexual orientation variables for 34 prenatally progesterone-exposed subjects (17 males and 17 females) were compared to matched controls (M age = 23.2 years). A case-control double-blind design was used drawing on existing data from the US/Denmark Prenatal Development Project. Index cases were exposed to lutocyclin (bioidentical progesterone = C21H30O2; M W : 314.46) and no other hormonal preparation. Controls were matched on 14 physical, medical, and socioeconomic variables. A structured interview conducted by a psychologist and self-administered questionnaires were used to collect data on sexual orientation, self-identification, attraction to the same and other sex, and history of sexual behavior with each sex. Compared to the unexposed, fewer exposed males and females identified as heterosexual and more of them reported histories of same-sex sexual behavior, attraction to the same or both sexes, and scored higher on attraction to males. Measures of heterosexual behavior and scores on attraction to females did not differ significantly by exposure. We conclude that, regardless of sex, exposure appeared to be associated with higher rates of bisexuality. Prenatal progesterone may be an underappreciated epigenetic factor in human sexual and psychosexual development and, in light of the current prevalence of progesterone treatment during pregnancy for a variety of pregnancy complications, warrants further investigation. These data on the effects of prenatal exposure to exogenous progesterone also suggest a potential role for natural early perturbations in progesterone levels in the development of sexual orientation.

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Schalkwijk FH, Koopman JJ, Ghariq E, de Beer JA, van Bodegom D, Westendorp RG. "Disentangling rectangularization and life span extension with the moving rectangle method" in Annals of Epidemiology. 26:218-221.

Abstract
The moving rectangle method is used to disentangle the contributions of rectangularization and life span extension to the increase in life expectancy. It requires the choice of an endpoint of the survival curve that approaches the maximum age at death. We examined the effect of choosing different end points on the outcomes of this method. For five developed countries, survival curves from age 50 years were constructed per calendar year from 1922 onward. Survival values of 0.1, 0.01, and 0.001 were chosen as end points of the survival curve, and the contributions of rectangularization and life span extension to the increase in life expectancy were calculated using the moving rectangle method. The choice of different survival values as end points profoundly influenced the estimated contributions of rectangularization and life span extension to the increase in life expectancy. When choosing 0.001, rectangularization contributed most years, whereas when choosing 0.1, life span extension contributed most years. When the moving rectangle method is used to estimate the contributions of rectangularization and life span extension to the increase in life  expectancy, its outcomes depend on the choice of the endpoint of the survival curve.

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Schreiber K, Magyari M, Sellebjerg F, Iversen P, Garde E, Madsen CG, Börnsen L, Romme Christensen J, Ratzer R, Siebner HR, Laursen B, Soelberg Sorensen P. "High-dose erythropoietin in patients with progressive multiple sclerosis: A randomized, placebo-controlled, phase 2 trial" in Multiple Sclerosis. Accepted.

Abstract
Erythropoietin (EPO) is a part of an endogenous neuroprotective system in the brain and may address pathophysiological mechanisms in progressive multiple sclerosis (MS). This trial aims to evaluate a treatment effect of EPO on progressive MS.The method was a single-center, randomized, double-blind, placebo-controlled phase 2 trial, in which 52 patients with secondary or primary progressive MS were allocated to treatment with recombinant EPO (48,000 IU) or placebo, administered intravenously 17 times during 24 weeks. Patients had an Expanded Disability Status Score (EDSS) from 4 to 6.5 and clinical progression without relapses in the 2 preceding years. The primary outcome was the change in a composite measure of maximum gait distance, hand dexterity, and cognition from baseline to 24 weeks. A total of 50 patients completed the study. Venesection was performed often but no thromboembolic events occurred. We found no difference in the primary outcome between the EPO and the placebo group using the intention-to-treat principle ( p = 0.22). None of the secondary outcomes, neither clinical nor magnetic resonance imaging (MRI) measures showed any significant differences. This study provides class II evidence that treatment with high-dose EPO is not an effective treatment in patients with moderately advanced progressive MS.

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Sondergard SD, Dela F, Helge JW, Larsen S. "Actovegin, a non-prohibited drug increases oxidative capacity in human skeletal muscle" in European Journal of Sport Science. 16: 801-807, 2016.

Abstract
Actovegin, a deproteinized haemodialysate of calf blood, is suggested to have ergogenic properties, but this potential effect has never been investigated in human skeletal muscle. To investigate this purported ergogenic effect, we measured the mitochondrial respiratory capacity in permeabilized human skeletal muscle fibres acutely exposed to Actovegin in a low and in a high dose. We found that Actovegin, in the presence of complex I-linked substrates increased the oxidative phosphorylation (OXPHOS) capacity significantly in a concentration-dependent manner. Maximal OXPHOS capacity with complex I and II-linked substrate was increased when the fibres were exposed to the high dose of Actovegin. The respiratory capacity of the electron transfer system as well as Vmax and Km were also increased in a concentration-dependent manner after Actovegin exposure. In summary, we report for the first time that Actovegin has a marked effect on mitochondrial oxidative function in human skeletal muscle. Mitochondrial adaptations like this are also seen after a training program in human subjects. Whether this improvement translates into an ergogenic effect in athletes and thus reiterates the need to include Actovegin on the World Anti-Doping Agency's active list remains to be investigated.

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Sonne C, Carlsson J, Bech P, Vindbjerg E, Mortensen EL, Elklit A. "Psychosocial predictors of treatment outcome for trauma-affected refugees" in European Journal of Psychotraumatology. 7: 30907. doi: 10.3402/ejpt.v7.30907. eCollection 2016

Abstract
The objective of the study was to examine possible psychosocial predictors of treatment outcome for trauma-affected refugees. The participants were 195 adult refugees with posttraumatic stress disorder (PTSD) who were enrolled in a 6- to 7-month treatment programme at the Competence Centre for Transcultural Psychiatry (CTP), Denmark. The CTP Predictor Index used in the study included 15 different possible outcome predictors concerning the patients' past, chronicity of mental health problems, pain, treatment motivation, prerequisites for engaging in psychotherapy, and social situation. The primary outcome measure was PTSD symptoms measured on the Harvard Trauma Questionnaire (HTQ). Overall, the total score of the CTP Predictor Index was significantly correlated to pre- to post treatment score changes on the majority of the ratings mentioned above. While employment status was the only single item significantly correlated to HTQ-score changes, a number of single items from the CTP Predictor Index correlated significantly with changes in depression and anxiety symptoms, but the size of the correlation coefficients were modest.

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Sundstrup E, Hansen ÅM, Mortensen EL, Poulsen OM, Clausen T, Rugulies R, Møller A, Andersen LL. "Influence of physical and psychosocial work environment throughout life and physical and cognitive capacity in midlife on labor market attachment among older workers: study protocol for a prospective cohort study" in BMC Public Health. 22;16:629. doi: 10.1186/s12889-016-3290-8. 2016.

Abstract
This study will investigate the influence of physical and psychosocial work environment throughout working life and physical and cognitive capacity in midlife on labor market attachment among older workers. Approximately 5000 participants (aged 50–60 years) from the Copenhagen Aging and Midlife Biobank (CAMB) will be followed prospectively in a national register (DREAM), containing information on a week-to-week basis about social transfer payments for about 5 million Danish residents. Using Cox regression, we will model the risk of long-term sickness absence, disability pension, early retirement and unemployment within a 4 to 6 year period from the baseline measurement as a function of the following predictors: 1) physical work demands throughout working life, 2) psychosocial working conditions throughout working life, 3) physical capacity in midlife, 4) cognitive capacity in midlife. Estimates will be adjusted for age, sex, lifestyle, socioeconomic position, chronic disease and long-term sickness absence prior to baseline. The project will generate new knowledge on risk factors for loss of labor market attachment. The results will potentially contribute in identifying factors that could be targeted in future interventions for maintaining a longer and healthier working life among older workers.

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Sundstrup E, Jakobsen MD, Andersen LL, Rostgaard Andersen T, Bredsgaard R M,  Helge JW, Suetta C, Friis Schmidt J, Bangsbo J , Krustrup P,  Aagaard P. "Positive effects of long-term football and strength training on neuromuscular performance and functional ability in elderly untrained men" in European Journal of Applied Physiology. Accepted, 2016.

Abstract
The overall aim of the present study was to determine the neuromuscular adaptations to long-term (1 year) football and strength training in older untrained adults, and to assess the concurrent effect on functional ADL capacity. Twenty-seven healthy elderly males were randomly assigned to 12 months of either recreational football training, strength training or served as inactive controls. Long-term (1 year) strength training led to increased quadriceps and hamstring strength, whereas the adaptations to football training mainly included enhanced strength and rapid force capacity of the hamstring muscles. Gains in functional ability were observed in response to both training regimens, evidenced by reduced stair-ascent time and increased chair-rising performance. Long-term football exercise and strength training both appear to be effective interventional strategies to improve factors of importance for ADL by counteracting the age-related decline in lower limb strength and functional capacity among old male adults. This could potentially be a way to improve work ability of senior workers.

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Søgaard D, Dela F and Helge JW. "Muscle fibre type specific ceramide content does not support ceramide´s role in insulin resistance" Comment in Journal of Physiology. Letter. May 2016.


Sørensen CE, Tritsaris K, Reibel J, Lauritzen M, Mortensen EL, Osler M, Pedersen AM. "Elevated p16ink4a Expression in Human Labial Salivary Glands as a Potential Correlate of Cognitive Aging in Late Midlife" in PLoS One. 11(3):e0152612. doi: 10.1371.

Abstract
The aim of this study was to examine the immunolocalization pattern of p16ink4a in human labial salivary gland (LSG) tissue, and to analyze whether its expression level in LSGs is a peripheral correlate of cognitive decline in late midlife. The participants were allocated to two groups based on the relative change in cognitive performance from young adulthood to late midlife. LSG biopsies were analyzed by qRT-PCR for the expression level of p16ink4a. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections of LSGs. p16ink4a immunoreactivity was observed in LSG ductal, myoepithelial, and stromal cells, but not in acinar cells. The mean relative expression of p16ink4a in LSGs was higher in the group of participants with decline in cognitive performance. A logistic regression analysis revealed that the relative p16 expression was predictive of the participant's group assignment. A negative correlation was found between relative p16ink4a expression and the participant's standardized regression residuals from early adulthood to late midlife cognitive performance scores. p16ink4a expression in human LSGs may constitute a potential peripheral correlate of cognitive decline. Human labial salivary glands seem suitable for studies on organismal as opposed to chronological age.

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Sørensen HJ, Gamborg M, Sørensen TI, Baker JL, Mortensen EL. "Childhood body mass index and risk of schizophrenia in relation to childhood age, sex and age of first contact with schizophrenia" in European Psychiatry. 34: 64-69, 2016. 

Abstract
Childhood leanness is associated with an increased risk of schizophrenia, but the effects of gender, age at anthropometric measurements and age at first diagnosis on this relationship are unclear. The present study aimed at elucidating these associations. Population-based cohort study with childhood anthropometric measures obtained annually from the age of 7 to 13 years in 253,353 Danes born 1930-1976 and followed to 31 December 2010. Childhood BMI was significantly inversely associated with risk of schizophrenia, however with different patterns among boys and girls. In boys, childhood BMI had an inverse non-linear association with schizophrenia risk dependent on age at diagnosis; in particular, a surprisingly strong association was found between leanness and later onset of schizophrenia. In girls, the risk of schizophrenia decreased linearly with increasing BMI z-score (HR: 0.93; 95% CI: 0.88-0.98). In both boys and girls, birth weight was inversely associated with later risk. In girls, but not in boys, birth weight appeared to significantly modify the associations; there was a somewhat stronger inverse association in the lowest birth weight category. Birth weight as well as childhood BMI at ages 7 through 13 years is associated with risk of schizophrenia in both genders, but with a particular high risk of late-onset in lean boys irrespective of birth weight, and in lean girls with low birth weight. If replicated, these observations may inform preventive efforts build on schizophrenia trajectories rooted in early life.

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Sørensen L, Igel C, Liv Hansen N, Osler M, Lauritzen M, Rostrup E, Nielsen M; "Alzheimer's Disease Neuroimaging Initiative and the Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing. Early detection of Alzheimer's disease using MRI hippocampal texture" in Hum Brain Mapping. 37(3):1148-1161, 2016.

