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  • 301.
    Figueira, Joao
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Öhman, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    NMR analysis of the human saliva metabolome distinguishes dementia patients from matched controls2016In: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 12, no 8, p. 2562-2571Article in journal (Refereed)
    Abstract [en]

    Saliva is a biofluid that is sensitive to metabolic changes and is straightforward to collect in a non-invasive manner, but it is seldom used for metabolite analysis when studying neurodegenerative disorders. We present a procedure for both an untargeted and targeted analysis of the saliva metabolome in which nuclear magnetic resonance (NMR) spectroscopy is used in combination with multivariate data analysis. The applicability of this approach is demonstrated on saliva samples selected from the 25 year prospective Betula study, including samples from dementia subjects with either Alzheimer's disease (AD) or vascular dementia at the time of sampling or who developed it by the next sampling/assessment occasion five years later, and age-, gender-, and education-matched control individuals without dementia. Statistically significant multivariate models were obtained that separated patients with dementia from controls and revealed seven discriminatory metabolites. Dementia patients showed significantly increased concentrations of acetic acid (fold change (fc) = 1.25, p = 2 x 10(-5)), histamine (fc = 1.26, p = 0.019), and propionate (fc = 1.35, p = 0.002), while significantly decreased levels were observed for dimethyl sulfone (fc = 0.81, p = 0.005), glycerol (fc = 0.79, p = 0.04), taurine (fc = 0.70, p = 0.007), and succinate (fc = 0.62, p = 0.008). Histamine, succinate, and taurine are known to be important in AD, and acetic acid and glycerol are involved in related pathways. Dimethyl sulfone and propionate originate from the diet and bacterial flora and might reflect poorer periodontal status in the dementia patients. For these seven metabolites, a weak but statistically significant pre-diagnostic value was observed. Taken together, we present a robust and general NMR analysis approach for studying the saliva metabolome that has potential use for screening and early detection of dementia.

  • 302.
    Fischer, Håkan
    et al.
    Karolinska Institute.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Bäckman, Lars
    Karolinska Institute.
    Age-related differences in brain regions supporting successful encoding of emotional faces.2010In: Cortex, ISSN 0010-9452, E-ISSN 1973-8102, Vol. 46, no 4, p. 490-497Article in journal (Refereed)
    Abstract [en]

    In an event-related functional Magnetic Resonance Imaging (fMRI) study, younger and older adults were presented with negative emotional (i.e., fearful) and neutral face pictures under incidental learning conditions. They were subsequently given a test of face recognition outside the scanner. Both age groups activated amygdala bilaterally as well as the right hippocampus during successful encoding of the fearful faces. Direct age comparisons revealed greater activation in right amygdala and bilateral hippocampus in the young, whereas older adults showed greater activation in the left insular and right prefrontal cortices. None of these brain areas was activated during successful encoding of neutral faces, suggesting specificity of these brain activation patterns. The results indicate an age-related shift in the neural underpinnings of negative emotional face processing from medial-temporal to neocortical regions.

  • 303.
    Fischer, Håkan
    et al.
    Karolinska Institute.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Karlsson, Sari
    Karolinska Institute.
    Karlsson, Per
    Karolinska Hospital.
    Brehmer, Yvonne
    Karolinska Institute.
    Rieckmann, Anna
    Karolinska Institute.
    Macdonald, Stuart WS
    University of Victoria.
    Farde, Lars
    Karolinska Hospital.
    Bäckman, Lars
    Karolinska Institute.
    Simulating neurocognitive aging: effects of a dopaminergic antagonist on brain activity during working memory2010In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 67, no 6, p. 575-580Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous correlational studies have indirectly linked dysfunctional dopaminergic neurotransmission to age-related cognitive deficits and associated reductions in task-induced functional brain activity.

    METHODS: We used an experimental-pharmacological functional magnetic resonance imaging (fMRI) approach to more directly examine the role of dopamine in neurocognitive aging. Twenty younger and 20 healthy older adults were included. During fMRI scanning, a spatial working memory (SWM) task was administered under two conditions, varying in cognitive load. Positron emission tomography measurements with the D1 receptor antagonist [(11)C]SCH23390 confirmed that a given experimental dose of unlabeled solution occupied 50% of D1 receptors in younger adults.

    RESULTS: An age-related reduction in SWM performance was observed, and fMRI data revealed that, relative to younger adults under placebo conditions, elderly persons under-recruited load-sensitive fronto-parietal regions during SWM. Critically, in younger adults, the D1 antagonist resulted in a similar reduction in SWM performance and fMRI response.