Abstract
Cognitive impairment in patients with Alzheimer's disease (AD) is associated with reduction in hippocampal volume in magnetic resonance imaging (MRI). However, it is unknown whether hippocampal texture changes in persons with mild cognitive impairment (MCI) that does not have a change in hippocampal volume. We tested the hypothesis that hippocampal texture has association to early cognitive loss beyond that of volumetric changes. The texture marker was trained and evaluated using T1-weighted MRI scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, and subsequently applied to score independent data sets from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) and the Metropolit 1953 Danish Male Birth Cohort (Metropolit). Hippocampal texture was superior to volume reduction as predictor of MCI-to-AD conversion in ADNI (area under the receiver operating characteristic curve [AUC] 0.74 vs. 0.67; DeLong test, p = 0.005), and provided even better prognostic results in AIBL (AUC 0.83). Hippocampal texture, but not volume, correlated with Addenbrooke's cognitive examination score (Pearson correlation, r = -0.25, p < 0.001) in the Metropolit cohort. The hippocampal texture marker correlated with hippocampal glucose metabolism as indicated by fluorodeoxyglucose-positron emission tomography (Pearson correlation, r = -0.57, p < 0.001). Texture statistics remained significant after adjustment for volume in all cases, and the combination of texture and volume did not improve diagnostic or prognostic AUCs significantly. Our study highlights the presence of hippocampal texture abnormalities in MCI, and the possibility that texture may serve as a prognostic neuroimaging biomarker of early cognitive impairment.

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Sørensen PS, Sellebjerg F, Lycke J, Färkkilä M, Créange A, Lund CG, Schluep M, Frederiksen JL, Stenager E, Pfleger C, Garde E, Kinnunen E, Marhardt K; "RECYCLINE Study Investigators. Minocycline added to subcutaneous interferon β-1a in multiple sclerosis: randomized RECYCLINE study" in European Journal of Neurology. 23(5):861-870, 2016.

Abstract
Combining different therapies may improve disease control in patients with relapsing-remitting multiple sclerosis (RRMS). This study assessed the efficacy and safety of minocycline added to subcutaneous (sc) interferon (IFN) β-1a therapy. One hundred and forty-nine patients received minocycline and 155 received placebo; MRI data were available for 23 and 27 patients, respectively. The time to first qualifying relapse did not differ significantly for minocycline versus placebo (hazard ratio 0.85; 95% confidence interval 0.53, 1.35; log-rank = 0.50; P = 0.48). There were no statistically significant differences between the two groups on other efficacy endpoints, although some numerical trends in favour of minocycline were observed. No unexpected adverse events were reported, but more patients discontinued because of adverse events with minocycline versus placebo. Minocycline showed no statistically significant beneficial effect when added to sc IFN β-1a therapy.

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Topp M, Vestbo J, Mortensen EL. "Personality Traits and Mental Symptoms are Associated with Impact of Chronic Obstructive Pulmonary Disease on Patients' Daily life" in COPD. Accepted.

Abstract
Previous research has shown that personality traits are associated with self-reported health status in the general population. COPD Assessment Test (CAT) is increasingly used to assess health status such as the impact of chronic obstructive pulmonary disease (COPD) on patients' daily life, but knowledge about the influence of personality traits on CAT score is lacking. The aim of this study was to examine the influence of Big Five personality traits on CAT score and the relation between personality traits and mental symptoms with respect to their influence on CAT score. A sample of 168 patients diagnosed with COPD was consecutively recruited in a secondary care outpatient clinic. All participants completed CAT, NEO Five-Factor Inventory, and Hospital Depression and Anxiety Scale. Multiple linear regression analysis was used to explore the association between personality traits and CAT scores and how this association was influenced by mental symptoms. The personality traits neuroticism, agreeableness and conscientiousness; and the mental symptoms depression and anxiety showed significant influence on CAT score when analysed in separate regression models. Identical R-square (R = 0.24) was found for personality traits and mental symptoms, but combining personality traits and mental symptoms in one regression model showed substantially reduced effect estimates of neuroticism, conscientiousness and anxiety, reflecting the strong correlations between personality traits and mental symptoms. We found that the impact of COPD on daily life measured by CAT was related to personality and mental symptoms, which illustrates the necessity of taking individual differences in personality and mental status into account in the management of COPD.

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Trompet S, Postmus I, Slagboom PE, Heijmans BT, Smit RA, Maier AB, Buckley BM, Sattar N, Stott DJ, Ford I, Westendorp RG, de Craen AJ, Jukema JW. "Non-response to (statin) therapy: the importance of distinguishing non-responders from non-adherers in pharmacogenetic studies" in European Journal of  Clinical Pharmacology . 72: 431-37, 2016.

Abstract
The aim of this study was to describe, within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), characteristics of both non-responders and high responders of statin treatment in order to possibly discriminate non-responders from non-adherers.Baseline characteristics of non-responders to statin therapy (≤10 % LDL-C reduction) were compared with those of high responders (>40 % LDL-C reduction) through a linear regression analysis. In addition, pharmacogenetic candidate gene analysis was performed to show the effect of excluding non-responders from the analysis. Our results suggest that non-responders to statin therapy are more likely to actually be non-adherers, since they have more characteristics that are viewed as indicators of high self-perceived health and low disease awareness, possibly making the subjects less adherent to study medication. We suggest that in pharmacogenetic research, extreme non-responders should be excluded to overcome the problem that non-adherence is investigated instead of non-responsiveness.

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Uth J, Hornstrup T, Christensen JF, Christensen KB, Jørgensen NR, Helge EW, Brasso  K, Helge JW, Andersen LL, Rørth  M, Midtgaard  J, Krustrup  P. "Football training in men with prostate cancer undergoing androgen deprivation therapy: activity profile and short-term skeletal and postural balance adaptations" in European Journal of Applied Physiology. 116:471-80, 2016.

Abstract
To investigate the activity profile of football training and its short-term effects on bone mass, bone turnover markers (BTMs) and postural balance in men with prostate cancer (PCa) undergoing androgen deprivation therapy (ADT).  This was a randomised 12-week study in which men with PCa undergoing ADT were assigned to a football intervention group training 2‒3 times per week for 45‒60 min or to a control group . The activity profile was measured using a 5-Hz GPS. The outcomes were total body and leg bone mineral content (BMC) and density, BTMs and postural balance. In the last part of the 12 weeks, FTG performed 194 ± 41 accelerations and 296 ± 65 decelerations at >0.6 m/s/s and covered a distance of 905 ± 297 m at speeds >6 km/h and 2646 ± 705 m per training session. Analysis of baseline-to-12-week change scores showed between-group differences in favour of FTG in total body BMC [26.4 g, 95 % confidence interval (CI): 5.8–46.9 g, p = 0.013], leg BMC (13.8 g, 95 % CI: 7.0‒20.5 g, p < 0.001) and markers of bone formation: P1NP (36.6 µg/L, 95 % CI: 10.4‒62.8 µg/L, p = 0.008) and osteocalcin (8.6 µg/L, 95 % CI: 3.3‒13.8 µg/L, p < 0.01). The number of decelerations correlated to the increase in leg BMC (r = 0.65, p = 0.012). No between-group differences were observed for the remaining outcomes. Football training involves numerous runs, accelerations and decelerations, which may be linked to marked increases in bone formation markers and preserved bone mass in middle-aged and elderly men with PCa undergoing ADT.

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Vigelso A, Gram M, Dybboe R, Kuhlman AB, Prats C, Greenhaff PL, Constantin-Teodosiu, D, Birk, JB, Wojtaszewski, J, Dela, F, Helge, JW. "The effect of age and unilateral leg immobilization for 2 weeks on substrate utilization during moderate intensity exercise in human skeletal muscle" in Journal of Physiology. 594: 2339-2358, 2016.

Abstract
This study aimed to provide molecular insight into the differential effects of age and physical inactivity on the regulation of substrate metabolism during moderate-intensity exercise. Using the arteriovenous balance technique, we studied the effect of immobilization of one leg for 2 weeks on leg substrate utilization in young and older men during two-legged dynamic knee-extensor moderate-intensity exercise, as well as changes in key proteins in muscle metabolism before and after exercise. Age and immobilization did not affect relative carbohydrate and fat utilization during exercise, but the older men had higher uptake of exogenous fatty acids, whereas the young men relied more on endogenous fatty acids during exercise. Using a combined whole-leg and molecular approach, we provide evidence that both age and physical inactivity result in intramuscular lipid accumulation, but this occurs only in part through the same mechanisms.

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Vigelsø A, Gram M, Wiuff C, Hansen CN, Prats C, Dela F, Helge JW. "Effects of immobilization and aerobic training on proteins related to intramuscular substrate storage and metabolism in young and older men" in European Journal of Applied Physiology. 116: 481-494, 2016.

Abstract
Aging and inactivity lead to skeletal muscle metabolic inflexibility, but the underlying molecular mechanisms are not entirely elucidated. Therefore, we investigated how muscle lipid and glycogen stores and major regulatory proteins were affected by short-term immobilization followed by aerobic training in young and older men. 17 young and 15 older men underwent 2 weeks' one leg immobilization followed by 6 weeks' cycle training. Biopsies were obtained from m. vastus lateralis just before immobilization (at inclusion), after immobilization, and the after 6 weeks' training. The biopsies were analyzed for muscle substrates; muscle perilipin protein (PLIN), glycogen synthase (GS), synaptosomal-associated protein of 23 kDa (SNAP23) protein content, and muscle 3-hydroxyacyl-CoA dehydrogenase (HAD) activity The older men had higher intramuscular triglyceride (IMTG) (73 %) and Glycogen (16%) levels compared to the young men, and IMTG tended to increase with immobilization. PLIN2 and 3 protein content increased with immobilization in the older men only. The young men had higher GS (74%) protein compared to the older men. Immobilization decreased and training restored HAD activity, GS and SNAP23 protein content in young and older men. Evidence of age-related metabolic inflexibility is presented, seen as body fat and IMTG accumulation. The question arises as to whether IMTG accumulation in the older men is caused by or leading to the increase in PLIN2 and 3 protein content. Training decreased body fat and IMTG levels in both young and older men; hence, training should be prioritized to reduce the detrimental effect of aging on metabolism.

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Vigelso A, Prats C, Ploug T, Dela F, Helge JW. "Higher muscle content of perilipin 5 and endothelial lipase protein in trained than untrained middle-aged men" in Physiology Research. 65: 293-302, 2016.

Abstract
A high VO(2)max in middle-age is related to high metabolic flexibility and lowered risk of metabolic diseases. However, the influence of a high VO(2)max induced by years of regular training in middle-age on protein expression related to muscle metabolism is not well studied. This study measures key proteins involved in mitochondrial oxidation, glucose and lipid metabolism in skeletal muscle of trained and untrained middle-aged men. 16 middle-aged men, matched for lean body mass, were recruited into an endurance trained (TR, n=8) or an untrained (CON, n=8) group based on their VO(2)max. A muscle biopsy was obtained from m. vastus lateralis and protein levels were analyzed by Western blotting. The TR had higher protein levels of mitochondrial complex III-V, endothelial lipase (EL) and perilipin 5 compared to the CON. Glycogen synthase (P=0.05), perilipin 3 (P=0.09) and ATGL (P=0.09) tended to be higher in TR than CON, but there was no difference in AKT I/II, HKII, GLUT4 and LPL protein expression. Lastly, there was a positive correlation between plasma HDL and EL (R(2)=0.53, P<0.01). In conclusion, a high VO(2)max in middle-aged men was as expected is reflected in higher muscle oxidative capacity, but also in higher endothelial lipase and perilipin 5 expression and a borderline higher glycogen synthase protein expression, which may contribute to a higher metabolic flexibility.

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van de Vijver PL, van Bodegom D, Westendorp RG. "Early and extraordinary peaks in physical performance come with a longevity cost" in Aging (Albany NY). Accepted.

Abstract
Life history theory postulates a trade-off between development and maintenance. This trade-off is observed when comparing life histories of different animal species. In humans, however, it is debated if variation in longevity is explained by differences in developmental traits. Observational studies found a trade-off between early and high fecundity and longevity in women. Development encompasses more than fecundity and also concerns growth and physical performance. Here, we show a life history trade-off between early and above average physical performance and longevity in male Olympic athletes. Athletes who peaked at an earlier age showed 17-percent increased mortality rates (95% CI 8-26% per SD, p≤0.001) and athletes who ranked higher showed 11-percent increased mortality rates (95% CI 1-22% per SD, p=0.025). Male athletes who had both an early and extraordinary peak performance suffered a 4.7-year longevity cost. (95% CI 2.1-7.5 years, p=0.001). This is the first time a life history trade-off between physical performance and longevity has been found in humans. This finding deepens our understanding of early developmental influences on the variation of longevity in humans.

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Waaijer ME, Croco E, Westendorp RG, Slagboom PE, Sedivy JM, Lorenzini A, Maier AB. "DNA damage markers in dermal fibroblasts in vitro reflect chronological donor age" in Aging (Albany NY). 8:147-157, 2016.

Abstract
The aging process is accompanied by an accumulation of cellular damage, which compromises the viability and function of cells and tissues. We aim to further explore the association between in vitro DNA damage markers and the chronological age of the donor, as well as long-lived family membership and presence of cardiovascular diseases. Therefore, numbers of 53BP1 foci, telomere-associated foci (TAF) and micronuclei were measured in cultured dermal fibroblasts obtained from three age groups of donors (mean age 22, 63 and 90 years). Fibroblasts were cultured without a stressor and with 0.6 μM rotenone for 3 days. We found that 53BP1 foci and TAF were more frequently present in fibroblasts of old donors compared to middle-aged and young donors. No association between micronuclei and donor age was found. Within the fibroblasts of the middle-aged donors we did not find associations between DNA damage markers and long-lived family membership or cardiovascular disease. Results were comparable when fibroblasts were stressed in vitro with rotenone. In conclusion, we found that DNA damage foci of cultured fibroblasts are significantly associated with the chronological age, but not biological age, of the donor.

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Waaijer ME, Gunn DA, Adams PD, Pawlikowski JS, Griffiths CE, van Heemst D, Slagboom PE, Westendorp RG, Maier AB. "P16INK4a Positive Cells in Human Skin Are Indicative of Local Elastic Fiber Morphology, Facial Wrinkling, and Perceived Age" in Journal of Gerontology Series A Biological Science and Medical Science. Accepted.

Abstract
Senescent cells are more prevalent in aged human skin compared to young, but evidence that senescent cells are linked to other biomarkers of aging is scarce. We counted cells positive for the tumor suppressor and senescence associated protein p16INK4a in sun-protected upper-inner arm skin biopsies from 178 participants (aged 45-81 years) of the Leiden Longevity Study. Local elastic fiber morphology, facial wrinkles, and perceived facial age were compared to tertiles of p16INK4a counts, while adjusting for chronological age and other potential confounders. The numbers of epidermal and dermal p16INK4a positive cells were significantly associated with age-associated elastic fiber morphologic characteristics, such as longer and a greater number of elastic fibers. The p16INK4a positive epidermal cells (identified as primarily melanocytes) were also significantly associated with more facial wrinkles and a higher perceived age. Participants in the lowest tertile of epidermal p16INK4a counts looked 3 years younger than those in the highest tertile, independently of chronological age and elastic fiber morphology.In conclusion, p16INK4a positive cell numbers in sun-protected human arm skin are indicative of both local elastic fiber morphology and the extent of aging visible in the face.

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Waaijer ME, Westendorp RG, Goldeck D, Gunn DA, Pawelec G, Stijntjes M, Slagboom PE, Maier AB. "Assessment of health status by molecular measures in adults ranging from middle-aged to old: Ready for clinical use?" in Experimental  Gerontology.  Accepted.

Abstract
In addition to measures already used in clinical practice, molecular measures have been proposed to assess health status, but these have not yet been introduced into clinical practice. We aimed to test the association of functional capacity measures used in current practice and molecular measures with age and health status. The cohort consisted of 178 middle-aged to old participants of the Leiden Longevity Study (range 42-82years). We tested associations between functional capacity measures (physical tests: grip strength, 4-meter walk, chair stand test; cognitive tests: Stroop test, digit symbol substitution test and 15-picture learning test) with age and with cardiovascular or metabolic disease as a measure of the health status. These associations with age and health status were also tested for molecular measures (C reactive protein (CRP), numbers of senescent p16INK4a positive cells in the epidermis and dermis and putative immunosenescence (presence of CD57+ T cells)). All functional capacity measures were associated with age. CRP and epidermal p16INK4a positivity were also associated with age, but with smaller estimates. Grip strength and the Stroop test were associated with cardiovascular or metabolic disease, as was epidermal p16INK4a positivity. All associations with cardiovascular or metabolic disease attenuated when adjusting for age. In conclusion, in middle-aged to old persons, the molecular measures tested here were more weakly associated with age and health status than functional capacity measures. Whether these molecular measures associate more closely with health status in the elderly or in specific groups of patients needs to be explored further.

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Waller KL, Mortensen EL, Avlund K, Fagerlund B, Lauritzen M, Gammeltoft S, Jennum P. "Melatonin and cortisol profiles in late midlife and their association with age-related changes in cognition". Journal of Nature and Science of Sleep. 8:47-53, 2016.

Abstract
Previous studies have reported an association between circadian disturbances and age-related cognitive impairment. The aim was to study the 24-hour profiles of melatonin and cortisol in relation to cognitive function in middle-aged male subjects. To the best of our knowledge, ours is the first study to assess circadian measures (ie, melatonin and cortisol) in healthy middle-aged men with different cognitive trajectories in midlife. We found evidence of altered circadian rhythms with a reduced nocturnal melatonin response at 4 am in men with cognitive impairment. The 24-hour concentration and AUC of melatonin and cortisol were similar in the cognitively high-functioning group and in the cognitively impaired.

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Waller KL, Mortensen EL, Avlund K, Osler M, Fagerlund B, Lauritzen M, Jennum P. "Subjective sleep quality and daytime sleepiness in late midlife and their association with age-related changes in cognition" in Sleep Medicine. 17: 265-173. 2016. 

Abstract
In an increasingly aged population, sleep disturbances and neurodegenerative disorders have become a major public health concern. Poor sleep quality and cognitive changes are complex health problems in aging populations that are likely to be associated with increased frailty, morbidity, and mortality, and to be potential risk factors for further cognitive impairment. We aimed to evaluate whether sleep quality and excessive daytime sleepiness may be considered as early predictors of cognitive impairment. The objective of this study was to examine whether subjective sleep quality and daytime sleepiness are associated with cognition in middle-aged males. The Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale measured subjective sleep quality and daytime sleepiness, respectively. Depressive symptoms were determined using Beck's Depression Inventory (BDI-II). A neuropsychological battery was administered to confirm group differences in cognitive functioning at the time when sleep data were collected. Self-reported poor sleep quality was related to cognitive changes, whereas daytime sleepiness was not related. Our results suggest that sleep quality may be an early marker of cognitive decline in midlife.


Weilner S, Schraml E, Wieser M, Messner P, Schneider K, Wassermann K, Micutkova L, Fortschegger K, Maier AB, Westendorp R, Resch H, Wolbank S, Redl H, Jansen-Dürr P, Pietschmann P, Grillari-Voglauer R, Grillari J. "Secreted microvesicular miR-31 inhibits osteogenic differentiation of mesenchymal stem cells" in Aging Cell. 15:744-54, 2016. 
Abstract
Damage to cells and tissues is one of the driving forces of aging and age-related diseases. Various repair systems are in place to counteract this functional decline. In particular, the property of adult stem cells to self-renew and differentiate is essential for tissue homeostasis and regeneration. However, their functionality declines with age (Rando, 2006). One organ that is notably affected by the reduced differentiation capacity of stem cells with age is the skeleton. Here, we found that circulating microvesicles impact on the osteogenic differentiation capacity of mesenchymal stem cells in a donor-age-dependent way. While searching for factors mediating the inhibitory effect of elderly derived microvesicles on osteogenesis, we identified miR-31 as a crucial component. We demonstrated that miR-31 is present at elevated levels in the plasma of elderly and of osteoporosis patients. As a potential source of its secretion, we identified senescent endothelial cells, which are known to increase during aging in vivo (Erusalimsky, 2009). Endothelial miR-31 is secreted within senescent cell-derived microvesicles and taken up by mesenchymal stem cells where it inhibits osteogenic differentiation by knocking down its target Frizzled-3. Therefore, we suggest that microvesicular miR-31 in the plasma of elderly might play a role in the pathogenesis of age-related impaired bone formation and that miR-31 might be a valuable plasma-based biomarker for aging and for a systemic environment that does not favor cell-based therapies whenever osteogenesis is a limiting factor.
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Wijsman LW, de Craen AJ, Muller M, Sabayan B, Stott D, Ford I, Trompet S, Jukema JW, Westendorp RG, Mooijaart SP. "Blood Pressure Lowering Medication, Visit-to-Visit Blood Pressure Variability, and Cognitive Function in Old Age" in American Journal of Hypertension. 29:311-318, 2016.

Abstract
Visit-to-visit blood pressure (BP) variability is associated with cognitive impairment. We assessed to what extent the association between BP variability and cognitive impairment is mediated by the association of BP lowering medication (BPLM) with both BP variability and cognition. We studied 5,606 participants from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). BP was measured every 3 months during 3.2 years; BP variability was defined as the SD of BP measurements during follow-up. Cognitive function was assessed at baseline and during follow-up using the Stroop test, Letter-Digit Coding test, and immediate and delayed Picture-Word Learning tests. Multivariate regression models were used with and without adjustments for BPLM to calculate the percentage to which BPLM mediated the association between BP variability and cognition. The association between BP variability and cognitive impairment was not mediated by BPLM.



Wijsman LW, de Craen AJ, Trompet S, Sabayan B, Muller M, Stott DJ, Ford I, Welsh P, Westendorp RG, Jukema JW, Sattar N, Mooijaart SP. "High-sensitivity cardiac troponin T is associated with cognitive decline in older adults at high cardiovascular risk" in European Journal of Preventive Cardiology. 23:1383-1392, 2016. 

Abstract
Cardiac troponin T (cTnT), measured with a high-sensitivity (hs) assay, is associated with cognitive decline, but the underlying mechanism is unknown. We investigated the association of hs-cTnT with cognitive function and decline, and studied whether this association was independent of cardiovascular diseases or risk factors, and N-terminal pro-brain natriuretic peptide (NT-proBNP). We studied 5407 participants (mean age 75.31 years) from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), who all had cardiovascular diseases or risk factors thereof. Participants with pre-existent advanced clinical heart failure were excluded. Hs-cTnT and NT-proBNP obtained after 6 months of follow-up were related with cognitive function, tested repeatedly during a mean follow-up of 3.2 years. Conclusions: Higher levels of hs-cTnT associate with worse cognitive function and steeper cognitive decline in older adults independent of cardiovascular diseases, risk factors and NT-proBNP.

Wimmelmann CL, Lund, MT, Hansen M, Dela F, Mortensen EL.  "The effect of preoperative type 2 diabetes and physical fitness on mental health and health-related quality of life after Roux en-Y gastric bypass" in Journal of Obesity. Accepted.
Abstract
To investigate the predictive value of type 2 diabetes and lack of physical activity for mental health and health-related quality of life after Roux-en-Y gastric bypass. Method. Forty severely obese patients undergoing Roux-en-Y gastric bypass were included in the GASMITO study. Information about physiological and psychological factors was prospectively assessed at four time points, two times prior to surgery and two times after surgery. Measures included oral and intravenous glucose tolerance tests, VO2max test, Symptoms Checklist (SCL-90), Short Form Health Survey 36 (SF-36), Body Image Questionnaire, and a questionnaire assessing sociodemographic factors and medical status. Results. Mean % excess weight loss was 65% (±12) at 18-month follow-up and 50% of the participants with diabetes experienced total remission. Also, significant improvements were observed with regard to physical fitness, mental distress, health-related quality of life, and weight-related body image (p < 0,05). The interaction between follow-up time and type 2 diabetes at baseline significantly predicted six of the thirteen psychological subscales (p < 0,05) and, across the follow-ups, physical fitness level made modest contributions to variations in mental symptoms and HRQOL but not weight-related body image. Conclusion. The results suggest that baseline difference in mental symptoms and physical HRQOL between diabetic and nondiabetic patients declines across follow-ups and resolves around the time of surgery.
Aarestrup J, Bjerregaard LG, Gamborg M, Ängquist L, Tjønneland A, Overvad K, Linneberg A, Osler M, Mortensen EL, Gyntelberg F, Lund R, Tia S, Baker JL. "Tracking of body mass index from 7 to 69 years of age" in International Journal of Obesity. 40: 1376-1383, 2016.
Abstract
Heavy children have an increased risk of being overweight young adults. Whether this risk remains in late adulthood is not well-understood. We investigated body mass index (BMI; kg m(-2)) tracking from childhood to late adulthood. From the Copenhagen School Health Records Register, 72 959 men and 25 252 women born between 1930 and 1989 with BMI values at 7 and/or 13 years and as adults were included. Using a meta-regression approach, age- and sex-specific partial correlation analyses and logistic regressions were performed. BMI tracking was weaker at late adult ages than at young adult ages. Although BMI tracks across the life course, childhood BMI is relatively poor at identifying later adult overweight or obesity at ages when chronic diseases generally emerge.

Theme 3

Nielsen, C.F. and Hickson, I.D. "PICH promotes mitotic chromosome segregation: identification of a novel role in ribosomal DNA disjunction" in Cell Cycle (in press), 2016.

Abstract
PICH is an SNF2-family DNA translocase that appears to play a role specifically in mitosis. Characterization of PICH in human cells led to the initial discovery of "ultra-fine DNA bridges" (UFBs) that connect the 2 segregating DNA masses in the anaphase of mitosis. These bridge structures, which arise from specific regions of the genome, are a normal feature of anaphase but had escaped detection previously because they do not stain with commonly used DNA dyes. Nevertheless, UFBs are important for genome maintenance because defects in UFB resolution can lead to cytokinesis failure. We reported recently that PICH stimulates the unlinking (decatenation) of entangled DNA by Topoisomerase IIα (Topo IIα), and is important for the resolution of UFBs. We also demonstrated that PICH and Topo IIα co-localize at the rDNA (rDNA). In this Extra View article, we discuss the mitotic roles of PICH and explore further the role of PICH in the timely segregation of the rDNA locus.