    CONCLUSIONS: These results suggest that depletion of dopamine, whether ontogenetically or pharmacologically, results in decreased SWM performance as well as reduced load-dependent modulation of the blood oxygen level dependent signal in fronto-parietal regions, possibly by decreasing the signal-to-noise ratio in relevant neural networks.

  • 304. Fischer, Håkan
    et al.
    Sandblom, Johan
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Herlitz, Agneta
    Bäckman, Lars
    Brain activation while forming memories of fearful and neutral faces in women and men.2007In: Emotion, ISSN 1528-3542, Vol. 7, no 4, p. 767-773Article in journal (Other academic)
    Abstract [en]

    Event-related functional MRI (fMRI) was used to assess brain activity during encoding of fearful and neutral faces in 12 women and 12 men. In a subsequent memory analysis, the authors separated successful from unsuccessful encoding of both types of faces, based on whether they were remembered or forgotten in a later recognition memory test. Overall, women and men recruited overlapping neural circuitries. Both sexes activated right-sided medial-temporal regions during successful encoding of fearful faces. Successful encoding of neutral faces was associated with left-sided lateral prefrontal and right-sided superior frontal activation in both sexes. In women, relatively greater encoding related activity for neutral faces was seen in the superior parietal and parahippocampal cortices. By contrast, men activated the left and right superior/middle frontal cortex more than women during successful encoding of the same neutral faces. These findings suggest that women and men use similar neural networks to encode facial information, with only subtle sex differences observed for neutral faces.

  • 305. Fischer, M Dominik
    et al.
    Budak, Murat T
    Bakay, Marina
    Gorospe, J Rafael
    Kjellgren, Daniel
    Pedrosa-Domellöf, F
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Hoffman, Eric P
    Khurana, Tejvir S
    Definition of the unique human extraocular muscle allotype by expression profiling.2005In: Physiol Genomics, ISSN 1531-2267, Vol. 22, no 3, p. 283-91Article in journal (Refereed)
    Abstract [en]

    The extraocular muscles (EOMs) are a unique group of specialized muscles that are anatomically and physiologically distinct from other skeletal muscles. Perhaps the most striking characteristic of the EOMs is their differential sensitivity to disease. EOMs are spared in Duchenne's muscular dystrophy (DMD) despite widespread involvement of other skeletal muscles. Conversely, they are early and prominent targets in myasthenia gravis and mitochondrial myopathies. It is unclear how EOMs achieve such specialization or a differential response to diseases; however, this has been attributed to a unique, group-specific pattern of gene expression or "allotype." To begin to address these issues as well as define the human EOM allotype, we analyzed the human EOM transcriptome using oligonucleotide-based expression profiling. Three hundred thirty-eight genes were found to be differentially expressed in EOM compared with quadriceps femoris limb muscle, using a twofold cutoff. Functional characterization revealed expression patterns corresponding to known metabolic and structural properties of EOMs such as expression of EOM-specific myosin heavy chain (MYH13) and high neural, vascular, and mitochondrial content, suggesting that the profiling was sensitive and specific. Genes related to myogenesis, stem cells, and apoptosis were detected at high levels in normal human EOMs, suggesting that efficient and continuous regeneration and/or myogenesis may be a mechanism by which the EOMs remain clinically and pathologically spared in diseases such as DMD. Taken together, this study provides insight into how human EOMs achieve their unique structural, metabolic, and pathophysiological properties.

  • 306.
    Fischer, M Dominik
    et al.
    University of Pennsylvania School of Medicine.
    Gorospe, J Rafael
    George Washington University, Washington.
    Felder, Edward
    University of Pennsylvania School of Medicine, Philadelphia.
    Bogdanovich, Sasha
    University of Pennsylvania School of Medicine.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Ahima, Rexford S
    University of Pennsylvania School of Medicine, Philadelphia.
    Rubinstein, Neal A
    University of Pennsylvania School of Medicine, Philadelphia.
    Hoffman, Eric P
    George Washington University, Washington.
    Khurana, Tejvir S
    University of Pennsylvania School of Medicine.
    Expression profiling reveals metabolic and structural components of extraocular muscles2002In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 9, no 2, p. 71-84Article in journal (Refereed)
    Abstract [en]