Ghamrasni, S.E., Cardoso, R., Li, L., Guturi, K.K.N., Bjerregaard, V.A., Liu, Y., Venkatesan, S., Hande, M.P., Henderson, J.T., Sanchez, O., Hickson, I.D., Hakem, A. and Hakem R. "Rad54 and Mus81 cooperation promotes DNA damage repair and restrains chromosome missegregation" in Oncogene (in press), 2016.

Abstract
Rad54 and Mus81 mammalian proteins physically interact and are important for the homologous recombination DNA repair pathway; however, their functional interactions in vivo are poorly defined. Here, we show that combinatorial loss of Rad54 and Mus81 results in hypersensitivity to DNA-damaging agents, defects on both the homologous recombination and non-homologous DNA end joining repair pathways and reduced fertility. We also observed that while Mus81 deficiency diminished the cleavage of common fragile sites, very strikingly, Rad54 loss impaired this cleavage to even a greater extent. The inefficient repair of DNA double-strand breaks (DSBs) in Rad54(-/-)Mus81(-/-) cells was accompanied by elevated levels of chromosome missegregation and cell death. Perhaps as a consequence, tumor incidence in Rad54(-/-)Mus81(-/-) mice remained comparable to that in Mus81(-/-) mice. Our study highlights the importance of the cooperation between Rad54 and Mus81 for mediating DNA DSB repair and restraining chromosome missegregation.

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Ahuja, A.K., Jodkowska, K., Teloni, F., Bizard., A.H., Zellweger, R., Herrador, R., Ortega, S., Hickson, I.D., Altmeyer, M., Mendez, J. and Lopes, M. "A short G1 phase imposes replicative stress and extensive fork remodeling in mouse embryonic stem cells" in Nature Communications 7, 10660, 2016.

Abstract
Embryonic stem cells (ESCs) represent a transient biological state, where pluripotency is coupled with fast proliferation. ESCs display a constitutively active DNA damage response (DDR), but its molecular determinants have remained elusive. Here we show in cultured ESCs and mouse embryos that H2AX phosphorylation is dependent on Ataxia telangiectasia and Rad3 related (ATR) and is associated with chromatin loading of the ssDNA-binding proteins RPA and RAD51. Single-molecule analysis of replication intermediates reveals massive ssDNA gap accumulation, reduced fork speed and frequent fork reversal. All these marks of replication stress do not impair the mitotic process and are rapidly lost at differentiation onset. Delaying the G1/S transition in ESCs allows formation of 53BP1 nuclear bodies and suppresses ssDNA accumulation, fork slowing and reversal in the following S-phase. Genetic inactivation of fork slowing and reversal leads to chromosomal breakage in unperturbed ESCs. We propose that rapid cell cycle progression makes ESCs dependent on effective replication-coupled mechanisms to protect genome integrity.

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Pitchai, G.P., Hickson, I.D., Streicher, W.W., Montoya, G. and Mesa, P. "Crystallization of the NTPR and BD1 interacting domains of the human PICH-BEND3 complex" in Acta Crystallographica 72, 646-651, 2016.

Abstract
Chromosome integrity depends on DNA structure-specific processing complexes that resolve DNA entanglement between sister chromatids. If left unresolved, these entanglements can generate either chromatin bridging or ultrafine DNA bridging in the anaphase of mitosis. These bridge structures are defined by the presence of the PICH protein, which interacts with the BEND3 protein in mitosis. To obtain structural insights into PICH-BEND3 complex formation at the atomic level, their respective NTPR and BD1 domains were cloned, overexpressed and crystallized using 1.56 M ammonium sulfate as a precipitant at pH 7.0. The protein complex readily formed large hexagonal crystals belonging to space group P6122, with unit-cell parameters a = b = 47.28, c = 431.58 Å and with one heterodimer in the asymmetric unit. A complete multiwavelength anomalous dispersion (MAD) data set extending to 2.2 Å resolution was collected from a selenomethionine-labelled crystal at the Swiss Light Source.

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Lecona E, Rodriguez-Acebes S, Specks J, Lopez-Contreras AJ, Ruppen I, Murga M, Muñoz J, Mendez J, Fernandez-Capetillo O. "USP7 is a SUMO deubiquitinase essential for DNA replication" in Nat Struct Mol Biol. 23:270-7, 2016.

Abstract
Post-translational modification of proteins by ubiquitin (Ub) and Ub-like modifiers regulates DNA replication. We have previously shown that chromatin around replisomes is rich in SUMO and poor in Ub, whereas mature chromatin exhibits an opposite pattern. How this SUMO-rich, Ub-poor environment is maintained at sites of DNA replication in mammalian cells remains unexplored. Here we identify USP7 as a replisome-enriched SUMO deubiquitinase that is essential for DNA replication. By acting on SUMO and SUMOylated proteins, USP7 counteracts their ubiquitination. Inhibition or genetic deletion of USP7 leads to the accumulation of Ub on SUMOylated proteins, which are displaced away from replisomes. Our findings provide a model explaining the differential accumulation of SUMO and Ub at replication forks and identify an essential role of USP7 in DNA replication that should be considered in the development of USP7 inhibitors as anticancer agents.

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Nieto-Soler M, Morgado-Palacin I, Lafarga V, Lecona E, Murga M, Callen E, Azorin D, Alonso J, Lopez-Contreras AJ, Nussenzweig A, Fernandez-Capetillo O. "Efficacy of ATR inhibitors as single agents in Ewing sarcoma" in Oncotarget. In press, 2016.

Abstract
Ewing sarcomas (ES) are pediatric bone tumors that arise from a driver translocation, most frequently EWS/FLI1. Current ES treatment involves DNA damaging agents, yet the basis for the sensitivity to these therapies remains unknown. Oncogene-induced replication stress (RS) is a known source of endogenous DNA damage in cancer, which is suppressed by ATR and CHK1 kinases. We here show that ES suffer from high endogenous levels of RS, rendering them particularly dependent on the ATR pathway. Accordingly, two independent ATR inhibitors show in vitro toxicity in ES cell lines as well as in vivo efficacy in ES xenografts as single agents. Expression of EWS/FLI1 or EWS/ERG oncogenic translocations sensitizes non-ES cells to ATR inhibitors. Our data shed light onto the sensitivity of ES to genotoxic agents, and identify ATR inhibitors as a potential therapy for Ewing Sarcomas.

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Peña-Diaz J, Rasmussen LJ. "Approaches to diagnose MMR gene defects in cancer" Review. DNA repair. 38:147-54, 2016.

Abstract
The DNA repair pathway mismatch repair (MMR) is responsible for the recognition and correction of DNA biosynthetic errors caused by inaccurate nucleotide incorporation during replication. Faulty MMR leads to failure to address the mispairs or insertion deletion loops (IDLs) left behind by the replicative polymerases and results in increased mutation load at the genome. The realization that defective MMR leads to a hypermutation phenotype and increased risk of tumorigenesis highlights the relevance of this pathway for human disease. The association of MMR defects with increased risk of cancer development was first observed in colorectal cancer patients that carried inactivating germline mutations in MMR genes and the disease was named as hereditary non-polyposis colorectal cancer (HNPCC). Currently, a growing list of cancers is found to be MMR defective and HNPCC has been renamed Lynch syndrome (LS) partly to include the associated risk of developing extra-colonic cancers. In addition, a number of non-hereditary, mostly epigenetic, alterations of MMR genes have been described in sporadic tumors. Besides conferring a strong cancer predisposition, genetic or epigenetic inactivation of MMR genes also renders cells resistant to some chemotherapeutic agents. Therefore, diagnosis of MMR deficiency has important implications for the management of the patients, the surveillance of their relatives in the case of LS and for the choice of treatment. Some of the alterations found in MMR genes have already been well defined and their pathogenicity assessed. Despite this substantial wealth of knowledge, the effects of a large number of alterations remain uncharacterized (variants of uncertain significance, VUSs). The advent of personalized genomics is likely to increase the list of VUSs found in MMR genes and anticipates the need of diagnostic tools for rapid assessment of their pathogenicity. This review describes current tools and future strategies for addressing the relevance of MMR gene alterations in human disease.

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Bregenhorn S, Kallenberger L, Artola-Borán M, Peña-Diaz J, Jiricny J. "Non-canonical uracil processing in DNA gives rise to double-strand breaks and deletions: relevance to class switch recombination" in Nucleic Acids Research.44(6):2691-705, 2016.

Abstract
During class switch recombination (CSR), antigen-stimulated B-cells rearrange their immunoglobulin constant heavy chain (CH) loci to generate antibodies with different effector functions. CSR is initiated by activation-induced deaminase (AID), which converts cytosines in switch (S) regions, repetitive sequences flanking the CH loci, to uracils. Although U/G mispairs arising in this way are generally efficiently repaired to C/Gs by uracil DNA glycosylase (UNG)-initiated base excision repair (BER), uracil processing in S-regions of activated B-cells occasionally gives rise to double strand breaks (DSBs), which trigger CSR. Surprisingly, genetic experiments revealed that CSR is dependent not only on AID and UNG, but also on mismatch repair (MMR). To elucidate the role of MMR in CSR, we studied the processing of uracil-containing DNA substrates in extracts of MMR-proficient and -deficient human cells, as well as in a system reconstituted from recombinant BER and MMR proteins. Here, we show that the interplay of these repair systems gives rise to DSBs in vitro and to genomic deletions and mutations in vivo, particularly in an S-region sequence. Our findings further suggest that MMR affects pathway choice in DSB repair. Given its amenability to manipulation, our system represents a powerful tool for the molecular dissection of CSR.

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Keijzers G, Liu D, Rasmussen LJ. "Exonuclease 1 and its Versatile Roles in DNA Repair" in Crit Rev Biochem Mol Biol. 5:1-12. 2016.

Abstract
Exonuclease 1 (EXO1) is a multifunctional 5' → 3' exonuclease and a DNA structure-specific DNA endonuclease. EXO1 plays roles in DNA replication, DNA mismatch repair (MMR) and DNA double-stranded break repair (DSBR) in lower and higher eukaryotes and contributes to meiosis, immunoglobulin maturation, and micro-mediated end-joining in higher eukaryotes. In human cells, EXO1 is also thought to play a role in telomere maintenance. Mutations in the human EXO1 gene correlate with increased susceptibility to some cancers. This review summarizes recent studies on the enzymatic functions and biological roles of EXO1, its possible protective role against cancer and aging, and regulation of EXO1 by posttranslational modification.

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Toft-Kehler AK, Gurubaran IS, Desler C, Rasmussen LJ, Skytt DM, Kolko M. "Oxidative Stress-Induced Dysfunction of Müller Cells During Starvation" in Invest Ophthalmol Vis Sci, 57:2721-2728. 2016.

Abstract
Müller cells support retinal neurons with essential functions. Here, we aim to examine the impact of starvation and oxidative stress on glutamate uptake and mitochondrial function in Müller cells. Cultured human retinal Müller cells (MIO-M1) were exposed to H2O2 and additional starvation for 24 hours. Effects of starvation and H2O2 on glutamate uptake and mitochondrial function were assessed by kinetic glutamate uptake assays and Seahorse assays, respectively. Cell survival was evaluated by cell viability assays. mRNA and protein expressions were assessed by quantitative PCR and Western blot. We identified an increased susceptibility toward oxidative stress in starved Müller cells in spite of unaffected viability and an apparent decreased ability to transport glutamate. Solely exposure to oxidative stress did not affect Müller cell functions. Thus, our study suggests an increased susceptibility of Müller cells in case of more than one cellular stressor. Extrapolating these findings, age-related neurodegenerative retinal diseases may be the result of impaired Müller cell function.

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Lu H, Shamanna RA, Keijzers G, Anand R, Rasmussen LJ, Cejka P, Croteau DL, Bohr VA. "RECQL4 Promotes DNA End Resection in Repair of DNA Double-Strand Breaks" in Cell Rep, pii: S2211-1247(16)30692-1. doi: 10.1016/j.celrep.2016.05.079. 2016.

Abstract
The RecQ helicase RECQL4, mutated in Rothmund-Thomson syndrome, regulates genome stability, aging, and cancer. Here, we identify a crucial role for RECQL4 in DNA end resection, which is the initial and an essential step of homologous recombination (HR)-dependent DNA double-strand break repair (DSBR). Depletion of RECQL4 severely reduces HR-mediated repair and 5' end resection in vivo. RECQL4 physically interacts with MRE11-RAD50-NBS1 (MRN), which senses DSBs and initiates DNA end resection with CtIP. The MRE11 exonuclease regulates the retention of RECQL4 at laser-induced DSBs. RECQL4 also directly interacts with CtIP via its N-terminal domain and promotes CtIP recruitment to the MRN complex at DSBs. Moreover, inactivation of RECQL4's helicase activity impairs DNA end processing and HR-dependent DSBR without affecting its interaction with MRE11 and CtIP, suggesting an important role for RECQL4's unwinding activity in the process. Thus, we report that RECQL4 is an important participant in HR-dependent DSBR.