    The extraocular muscles (EOM) are anatomically and physiologically distinct from other skeletal muscles. EOM are preferentially affected in mitochondrial myopathies, but spared in Duchenne's muscular dystrophy. The anatomical and pathophysiological properties of EOM have been attributed to their unique molecular makeup: an allotype. We used expression profiling to define molecular features of the EOM allotype. We found 346 differentially expressed genes in rat EOM compared with tibialis anterior, based on a twofold difference cutoff. Genes required for efficient, fatigue-resistant, oxidative metabolism were increased in EOM, whereas genes for glycogen metabolism were decreased. EOM also showed increased expression of genes related to structural components of EOM such as vessels, nerves, mitochondria, and neuromuscular junctions. Additionally, genes related to specialized functional roles of EOM such as the embryonic and EOM-specific myosin heavy chains and genes for muscle growth, development, and/or regeneration were increased. The EOM expression profile was validated using biochemical, structural, and molecular methods. Characterization of the EOM expression profile begins to define gene transcription patterns associated with the unique anatomical, metabolic, and pathophysiological properties of EOM.

  • 307. Flanagan, J R
    et al.
    King, S
    Wolpert, D M
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Sensorimotor prediction and memory in object manipulation2001In: Canadian journal of experimental psychology, ISSN 1196-1961, E-ISSN 1878-7290, Vol. 55, no 2, p. 87-95Article in journal (Refereed)
    Abstract [en]

    When people lift objects of different size but equal weight, they initially employ too much force for the large object and too little force for the small object. However, over repeated lifts of the two objects, they learn to suppress the size-weight association used to estimate force requirements and appropriately scale their lifting forces to the true and equal weights of the objects. Thus, sensorimotor memory from previous lifts comes to dominate visual size information in terms of force prediction. Here we ask whether this sensorimotor memory is transient, preserved only long enough to perform the task, or more stable. After completing an initial lift series in which they lifted equally weighted large and small objects in alternation, participants then repeated the lift series after delays of 15 minutes or 24 hours. In both cases, participants retained information about the weights of the objects and used this information to predict the appropriate fingertip forces. This preserved sensorimotor memory suggests that participants acquired internal models of the size-weight stimuli that could be used for later prediction.

  • 308. Flanagan, J Randall
    et al.
    Bittner, Jennifer P
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Experience can change distinct size-weight priors engaged in lifting objects and judging their weights.2008In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 18, no 22, p. 1742-7Article in journal (Refereed)
    Abstract [en]

    The expectation that object weight increases with size guides the control of manipulatory actions [1-6] and also influences weight perception. Thus, the size-weight illusion, whereby people perceive the smaller of two equally weighted objects to be heavier, is thought to arise because weight is judged relative to expected weight that, for a given family of objects, increases with size [2, 7]. Here, we show that the fundamental expectation that weight increases with size can be altered by experience and neither is hard-wired nor becomes crystallized during development. We demonstrate that multiday practice in lifting a set of blocks whose color and texture are the same and whose weights vary inversely with volume gradually attenuates and ultimately inverts the size-weight illusion tested with similar blocks. We also show that in contrast to this gradual change in the size-weight illusion, the sensorimotor system rapidly learns to predict the inverted object weights, as revealed by lift forces. Thus, our results indicate that distinct adaptive size-weight maps, or priors, underlie weight predictions made in lifting objects and in judging their weights. We suggest that size-weight priors that influence weight perception change slowly because they are based on entire families of objects. Size-weight priors supporting action are more flexible, and adapt more rapidly, because they are tuned to specific objects and their current state.

  • 309. Flanagan, J Randall
    et al.
    Bowman, Miles C
    Johansson, Roland
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Control strategies in object manipulation tasks.2006In: Current Opinion in Neurobiology, ISSN 0959-4388, Vol. 16, no 6, p. 650-9Article in journal (Other academic)
    Abstract [en]

    The remarkable manipulative skill of the human hand is not the result of rapid sensorimotor processes, nor of fast or powerful effector mechanisms. Rather, the secret lies in the way manual tasks are organized and controlled by the nervous system. At the heart of this organization is prediction. Successful manipulation requires the ability both to predict the motor commands required to grasp, lift, and move objects and to predict the sensory events that arise as a consequence of these commands.