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Nygaard RH, Maynard S, Schjerling P, Kjaer M, Qvortrup K, Bohr VA, Rasmussen LJ, Jemec GB, Heidenheim M. 2016. "Acquired cutis laxa localized to the upper body in an adult female" in Case Rep Dermatol, 8:42–51. 2016.

Abstract
Cutis laxa is a rare disease characterized by abnormal skin wrinkling and laxity, due to decreased elastin synthesis or structural extracellular matrix defects. We have explored elastin metabolism in a case of adult onset cutis laxa localized to the upper body of a woman. For this purpose, we obtained skin biopsies from affected and unaffected skin areas of the patient and analyzed these with microscopy, polymerase chain reaction, western blotting and cell culture experiments. Skin from the affected area lacked elastin fibers in electron microscopy but had higher mRNA expression of elastin and total RNA. Levels of an apparent tropoelastin degradation product were higher in the affected area. Fibroblast cultures from the affected area were able to produce elastin and showed higher proliferation and survival after oxidative and UVB stress compared to fibroblasts from the unaffected area. In conclusion, we report a case of acquired localized cutis laxa with a lack of elastic fibers in the skin of the patient's upper body. The lack of elastic fibers in the affected skin was combined with increased mRNA expression and protein levels of elastin. These findings indicate that elastin synthesis was increased but did not lead to deposited elastic fibers in the tissue.

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de Cabo R, Martin-Montalvo A, Sun Y, Diaz-Ruiz A, Ali A, Gutierrez V, Palacios H, Curtis J, Siendones E, Ariza J, Abulwerdi G, Sun X, Wang A, Pearson K, Fishbein K, Spencer R, Wang M, Han X, Scheibye-Knudsen M, Baur J, Shertzer H, Navas P, Villalba J, Zou S, Bernier M; "Cytochrome b5 reductase and the control of lipid metabolism and healthspan" in Aging and Mechanisms of Disease, In press

Abstract
Cytochrome b5 reductases (CYB5R) are required for the elongation and desaturation of fatty acids, cholesterol synthesis and mono-oxygenation of cytochrome P450 enzymes, all of which are associated with protection against metabolic disorders. However, the physiological role of CYB5R in the context of metabolism, healthspan and aging remains ill-defined. We generated CYB5R-overexpressing flies (CYB5R-OE) and created a transgenic mouse line overexpressing CYB5R3 (CYB5R3-Tg) in the C57BL/6J background to investigate the function of this class of enzymes as regulators of metabolism and age-associated pathologies. Gender- and/or stage-specific induction of CYB5R, and pharmacological activation of CYB5R with tetrahydroindenoindole extended fly lifespan. Increased expression of CYB5R3 was associated with significant improvements in several metabolic parameters that resulted in modest lifespan extension in mice. Diethylnitrosamine-induced liver carcinogenesis was reduced in CYB5R3-Tg mice. Accumulation of high levels of long-chain polyunsaturated fatty acids, improvement in mitochondrial function, decrease in oxidative damage and inhibition of chronic pro-inflammatory pathways occurred in the transgenic animals. These results indicate that CYB5R represents a new target in the study of genes that regulate lipid metabolism and healthspan.

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Fang EF, Kassahun H, Croteau DL, Scheibye-Knudsen M, Marosi K, Lu H, Shamanna RA, Kalyanasundaram S, Bollineni RC, Wilson MA, Iser WB, Wollman BN, Morevati M, Li J, Tian J, Sinclair DA, Mattson MP, Nilsen H, Bohr VA; "NAD+ Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair" in Cell Metabolism, In press

Abstract
Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked to defects in ATM, a master regulator of the response to and repair of DNA double-strand breaks. The molecular basis of cerebellar atrophy and neurodegeneration in A-T patients is unclear. Here we report and examine the significance of increased PARylation, low NAD+, and mitochondrial dysfunction in ATM-deficient neurons, mice, and worms. Treatments that replenish intracellular NAD+ reduce the severity of A-T neuropathology, normalize neuromuscular function, delay memory loss, and extend lifespan in both animal models. Mechanistically, treatments that increase intracellular NAD+ also stimulate neuronal DNA repair and improve mitochondrial quality via mitophagy. This work links two major theories on aging, DNA damage accumulation, and mitochondrial dysfunction through nuclear DNA damage-induced nuclear-mitochondrial signaling, and demonstrates that they are important pathophysiological determinants in premature aging of A-T, pointing to therapeutic interventions.

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Lauritzen KH, Hasan-Olive MM, Regnell, CE; Kleppa L, Scheibye-Knudsen M, Gjedde A, Klungland A, Bohr VA, Storm-Mathisen J, Bergersen L; "A ketogenic diet accelerates neurodegeneration in mice with induced mitochondrial DNA toxicity in the forebrain" in Neurobiology of Aging, In press

Abstract
Mitochondrial genome maintenance plays a central role in preserving brain health. We previously demonstrated accumulation of mitochondrial DNA damage and severe neurodegeneration in transgenic mice inducibly expressing a mutated mitochondrial DNA repair enzyme (mutUNG1) selectively in forebrain neurons. Here, we examine whether severe neurodegeneration in mutUNG1-expressing mice could be rescued by feeding the mice a ketogenic diet, which is known to have beneficial effects in several neurological disorders. The diet increased the levels of superoxide dismutase 2, and mitochondrial mass, enzymes, and regulators such as SIRT1 and FIS1, and appeared to downregulate N-methyl-D-aspartic acid (NMDA) receptor subunits NR2A/B and upregulate γ-aminobutyric acid A (GABAA) receptor subunits α1. However, unexpectedly, the ketogenic diet aggravated neurodegeneration and mitochondrial deterioration. Electron microscopy showed structurally impaired mitochondria accumulating in neuronal perikarya. We propose that aggravation is caused by increased mitochondrial biogenesis of generally dysfunctional mitochondria. This study thereby questions the dogma that a ketogenic diet is unambiguously beneficial in mitochondrial disorders.

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Karikkineth AC, Scheibye-Knudsen M, Fivenson E, Croteau DL, Bohr VA; "Cockayne syndrome: Clinical features, model systems and pathways" in Ageing Res Rev. S1568-1637(16)30177-5 2016

Abstract
Cockayne syndrome (CS) is a disorder characterized by a variety of clinical features including cachectic dwarfism, severe neurological manifestations including microcephaly and cognitive deficits, pigmentary retinopathy, cataracts, sensorineural deafness, and ambulatory and feeding difficulties, leading to death by 12 years of age on average. It is an autosomal recessive disorder, with a prevalence of approximately 2.5 per million. There are several phenotypes (1-3) and two complementation groups (CSA and CSB), and CS overlaps with xeroderma pigmentosum (XP). It has been considered a progeria, and many of the clinical features resemble accelerated aging. As such, the study of CS affords an opportunity to better understand the underlying mechanisms of aging. The molecular basis of CS has traditionally been ascribed to defects in transcription and transcription-coupled nucleotide excision repair (TC-NER). However, recent work suggests that defects in base excision DNA repair and mitochondrial functions may also play key roles. This opens up the possibility for molecular interventions in CS, and by extrapolation, possibly in aging.

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Mitchell SJ, Madrigal-Matute J, Scheibye-Knudsen M, Fang E, Aon M, González-Reyes JA, Cortassa S, Kaushik S, Gonzalez-Freire M, Patel B, Wahl D, Ali A, Calvo-Rubio M, Burón MI, Guiterrez V, Ward TM, Palacios HH, Cai H, Frederick DW, Hine C, Broeskamp F, Habering L, Dawson J, Beasley TM, Wan J, Ikeno Y, Hubbard G, Becker KG, Zhang Y, Bohr VA, Longo DL, Navas P, Ferrucci L, Sinclair DA, Cohen P, Egan JM, Mitchell JR, Baur JA, Allison DB, Anson RM, Villalba JM, Madeo F, Cuervo AM, Pearson KJ, Ingram DK, Bernier M, de Cabo R; "Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice" in Cell Metab. 14;23(6):1093-112 2016.

Abstract
Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlate with lifespan extension, although it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions.

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Fang EF, Scheibye-Knudsen M, Chua KF, Mattson MP, Croteau DL, Bohr VA. "Nuclear DNA damage signalling to mitochondria in ageing" in Nat Rev Mol Cell Biol. 308-21 2016

Abstract
Mitochondrial dysfunction is a hallmark of ageing, and mitochondrial maintenance may lead to increased healthspan. Emerging evidence suggests a crucial role for signalling from the nucleus to mitochondria (NM signalling) in regulating mitochondrial function and ageing. An important initiator of NM signalling is nuclear DNA damage, which accumulates with age and may contribute to the development of age-associated diseases. DNA damage-dependent NM signalling constitutes a network that includes nuclear sirtuins and controls genomic stability and mitochondrial integrity. Pharmacological modulation of NM signalling is a promising novel approach for the prevention and treatment of age-associated diseases.

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Hansen RK, Mund A, Poulsen SL, Klement K, Räschle M, Romero RS, Offermanns S, Worzfeld T, Grosse R, Brandt DT, Rozell B, Mann M, Goodarzi AG, Daniel J, Mailand N, Bekker‐Jensen S. "SCAI promotes heterochromatin‐associated DNA double‐strand break repair and genome stability maintenance in vivo" in Nature Cell Biology – in press.

Abstract
DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions, whose accurate repair by non-homologous end-joining (NHEJ) or homologous recombination (HR) is crucial for genome integrity and is strongly influenced by the local chromatin environment12. Here, we identify SCAI (suppressor of cancer cell invasion) as a 53BP1-interacting chromatin-associated protein that promotes the functionality of several DSB repair pathways in mammalian cells. SCAI undergoes prominent enrichment at DSB sites through dual mechanisms involving 53BP1-dependent recruitment to DSB-surrounding chromatin and 53BP1-independent accumulation at resected DSBs. Cells lacking SCAI display reduced DSB repair capacity, hypersensitivity to DSB-inflicting agents and genome instability. We demonstrate that SCAI is a mediator of 53BP1-dependent repair of heterochromatin-associated DSBs, facilitating ATM kinase signalling at DSBs in repressive chromatin environments. Moreover, we establish an important role of SCAI in meiotic recombination, as SCAI deficiency in mice leads to germ cell loss and subfertility associated with impaired retention of the DMC1 recombinase on meiotic chromosomes. Collectively, our findings uncover SCAI as a physiologically important component of both NHEJ- and HR-mediated pathways that potentiates DSB repair efficiency in specific chromatin contexts.

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Saredi G, Huang H, Hammond CM, Alabert C, Bekker-Jensen S, Forne I, Reverón-Gómez N, Foster BM, Mlejnkova L, Bartke T, Cejka P, Mailand N, Imhof A, Patel DJ, Groth A. "H4K20me0 marks post-replicative chromatin and recruits the TONSL–MMS22L DNA repair complex" in Nature. 2016 Jun 30;534(7609):714-8.

Abstract
After DNA replication, chromosomal processes including DNA repair and transcription take place in the context of sister chromatids. While cell cycle regulation can guide these processes globally, mechanisms to distinguish pre- and post-replicative states locally remain unknown. Here we reveal that new histones incorporated during DNA replication provide a signature of post-replicative chromatin, read by the human TONSL–MMS22L homologous recombination complex. We identify the TONSL ankyrin repeat domain (ARD) as a reader of histone H4 tails unmethylated at K20 (H4K20me0), which are specific to new histones incorporated during DNA replication and mark post-replicative chromatin until the G2/M phase of the cell cycle. Accordingly, TONSL–MMS22L binds new histones H3–H4 both before and after incorporation into nucleosomes, remaining on replicated chromatin until late G2/M. H4K20me0 recognition is required for TONSL–MMS22L binding to chromatin and accumulation at challenged replication forks and DNA lesions. Consequently, TONSL ARD mutants are toxic, compromising genome stability, cell viability and resistance to replication stress. Together, these data reveal a histone-reader-based mechanism for recognizing the post-replicative state, offering a new angle to understand DNA repair with the potential for targeted cancer therapy.

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Airik R, Schueler M, Airik M, Cho J, Ulanowicz KA, Porath JD, Hurd TW, Bekker-Jensen S, Schrøder JM, Andersen JS, Hildebrandt F. "SDCCAG8 Interacts with RAB Effector Proteins RABEP2 and ERC1 and Is Required for Hedgehog Signaling" in PLoS One. 2016 May 25;11(5):e0156081.

Abstract
Recessive mutations in the SDCCAG8 gene cause a nephronophthisis-related ciliopathy with Bardet-Biedl syndrome-like features in humans. Our previous characterization of the orthologous Sdccag8gt/gt mouse model recapitulated the retinal-renal disease phenotypes and identified impaired DNA damage response signaling as an underlying disease mechanism in the kidney. However, several other phenotypic and mechanistic features of Sdccag8gt/gt mice remained unexplored. Here we show that Sdccag8gt/gt mice exhibit developmental and structural abnormalities of the skeleton and limbs, suggesting impaired Hedgehog (Hh) signaling. Indeed, cell culture studies demonstrate the requirement of SDCCAG8 for ciliogenesis and Hh signaling. Using an affinity proteomics approach, we demonstrate that SDCCAG8 interacts with proteins of the centriolar satellites (OFD1, AZI1), of the endosomal sorting complex (RABEP2, ERC1), and with non-muscle myosin motor proteins (MYH9, MYH10, MYH14) at the centrosome. Furthermore, we show that RABEP2 localization at the centrosome is regulated by SDCCAG8. siRNA mediated RABEP2 knockdown in hTERT-RPE1 cells leads to defective ciliogenesis, indicating a critical role for RABEP2 in this process. Together, this study identifies several centrosome-associated proteins as novel SDCCAG8 interaction partners, and provides new insights into the function of SDCCAG8 at this structure.