  • 310.
    Flanagan, J Randall
    et al.
    Queen's University, Kingston, Ontario K7L 3N6.
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Action plans used in action observation2003In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, ISSN 1476-4687, Vol. 424, no 6950, p. 769-771Article in journal (Refereed)
    Abstract [en]

    How do we understand the actions of others? According to the direct matching hypothesis, action understanding results from a mechanism that maps an observed action onto motor representations of that action. Although supported by neurophysiological and brain-imaging studies, direct evidence for this hypothesis is sparse. In visually guided actions, task-specific proactive eye movements are crucial for planning and control. Because the eyes are free to move when observing such actions, the direct matching hypothesis predicts that subjects should produce eye movements similar to those produced when they perform the tasks. If an observer analyses action through purely visual means, however, eye movements will be linked reactively to the observed action. Here we show that when subjects observe a block stacking task, the coordination between their gaze and the actor's hand is predictive, rather than reactive, and is highly similar to the gaze-hand coordination when they perform the task themselves. These results indicate that during action observation subjects implement eye motor programs directed by motor representations of manual actions and thus provide strong evidence for the direct matching hypothesis.

  • 311.
    Flanagan, J Randall
    et al.
    Department of Psychology and Centre for Neuroscience Studies, Queen’s University, Kingston, Ontario, Canada.
    Merritt, Kyle
    Department of Psychology and Centre for Neuroscience Studies, Queen’s University, Kingston, Ontario, Canada.
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Predictive mechanisms and object representations used in object manipulation2009In: Sensorimotor Control of Grasping: Physiology and Pathophysiology, Cambridge: Cambridge University Press , 2009, p. 161-177Chapter in book (Other (popular science, discussion, etc.))
    Abstract [en]

    Skilled object manipulation requires the ability to estimate, in advance, the motor commands needed to achieve desired sensory outcomes and the ability to predict the sensory consequences of the motor commands. Because the mapping between motor commands and sensory outcomes depends on the physical properties of grasped objects, the motor system may store and access internal models of objects in order to estimate motor commands and predict sensory consequences. In this chapter, we outline evidence for internal models and discuss their role in object manipulation tasks. We also consider the relationship between internal models of objects employedby the sensorimotor system and representations of the same objects used by the perceptual system to make judgments about objects.

  • 312.
    Flanagan, J Randall
    et al.
    Department of Psychology, Queen's University, Kingston, Ontario, Canada, Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada.
    Rotman, Gerben
    Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada.
    Reichelt, Andreas F
    Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada.
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    The role of observers' gaze behaviour when watching object manipulation tasks: predicting and evaluating the consequences of action2013In: Philosophical Transactions of the Royal Society of London. Biological Sciences, ISSN 0962-8436, E-ISSN 1471-2970, Vol. 368, no 1628, p. 20130063-Article in journal (Refereed)
    Abstract [en]

    When watching an actor manipulate objects, observers, like the actor, naturally direct their gaze to each object as the hand approaches and typically maintain gaze on the object until the hand departs. Here, we probed the function of observers' eye movements, focusing on two possibilities: (i) that observers' gaze behaviour arises from processes involved in the prediction of the target object of the actor's reaching movement and (ii) that this gaze behaviour supports the evaluation of mechanical events that arise from interactions between the actor's hand and objects. Observers watched an actor reach for and lift one of two presented objects. The observers' task was either to predict the target object or judge its weight. Proactive gaze behaviour, similar to that seen in self-guided action-observation, was seen in the weight judgement task, which requires evaluating mechanical events associated with lifting, but not in the target prediction task. We submit that an important function of gaze behaviour in self-guided action observation is the evaluation of mechanical events associated with interactions between the hand and object. By comparing predicted and actual mechanical events, observers, like actors, can gain knowledge about the world, including information about objects they may subsequently act upon.

  • 313. Flanagan, J Randall
    et al.
    Terao, Yasuo
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Gaze behavior when reaching to remembered targets.2008In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 100, no 3, p. 1533-43Article in journal (Refereed)
    Abstract [en]

    People naturally direct their gaze to visible hand movement goals. Doing so improves reach accuracy through use of signals related to gaze position and visual feedback of the hand. Here, we studied where people naturally look when acting on remembered target locations. Four targets were presented on a screen, in peripheral vision, while participants fixed a central cross (encoding phase). Four seconds later, participants used a pen to mark the remembered locations while free to look wherever they wished (recall phase). Visual references, including the screen and the cross, were present throughout. During recall, participants neither looked at the marked locations nor prevented eye movements. Instead, gaze behavior was erratic and was comprised of gaze shifts loosely coupled in time and space with hand movements. To examine whether eye and hand movements during encoding affected gaze behavior during recall, in additional encoding conditions, participants marked the visible targets with either free gaze or with central cross fixation or just looked at the targets. All encoding conditions yielded similar erratic gaze behavior during recall. Furthermore, encoding mode did not influence recall performance, suggesting that participants, during recall, did not exploit sensorimotor memories related to hand and gaze movements during encoding. Finally, we recorded a similar lose coupling between hand and eye movements during an object manipulation task performed in darkness after participants had viewed the task environment. We conclude that acting on remembered versus visible targets can engage fundamentally different control strategies, with gaze largely decoupled from movement goals during memory-guided actions.