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Schwertman P, Bekker-Jensen S, Mailand N. "Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers" in Nat Rev Mol Cell Biol. 2016 May 23;17(6):379-94.

Abstract
DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions. The swift recognition and faithful repair of such damage is crucial for the maintenance of genomic stability, as well as for cell and organismal fitness. Signalling by ubiquitin, SUMO and other ubiquitin-like modifiers (UBLs) orchestrates and regulates cellular responses to DSBs at multiple levels, often involving extensive crosstalk between these modifications. Recent findings have revealed compelling insights into the complex mechanisms by which ubiquitin and UBLs regulate protein interactions with DSB sites to promote accurate lesion repair and protection of genome integrity in mammalian cells. These advances offer new therapeutic opportunities for diseases linked to genetic instability.

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Diehl C, Akke M, Bekker-Jensen S, Mailand N, Streicher W, Wikström M. "Structural analysis of a complex between small ubiquitin-like modifier 1 (SUMO1) and the ZZ domain of CREB-binding Protein (CBP/p300) reveals a new interaction surface on SUMO" in J Biol Chem. 2016 Jun 10;291(24):12658-72.

Abstract
We have recently discovered that the ZZ zinc finger domain represents a novel small ubiquitin-like modifier (SUMO) binding motif. In this study we identify the binding epitopes in the ZZ domain of CBP (CREB-binding protein) and SUMO1 using NMR spectroscopy. The binding site on SUMO1 represents a unique epitope for SUMO interaction spatially opposite to that observed for canonical SUMO interaction motifs (SIMs). HADDOCK docking simulations using chemical shift perturbations and residual dipolar couplings was employed to obtain a structural model for the ZZ domain-SUMO1 complex. Isothermal titration calorimetry experiments support this model by showing that the mutation of key residues in the binding site abolishes binding and that SUMO1 can simultaneously and non-cooperatively bind both the ZZ domain and a canonical SIM motif. The binding dynamics of SUMO1 was further characterized using (15)N Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersions, which define the off rates for the ZZ domain and SIM motif and show that the dynamic binding process has different characteristics for the two cases. Furthermore, in the absence of bound ligands SUMO1 transiently samples a high energy conformation, which might be involved in ligand binding.

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Hoffmann S, Smedegaard S, Nakamura K, Räschle M, Oka Y, Feng Y, Groth A, Bekker‐Jensen S, Mailand N. "TRAIP is a PCNA‐associated ubiquitin ligase that protects genome stability after replication stress" in J Cell Biol. 2016 Jan 4;212(1):63-75

Abstract
Cellular genomes are highly vulnerable to perturbations to chromosomal DNA replication. Proliferating cell nuclear antigen (PCNA), the processivity factor for DNA replication, plays a central role as a platform for recruitment of genome surveillance and DNA repair factors to replication forks, allowing cells to mitigate the threats to genome stability posed by replication stress. We identify the E3 ubiquitin ligase TRAIP as a new factor at active and stressed replication forks that directly interacts with PCNA via a conserved PCNA-interacting peptide (PIP) box motif. We show that TRAIP promotes ATR-dependent checkpoint signaling in human cells by facilitating the generation of RPA-bound single-stranded DNA regions upon replication stress in a manner that critically requires its E3 ligase activity and is potentiated by the PIP box. Consequently, loss of TRAIP function leads to enhanced chromosomal instability and decreased cell survival after replication stress. These findings establish TRAIP as a PCNA-binding ubiquitin ligase with an important role in protecting genome integrity after obstacles to DNA replication.

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Hou Y, Song H, Croteau DL, Akbari M, Bohr VA. "Genome instability in Alzheimer disease" in  Mech Ageing Dev.  pii: S0047-6374(16)30047-1, 2016.

Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Autosomal dominant, familial AD (fAD) is very rare and caused by mutations in amyloid precursor protein (APP), presenilin-1 (PSEN-1), and presenilin-2 (PSEN-2) genes. The pathogenesis of sporadic AD (sAD) is more complex and variants of several genes are associated with an increased lifetime risk of AD. Nuclear and mitochondrial DNA integrity is pivotal during neuronal development, maintenance and function. DNA damage and alterations in cellular DNA repair capacity have been implicated in the aging process and in age-associated neurodegenerative diseases, including AD. These findings are supported by research using animal models of AD and in DNA repair deficient animal models. In recent years, novel mechanisms linking DNA damage to neuronal dysfunction have been identified and have led to the development of noninvasive treatment strategies. Further investigations into the molecular mechanisms connecting DNA damage to AD pathology may help to develop novel treatment strategies for this debilitating disease. Here we provide an overview of the role of genome instability and DNA repair deficiency in AD pathology and discuss research strategies that include genome instability as a component.

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Kolko M, Vosborg F, Henriksen UL, Hasan-Olive MM, Diget EH, Vohra R, Gurubaran IR, Gjedde A, Mariga ST, Skytt DM, Utheim TP, Storm-Mathisen J, Bergersen LH. "Lactate Transport and Receptor Actions in Retina: Potential Roles in Retinal Function and Disease" in Neurochem Res. 41:1229-36, 2016 

Abstract
In retina, like in brain, lactate equilibrates across cell membranes via monocarboxylate transporters and in the extracellular space by diffusion, forming a basis for the action of lactate as a transmitter of metabolic signals. In the present paper, we argue that the lactate receptor GPR81, also known as HCAR1, may contribute importantly to the control of retinal cell functions in health and disease. GPR81, a G-protein coupled receptor, is known to downregulate cAMP both in adipose and nervous tissue. The receptor also acts through other down-stream mechanisms to control functions, such as excitability, metabolism and inflammation. Recent publications predict effects of the lactate receptor on neurodegeneration. Neurodegenerative diseases in retina, where the retinal ganglion cells die, notably glaucoma and diabetic retinopathy, may be linked to disturbed lactate homeostasis. Pilot studies reveal high GPR81 mRNA in retina and indicate GPR81 localization in Müller cells and retinal ganglion cells. Moreover, monocarboxylate transporters are expressed in retinal cells. We envision that lactate receptors and transporters could be useful future targets of novel therapeutic strategies to protect neurons and prevent or counteract glaucoma as well as other retinal diseases.

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Rinholm JE, Vervaeke K, Tadross MR, Tkachuk AN, Kopek BG, Brown TA, Bergersen LH, Clayton DA. "Movement and structure of mitochondria in oligodendrocytes and their myelin sheaths" in Glia. 64:810-25, 2016.

Abstract
Mitochondria play several crucial roles in the life of oligodendrocytes. During development of the myelin sheath they are essential providers of carbon skeletons and energy for lipid synthesis. During normal brain function their consumption of pyruvate will be a key determinant of how much lactate is available for oligodendrocytes to export to power axonal function. Finally, during calcium-overload induced pathology, as occurs in ischemia, mitochondria may buffer calcium or induce apoptosis. Despite their important functions, very little is known of the properties of oligodendrocyte mitochondria, and mitochondria have never been observed in the myelin sheaths. We have now used targeted expression of fluorescent mitochondrial markers to characterize the location and movement of mitochondria within oligodendrocytes. We show for the first time that mitochondria are able to enter and move within the myelin sheath. Within the myelin sheath the highest number of mitochondria was in the cytoplasmic ridges along the sheath. Mitochondria moved more slowly than in neurons and, in contrast to their behavior in neurons and astrocytes, their movement was increased rather than inhibited by glutamate activating NMDA receptors. By electron microscopy we show that myelin sheath mitochondria have a low surface area of cristae, which suggests a low ATP production. These data specify fundamental properties of the oxidative phosphorylation system in oligodendrocytes, the glial cells that enhance cognition by speeding action potential propagation and provide metabolic support to axons.

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Holm-Hansen S, Low JK, Zieba J, Gjedde A, Bergersen LH, Karl T. "Behavioural effects of high fat diet in a mutant mouse model for the schizophrenia risk gene neuregulin 1" in Genes Brain Behav.15:295-304, 2016 

Abstract
Schizophrenia patients are often obese or overweight and poor dietary choices appear to be a factor in this phenomenon. Poor diet has been found to have complex consequences for the mental state of patients. Thus, this study investigated whether an unhealthy diet [i.e. high fat diet (HFD)] impacts on the behaviour of a genetic mouse model for the schizophrenia risk gene neuregulin 1 (i.e. transmembrane domain Nrg1 mutant mice: Nrg1 HET). Female Nrg1 HET and wild-type-like littermates (WT) were fed with either HFD or a control chow diet. The mice were tested for baseline (e.g. anxiety) and schizophrenia-relevant behaviours after 7 weeks of diet exposure. HFD increased body weight and impaired glucose tolerance in all mice. Only Nrg1 females on HFD displayed a hyper-locomotive phenotype as locomotion-suppressive effects of HFD were only evident in WT mice. HFD also induced an anxiety-like response and increased freezing in the context and the cued version of the fear conditioning task. Importantly, CHOW-fed Nrg1 females displayed impaired social recognition memory, which was absent in HFD-fed mutants. Sensorimotor gating deficits of Nrg1 females were not affected by diet. In summary, HFD had complex effects on the behavioural phenotype of test mice and attenuated particular cognitive deficits of Nrg1 mutant females. This topic requires further investigations thereby also considering other dietary factors of relevance for schizophrenia as well as interactive effects of diet with medication and sex.

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Skytt DM, Toft-Kehler AK, Brændstrup CT, Cejvanovic S, Gurubaran IS, Bergersen LH, Kolko M. "Glia-Neuron Interactions in the Retina Can Be Studied in Cocultures of Müller Cells and Retinal Ganglion Cells" in Biomed Res Int. 1087647, 2016

Abstract
Glia-neuron partnership is important for inner retinal homeostasis and any disturbances may result in retinal ganglion cell (RGC) death. Müller cells support RGCs with essential functions such as removing excess glutamate and providing energy sources. The aim was to explore the impact of Müller cells on RGC survival. To investigate the Müller cell/RGC interactions we developed a coculture model, in which primary Müller cells were grown in inserts on top of pure primary RGC cultures. The impact of starvation and mitochondrial inhibition on the Müller cell ability to protect RGCs was studied. Moreover, the ability of Müller cells to remove glutamate from the extracellular space was investigated. RGC survival was evaluated by cell viability assays and glutamate uptake was assessed by kinetic uptake assays. We demonstrated a significantly increased RGC survival in presence of untreated and prestarved Müller cells. Additionally, prestarved Müller cells significantly increased RGC survival after mitochondrial inhibition. Finally, we revealed a significantly increased ability to take up glutamate in starved Müller cells. Overall, our study confirms essential roles of Müller cells in RGC survival. We suggest that targeting Müller cell function could have potential for future treatment strategies to prevent blinding neurodegenerative retinal diseases.

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Couppe C, Svensson RB, Kongsgaard M, Kovanen V, Grosset JF, Snorgaard O, Bencke J, Larsen JO, Bandholm T, Christensen TM, Boesen AP, Helmark IC, Aagaard P, Kjaer M, Magnusson SP. "Human Achilles tendon glycation and function in diabetes" in J Appl Physiol. 120: 130-137, 2016.

Abstract
Diabetic patients have an increased risk of foot ulcers, and glycation of collagen may increase tissue stiffness. We hypothesized that the level of glycemic control (glycation) may affect Achilles tendon stiffness, which can influence gait pattern. We therefore investigated the relationship between collagen glycation, Achilles tendon stiffness parameters, and plantar pressure in poorly and well controlled diabetic patients, including healthy age-matched (45-70 yr) controls. There were no differences in any of the outcome parameters (collagen cross-linking or tendon stiffness) between patients with well-controlled and poorly controlled diabetes. The overall effect of diabetes was explored by collapsing the diabetes groups (DB) compared with the controls. Skin collagen cross-linking lysylpyridinoline, hydroxylysylpyridinoline and pentosidine concentrations were markedly greater in DB. Furthermore, Achilles tendon material stiffness was higher in DB. Notably, DB also demonstrated higher forefoot/rearfoot peak-plantar-pressure ratio. Overall, Achilles tendon material stiffness and skin connective tissue cross-linking were greater in diabetic patients compared with controls. The higher foot pressure indicates that material stiffness of tendon and other tissue (e.g., skin and joint capsule) may influence foot gait. The difference in foot pressure distribution may contribute to the development of foot ulcers in diabetic patients.

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Bulow J, Agergaard J, Kjaer M, Holm L, Reitelseder S. "No additional effect of different types of physical activity on 10-hour muscle protein synthesis in elderly men on a controlled energy- and protein-sufficient diet" in Exp Gerontol. 79: 16-25, 2016.

Abstract
The elderly lose skeletal muscle mass with age, which may be detrimental for function and quality of life. The aim of this study was to determine the effects of daily physical activities upon muscle protein synthesis (MPS)in elderly individuals. A total of 24 elderly men were recruited and randomly assigned: inactivity in form of bed-rest (IA), daily physical activities (DA), or heavy resistance exercise (RE). Physical activity was highest in the DA compared to both the IA and RE groups. Nutrient ingestion increased insulin, leucine, and phenylalanine plasma concentrations in all groups. [1-(13)C]leucine enrichment was stable throughout the 10-hour FSR period. Myofibrillar protein FSR were similar for IA, DA, and RE groups, 0.055±0.003%/h, 0.058±0.006%/h, and 0.065±0.008%/h, respectively (means±SE, P=0.44). In elderly males, inactivity, daily activities, and resistance exercise interventions result in equal 10-hour, whole day MPS during an energy- and protein-sufficient diet regimen.

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Mackey AL and Kjaer M. "Connective tissue regeneration in skeletal muscle after eccentric contraction-induced injury" in J Appl Physiol. In press, 2016.

Abstract
Human skeletal muscle has the potential to regenerate completely after injury induced under controlled experimental conditions. The events inside the myofibers as they undergo necrosis, followed closely by satellite cell-mediated myogenesis, have been mapped in detail. Much less is known about the adaptation throughout this process of both the connective tissue structures surrounding the myofibers and the fibroblasts, the cells responsible for synthesizing this connective tissue. However, the few studies investigating muscle connective tissue remodeling demonstrate a strong response that appears to be sustained for a long time after the major myofiber responses have subsided. While the use of electrical stimulation to induce eccentric contractions vs. voluntary eccentric contractions appears to lead to a greater extent of myofiber necrosis and regenerative response, this difference is not apparent when the muscle connective tissue responses are compared, although further work is required to confirm this. Pharmacological agents (growth hormone and angiotensin II type I receptor blockers) are considered in the context of accelerating the muscle connective tissue adaptation to loading. Cautioning against this, however, is the association between muscle matrix protein remodeling and protection against reinjury, which suggests that a (so far undefined) period of vulnerability to reinjury may exist during the remodeling phases. The role of individual muscle matrix components and their spatial interaction during adaptation to eccentric contractions is an unexplored field in human skeletal muscle and may provide insight into the optimal timing of rest vs. return to activity after muscle injury.

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Magnusson SP, Heinemeier KM, Kjaer M. "Collagen homeostasis and metabolism" in Adv Exp Med Biol 920: 11-25, 2016.

Abstract
The musculoskeletal system and its collagen rich tissue is important for ensuring architecture of skeletal muscle, energy storage in tendon and ligaments, joint surface protection, and for ensuring the transfer of muscular forces into resulting limb movement. Structure of tendon is stable and the metabolic activity is low, but mechanical loading and subsequent mechanotransduction and molecular anabolic signaling can result in some adaptation of the tendon especially during youth and adolescence. Within short time, tendon will get stiffer with training and lack of mechanical tissue loading through inactivity or immobilization of the human body will conversely result in a dramatic loss in tendon stiffness and collagen synthesis. This illustrates the importance of regular mechanical load in order to preserve the stabilizing role of the connective tissue for the overall function of the musculoskeletal system in both daily activity and exercise. Adaptive responses may vary along the tendon, and differ between mid-substance and insertional areas of the tendon.

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Heinemeier KM, Lorentzen MP, Jensen JK, Schjerling P, Seynnes OR, Narici MV, Kjaer M. "Local trauma in human patellar tendon leads to a widespread change in gene expression" in J Appl Physiol. 120: 1000-1007, 2016.

Abstract
Low cellular activity and slow tissue turnover in human tendon may prolong resolution of tendinopathy. This may be stimulated by moderate localized traumas such as needle penetrations, but whether this results in a widespread cellular response in tendons is unknown. In an initial hypothesis-generating study, a trauma-induced tendon cell activity (increased total RNA and collagen I mRNA) was observed after repeated patellar tendon biopsies in young men. In a subsequent controlled study, 25 young men were treated with two 0.8-mm-diameter needle penetrations [n = 13, needle-group (NG)] or one 2.1-mm-diameter needle biopsy [n = 12, biopsy-group (BG)] in one patellar tendon. Four weeks later biopsies were taken from treated (5 mm lateral from trauma site) and contralateral tendons for analyses of RNA content (ribogreen assay), DNA content (PCR based), and gene expression for relevant target genes (Real-time RT-PCR) (NG, n = 11 and BG, n = 8). Intervention increased RNA content, and mRNA expression of collagen I and III and TGF-β1 (P < 0.05), with biopsy treatment having greatest effect (tendency for RNA and collagen I). Results for DNA content were inconclusive, and no changes were detected in expression of insulin-like growth factor-I, connective tissue growth factor, scleraxis, decorin, fibromodulin, tenascin-C, tenomodulin, VEGFa, CD68, IL-6, MMP12, and MMP13. In conclusion, a moderate trauma to a healthy human tendon (e.g., biopsy sampling) results in a widespread upregulation of tendon cell activity and their matrix protein expression. The findings have implications for design of studies on human tendon and may provide perspectives in future treatment strategies in tendinopathy.

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Mackey AL, Rasmussen LK, Kadi F, Schjerling P, Helmark IC, Ponsot E, Aagaard P, Durigan JLQ, Kjaer M. "Activation of satellite cells and the regeneration of human skeletal muscle are expedited by ingestion of non-steroidal anti-inflammatory medication" in FASEB J, 30: 2266-2281.

Abstract
With this study we investigated the role of nonsteroidal anti-inflammatory drugs (NSAIDs) in human skeletal muscle regeneration. Young men ingested NSAID  [1200 mg/d ibuprofen (IBU)]or placebo (PLA) daily for 2 wk before and 4 wk after an electrical stimulation-induced injury to the leg extensor muscles of one leg. Muscle biopsies were collected from the vastus lateralis muscles before and after stimulation and were assessed for satellite cells and regeneration by immunohistochemistry and real-time RT-PCR, and we also measured telomere length. After injury, and compared with PLA, IBU was found to augment the proportion of ActiveNotch1(+) satellite cells at 2 d [IBU, 29 ± 3% vs. PLA, 19 ± 2% (means ± sem)], satellite cell content at 7 d [IBU, 0.16 ± 0.01 vs. PLA, 0.12 ± 0.01 (Pax7(+) cells/fiber)], and to expedite muscle repair at 30 d. The PLA group displayed a greater proportion of embryonic myosin(+) fibers and a residual ∼2-fold increase in mRNA levels of matrix proteins (all P < 0.05). Endomysial collagen was also elevated with PLA at 30 d. Minimum telomere length shortening was not observed. In conclusion, ingestion of NSAID has a potentiating effect on Notch activation of satellite cells and muscle remodeling during large-scale regeneration of injured human skeletal muscle. -Mackey, A. L., Rasmussen, L. K., Kadi, F., Schjerling, P., Helmark, I. C., Ponsot, E., Aagaard, P., Durigan, J. L. Q., Kjaer, M. Activation of satellite cells and the regeneration of human skeletal muscle are expedited by ingestion of nonsteroidal anti-inflammatory medication.

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Hansen M and Kjaer M. "Sex hormones and tendon" in Adv Exp Med Biol 920: 139-149, 2016.

Abstract
The risk of overuse and traumatic tendon and ligament injuries differ between women and men. Part of this gender difference in injury risk is probably explained by sex hormonal differences which are specifically distinct during the sexual maturation in the teenage years and during young adulthood. The effects of the separate sex hormones are not fully elucidated. However, in women, the presence of estrogen in contrast to very low estrogen levels may be beneficial during regular loading of the tissue or during recovering after an injury, as estrogen can enhance tendon collagen synthesis rate. Yet, in active young female athletes, physiological high concentration of estrogen may enhance the risk of injuries due to reduced fibrillar crosslinking and enhanced joint laxity. In men, testosterone can enhance tendon stiffness due to an enhanced tendon collagen turnover and collagen content, but testosterone has also been linked to a reduced responsiveness to relaxin. The present chapter will focus on sex difference in tendon injury risk, tendon morphology and tendon collagen turnover, but also on the specific effects of estrogen and androgens.

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Eliasson P, Couppe C, Lonsdale M, Svensson RB, Neergaard C, Kjaer M, Friberg L, Magnusson SP. "Ruptured human Achilles tendon has elevated metabolic activity up to 1 year after repair" in Eur J Nucl Med Mol Imaging. 43: 1868-1877, 2016.

Abstract
The purpose of this study was to investigate tendon metabolism (glucose uptake) and vascularization at 3, 6 and 12 months after Achilles tendon rupture as measured using PET and power Doppler ultrasonography (PDUS). The study group comprised 23 patients with surgically repaired Achilles tendon rupture who were investigated at 3, 6 and 12 months after surgery. Relative glucose uptake was higher in repaired tendons than in intact tendons at all time-points, and was also higher in the tendon core than in the periphery at 3 and 6 months, but lower at 12 months. Relative glucose uptake was negatively related to ATRS at 6 months after repair. PDUS flow activity was higher in repaired tendons than in intact tendons at 3 and 6 months, but had normalized by 12 months. These data demonstrate that the healing process as determined by metabolic activity and vascularization continues for 6 months after injury when large loads are typically allowed on the tendon. Indeed, metabolic activity remained elevated for more than 1 year after injury despite normalized vascularization. The robust negative correlation between tendon metabolism and patient-reported outcome suggests that a high metabolic activity 6 months after the injury may be related to a poor clinical healing outcome.

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Bieler T, Siersma V, Magnusson SP, Kjaer M, Christensen HR, Beyer N. "In hip osteoarthritis, Nordic Walking is superior to strength training and home-based exercise for improving function" in Scand J Med Sci Sports. In press 2016.

This observer-blinded, randomized controlled trial compared the short- and long-term effects of 4 months of supervised strength training (ST) in a local fitness center, supervised Nordic Walking (NW) in a local park, and unsupervised home-based exercise (HBE, control) on functional performance in 60+-year-old persons with hip osteoarthritis (OA) not awaiting hip replacement. Functional performance [i.e., 30-s chair stand test (primary outcome), timed stair climbing, and 6-min walk test] and self-reported outcomes were measured at baseline and at 2, 4, and 12 months. Based on intention-to-treat-analyses improvements [mean (95% CI)] after intervention in number of chair stands were equal in all three groups at 4 months but greater in the NW group than in the ST group at 12 months. Generally, improvements in functional performance were greater after NW compared with HBE and ST at all follow-up time points. Furthermore, NW was superior to HBE for improving vigorous physical activity and to both ST and HBE for improving mental health. These data suggest that NW is the recommended exercise modality compared with ST and HBE.

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Jensen KK, Kjaer M, Jorgensen LN. "Isometric abdominal wall muscle strength assessment in individuals with incisional hernia: A prospective reliability story" in Hernia, in press 2016.

Abstract
To determine the reliability of measurements obtained by the Good Strength dynamometer, determining isometric abdominal wall and back muscle strength in patients with ventral incisional hernia (VIH) and healthy volunteers with an intact abdominal wall.Ten patients with VIH and ten healthy volunteers with an intact abdominal wall were each examined twice with a 1 week interval. Examination included the assessment of truncal flexion and extension as measured with the Good Strength dynamometer, the completion of the International Physical Activity Questionnaire (IPAQ) and the self-assessment of truncal strength on a visual analogue scale (SATS). The test-retest reliability of truncal flexion and extension was assessed by interclass correlation coefficient (ICC), and Bland and Altman graphs. Finally, correlations between truncal strength, and IPAQ and SATS were examined. Truncal flexion and extension showed excellent test-retest reliability for both patients with VIH (ICC 0.91 and 0.99) and healthy controls (ICC 0.97 and 0.96). Bland and Altman plots showed that no systematic bias was present for neither truncal flexion nor extension when assessing reliability. For patients with VIH, no significant correlations between objective measures of truncal strength and IPAQ or SATS were found. For healthy controls, both truncal flexion (τ 0.58, p = 0.025) and extension (τ 0.58, p = 0.025) correlated significantly with SATS, while no other significant correlation between truncal strength measures and IPAQ was found. The Good Strength dynamometer provided a reliable, low-cost measure of truncal flexion and extension in patients with VIH.

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Dideriksen K, Boesen AP, Kristiansen JF, Magnusson SP, Schjerling P, Holm L, Kjaer M. "Skeletal muscle adaptation to immobilization and subsequent retraining in elderly men. No effect of anti-inflammatory medication" in Exp Gerontol, 82: 8-18, 2016.

Abstract
We studied the influence of NSAID treatment on human skeletal muscle during immobilization and rehabilitation resistance training (retraining). 19 men (60-80yrs) were randomly assigned to ibuprofen (1200mg/d, Ibu) or placebo (Plc). One lower limb was immobilized in a cast for 2weeks and retrained for 6weeks. Moreover, whey protein isolate was ingested (2×20g/d) throughout the whole study period. Plasma inflammatory markers, quadriceps muscle mass and strength, and muscle gene expression were investigated. Muscle mass and strength decreased after 2weeks of immobilization, but returned to baseline levels after 2weeks of retraining combined with whey protein supplementation. Furthermore, muscle mass and strength reached beyond baseline levels after 6weeks of retraining, and NSAID did not significantly affect this. No group-differences, but differences over time, were observed for muscle gene expression of proteolytic and anabolic factors. Plasma inflammatory markers were unaffected by the study intervention and NSAID treatment. Two weeks of lower limb immobilization lead to a reduction in muscle mass and strength, but these parameters were restored already after2 weeks of retraining and whey protein supplementation. After 6weeks of retraining and whey protein supplementation, muscle mass and strength increased beyond baseline levels, and NSAID treatment did not significantly influence this in elderly.

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Jensen KK, Munim K, Kjaer M, Jorgensen LN. "Abdominal wall reconstruction for incisional hernia optimizes truncal function and quality of life – a prospective controlled study" in Ann Surg, in press 2016.

Abstract
The aim of the study was to examine abdominal wall function in patients undergoing abdominal wall reconstruction (AWR) for incisional hernia. We performed a prospective case-control study of 18 consecutive patients with large incisional hernia undergoing AWR with linea alba restoration. Truncal flexion and extension strength, hand grip strength, leg extension power, and quality of life were assessed preoperatively and 1 year postoperatively. Patients were compared with a control group of patients with an intact abdominal wall undergoing colorectal resection. Compared with preoperative measurements, 1-year follow-up after AWR demonstrated an increase of both truncal flexion strength and truncal extension strength. There was no significant change of either hand grip strength or leg extension power. After AWR, the physical component of overall quality of life improved, whereas the mental component score remained unchanged. In the control group, surgery resulted in a decrease in both truncal flexion and truncal extension. AWR for incisional hernia specifically improved long-term abdominal wall muscular function and quality of life.

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Svensson RB, Heinemeier KM, Couppe C, Kjaer M, Magnusson SP. "The effect of aging and exercise on the tendon" in J Appl Physiol. In press 2016.

Abstract
The aim of the study was to examine abdominal wall function in patients undergoing abdominal wall reconstruction (AWR) for incisional hernia. We performed a prospective case-control study of 18 consecutive patients with large incisional hernia undergoing AWR with linea alba restoration. Truncal flexion and extension strength, hand grip strength, leg extension power, and quality of life were assessed preoperatively and 1 year postoperatively. Patients were compared with a control group of patients with an intact abdominal wall undergoing colorectal resection. Compared with preoperative measurements, 1-year follow-up after AWR demonstrated an increase of both truncal flexion strength and truncal extension strength. There was no significant change of either hand grip strength or leg extension power. After AWR, the physical component of overall quality of life improved, whereas the mental component score remained unchanged. In the control group, surgery resulted in a decrease in both truncal flexion and truncal extension. AWR for incisional hernia specifically improved long-term abdominal wall muscular function and quality of life.

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Bieler T, Magnusson SP, Christensen HE, Kjaer M, Beyer N. "Muscle power is an important measure to detect deficits in muscle function in hip osteoarthritis: a cross-sectional study" in Disabil Rehabil, 3: 1-8, 2016.

Abstract
To investigate between-leg differences in hip and thigh muscle strength and leg extensor power in patients with unilateral hip osteoarthritis. Further, to compare between-leg differences in knee extensor strength and leg extensor power between patients and healthy peers. Seventy-two patients (60-87 years) with radiographic and symptomatic hip osteoarthritis not awaiting hip replacement and 35 healthy peers (63-82 years) were included. Hip and thigh muscle strength and leg extensor power were measured in patients and knee extensor strength and leg extensor power in healthy. Patients had generalized weakening of the affected lower extremity and numerically the largest asymmetry was evident for leg extensor power. In contrast, healthy peers had no asymmetry in leg extensor power. These results indicate that exercise interventions focusing on improving leg extensor power of the symptomatic lower extremity and reducing asymmetry may be beneficial for patients with hip osteoarthritis. Implications for Rehabilitation Even in patients with mild symptoms not awaiting hip replacement a generalized muscle weakening of the symptomatic lower extremity seems to be present. Between-leg differences in leg extensor power (force × velocity) appears to be relatively large (19%) in patients with unilateral hip osteoarthritis in contrast to healthy peers who show no asymmetry. Compared to muscle strength the relationship between functional performance and leg extensor power seems to be stronger, and more strongly related to power of the symptomatic lower extremity. Our results indicate that exercise interventions focusing on improving leg extensor power of the symptomatic lower extremity and reducing asymmetry may be beneficial for patients with mild symptoms not awaiting hip replacement.

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Heinemeier KM, Kjaer M, Magnusson SP. "Methods of assessing human tendon metabolism and tissue properties in response to changes in mechanical loading" in Adv Exp Med Biol 920: 97-106, 2016.

Abstract
In recent years a number of methodological developments have improved the opportunities to study human tendon. Microdialysis enables sampling of interstitial fluid in the peritendon tissue, while sampling of human tendon biopsies allows direct analysis of tendon tissue for gene- and protein expression as well as protein synthesis rate. Further the (14)C bomb-pulse method has provided data on long-term tissue turnover in human tendon. Non-invasive techniques allow measurement of tendon metabolism (positron emission tomography (PET)), tendon morphology (magnetic resonance imaging (MRI)), and tendon mechanical properties (ultrasonography combined with force measurement during movement). Finally, 3D cell cultures of human tendon cells provide the opportunity to investigate cell-matrix interactions in response to various interventions.

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Couppe C, Svensson RB, Heinemeier KM, Thomsen EW, Bayer ML, Christensen L, Kjaer M, Magnusson SP, Schjerling P. "Quantification of cell density in rat Achilles tendon development and application of a new method" in Histochem Cell Biol, in press 2016.

Abstract
Increased tendon cell nuclei density (TCND) has been proposed to induce tendon mechanical adaptations. However, it is unknown whether TCND is increased in tendon tissue after mechanical loading and whether such an increase can be quantified in a reliable manner. The aim of this study was to develop a reliable method for quantification of TCND and to investigate potential changes in TCND in rat Achilles tendons in response to 12 weeks of running. Eight adult male Sprague-Dawley rats ran (RUN) on a treadmill with 10° incline, 1 h/day, 5 days/wk (17-20 m/min) for 12 weeks (which improved tendon mechanical properties) and were compared with 11 control rats (SED). Tissue-Tek-embedded cryosections (10 µm) from the mid region of the Achilles tendon were cut longitudinally on a cryostat. Sections were stained with alcian blue and picrosirius red. One blinded investigator counted the number of tendon cell nuclei 2-3 times in three separate regions of the mid longitudinal tendon sections with fields of 390 μm × 280 μm. Unpaired t tests were used for the statistical analysis (mean ± SE). Typical Error % for replicate counts was 5.5 and 14 % coefficient of variation for the three regions. There was no difference in TCND between running rats versus control rats (nuclei per image (≈105 μm2): RUN, 152 ± 9; SED, 146 ± 8, p = 0.642). This new method provided reproducible quantification of TCND. There was no difference in TCND despite improvements in tendon mechanics, which suggests that cell number is not a major cause for altered tendon mechanical properties with loading.

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Christensen JF, Schjerling P, Andersen JL, Daugaard G, Rørth M, Mackey AL. "Muscle satellite cell content and mRNA signaling in germ cell cancer patients – effect of chemotherapy and resistance training" in Anca Oncologica. In press 2016.

Abstract
Cisplatin-based chemotherapy has significantly improved treatment outcomes in testicular germ cell cancer (GCC)patients, but is associated with elevated risk of serious long-term complications and preventive measures are an unmet need. Physical exercise is known to mitigate chemotherapy toxicities, and current cancer-specific guidelines emphasize the capacity of exercise to ameliorate muscle dysfunction by retaining muscle mass and improving physical function in patients undergoing toxic anti-cancer therapies  dysregulated pathways involved in myofibrillar protein turnover. In a randomized  controlled trial, our group recently found that GCC patients undergoing standard care lost approximately 2.5 kg of lean mass over nine weeks of cis-platin-based chemotherapy,  while resistance exercise tended to attenuate the loss of lean mass and improved muscle strength. Here, we extend on our previous findings with the objective to describe intramuscular adaptations induced by chemotherapy with or without concurrent resistance exercise. Specifically, we present an explorative substudy in subjects who had repeated muscle biopsies taken before and after chemotherapy and/or resistance exercise, in order to evaluate changes in muscle satellite cell content and gene expression in GCC patients and healthy individuals.

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Heinemeier KM, Schjerling P, Heinemeier J, Møller MB, Krogsgaard MR, Grum-Schwensen T, Petersen MM, Kjaer M. "Radiocarbon dating of adult human articular cartilage shows minimal collagen turnover in both healthy and osteoarthritic tissue" in Science Transl Med, 8: 346-56, 2016.

Abstract
The poor regenerative capacity of articular cartilage presents a major clinical challenge and may relate to a limited turnover of the cartilage collagen matrix. However, the collagen turnover rate during life is not clear, and it is debated whether osteoarthritis (OA) can influence it. Using the carbon-14 ((14)C) bomb-pulse method, life-long replacement rates of collagen were measured in tibial plateau cartilage from 23 persons born between 1935 and1997 (15 and 8 persons with OA and healthy cartilage, respectively). The (14)C levels observed in cartilage collagen showed that, virtually, no replacement of the collagen matrix happened after skeletal maturity and that neither OA nor tissue damage, per se, influenced collagen turnover. Regional differences in (14)C content across the joint surface showed that cartilage collagen located centrally on the joint surface is formed several years earlier than collagen located peripherally. The collagen matrix of human articular cartilage is an essentially permanent structure that has no significant turnover in adults, even with the occurrence of disease.

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Scheibye-Knudsen M*, Tseng AHH, Jensen MB, Scheibye-Alsing K, Fang EF, Iyama T, Bharti SK, Marosi K, Froetscher L, Kassahun H, Eckley DM, Maul R, Bastian P, De S, Ghosh S, Nilsen H, Goldberg I, Mattson MP, Wilson III D, Brosh RM, Gorospe M, Bohr VA*; "CSA and CSB Converge on Transcription-Linked Resolution of Non-B DNA" in Proceedings of the National Academy of Sciences, In press [*co-corresponding]

Abstract
Cockayne syndrome is a neurodegenerative accelerated aging disorder caused by mutations in the CSA or CSB genes. Although the pathogenesis of Cockayne syndrome has remained elusive, recent work implicates mitochondrial dysfunction in the disease progression. Here, we present evidence that loss of CSA or CSB in a neuroblastoma cell line converges on mitochondrial dysfunction caused by defects in ribosomal DNA transcription and activation of the DNA damage sensor poly-ADP ribose polymerase 1 (PARP1). Indeed, inhibition of ribosomal DNA transcription leads to mitochondrial dysfunction in a number of cell lines. Furthermore, machine-learning algorithms predict that diseases with defects in ribosomal DNA (rDNA) transcription have mitochondrial dysfunction, and, accordingly, this is found when factors involved in rDNA transcription are knocked down. Mechanistically, loss of CSA or CSB leads to polymerase stalling at non-B DNA in a neuroblastoma cell line, in particular at G-quadruplex structures, and recombinant CSB can melt G-quadruplex structures. Indeed, stabilization of G-quadruplex structures activates PARP1 and leads to accelerated aging in Caenorhabditis elegans In conclusion, this work supports a role for impaired ribosomal DNA transcription in Cockayne syndrome and suggests that transcription-coupled resolution of secondary structures may be a mechanism to repress spurious activation of a DNA damage response.

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Kowald A, Kirkwood TB. "Can aging be programmed? A critical literature review" in Aging Cell (2016) pp1–13

Abstract
The evolution of the aging process has long been a biological riddle, because it is difficult to explain the evolution of a trait that has apparently no benefit to the individual. Over 60 years ago, Medawar realized that the force of natural selection declines with chronological age because of unavoidable environmental risks. This forms the basis of the mainstream view that aging arises as a consequence of a declining selection pressure to maintain the physiological functioning of living beings forever. Over recent years, however, a number of articles have appeared that nevertheless propose the existence of specific aging genes; that is, that the aging process is genetically programmed. If this view were correct, it would have serious implications for experiments to understand and postpone aging. Therefore, we studied in detail various specific proposals why aging should be programmed. We find that not a single one withstands close scrutiny of its assumptions or simulation results. Nonprogrammed aging theories based on the insight of Medawar (as further developed by Hamilton and Charlesworth) are still the best explanation for the evolution of the aging process. We hope that this analysis helps to clarify the problems associated with the idea of programmed aging.

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