  • 314.
    Flanagan, J Randall
    et al.
    Queen's University, Kingston, Ontario.
    Vetter, Philipp
    University College London, Queen Square, London.
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Wolpert, Daniel M
    University College London, Queen Square, London.
    Prediction precedes control in motor learning2003In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 13, no 2, p. 146-150, Article Number: PII S0960-9822(03)00007-1Article in journal (Refereed)
    Abstract [en]

    Skilled motor behavior relies on the brain learning both to control the body and predict the consequences of this control. Prediction turns motor commands into expected sensory consequences, whereas control turns desired consequences into motor commands. To capture this symmetry, the neural processes underlying prediction and control are termed the forward and inverse internal models, respectively. Here, we investigate how these two fundamental processes are related during motor learning. We used an object manipulation task in which subjects learned to move a hand-held object with novel dynamic properties along a prescribed path. We independently and simultaneously measured subjects' ability to control their actions and to predict their consequences. We found different time courses for predictor and controller learning, with prediction being learned far more rapidly than control. In early stages of manipulating the object, subjects could predict the consequences of their actions, as measured by the grip force they used to grasp the object, but could not generate appropriate actions for control, as measured by their hand trajectory. As predicted by several recent theoretical models of sensorimotor control, our results indicate that people can learn to predict the consequences of their actions before they can learn to control their actions.

  • 315.
    Flodin, Pär
    et al.
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Jonasson, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Boraxbekk, Carl-Johan
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital, Hvidovre, Denmark.
    Does Aerobic Exercise Influence Intrinsic Brain Activity? An Aerobic Exercise Intervention among Healthy Old Adults2017In: Frontiers in Aging Neuroscience, ISSN 1663-4365, E-ISSN 1663-4365, Vol. 9, article id 267Article in journal (Refereed)
    Abstract [en]

    Previous studies have indicated that aerobic exercise could reduce age related decline in cognition and brain functioning. Here we investigated the effects of aerobic exercise on intrinsic brain activity. Sixty sedentary healthy males and females (64–78 years) were randomized into either an aerobic exercise group or an active control group. Both groups recieved supervised training, 3 days a week for 6 months. Multimodal brain imaging data was acquired before and after the intervention, including 10 min of resting state brain functional magnetic resonance imaging (rs-fMRI) and arterial spin labeling (ASL). Additionally, a comprehensive battery of cognitive tasks assessing, e.g., executive function and episodic memory was administered. Both the aerobic and the control group improved in aerobic capacity (VO2-peak) over 6 months, but a significant group by time interaction confirmed that the aerobic group improved more. Contrary to our hypothesis, we did not observe any significant group by time interactions with regard to any measure of intrinsic activity. To further probe putative relationships between fitness and brain activity, we performed post hoc analyses disregarding group belongings. At baseline, VO2-peak was negativly related to BOLD-signal fluctuations (BOLDSTD) in mid temporal areas. Over 6 months, improvements in aerobic capacity were associated with decreased connectivity between left hippocampus and contralateral precentral gyrus, and positively to connectivity between right mid-temporal areas and frontal and parietal regions. Independent component analysis identified a VO2-related increase in coupling between the default mode network and left orbitofrontal cortex, as well as a decreased connectivity between the sensorimotor network and thalamus. Extensive exploratory data analyses of global efficiency, connectome wide multivariate pattern analysis (connectome-MVPA), as well as ASL, did not reveal any relationships between aerobic fitness and intrinsic brain activity. Moreover, fitness-predicted changes in functional connectivity did not relate to changes in cognition, which is likely due to absent cross- sectional or longitudinal relationships between VO2-peak and cognition. We conclude that the aerobic exercise intervention had limited influence on patterns of intrinsic brain activity, although post hoc analyses indicated that individual changes in aerobic capacity preferentially influenced mid-temporal brain areas.

  • 316.
    Florea, Cristina
    et al.
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Tanska, Petri
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Mononen, Mika
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Qu, Chengjuan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). School of Public Health, Health Science Center of Xi’an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi’an, China.
    Laasanen, Mikko
    School of Engineering and Technology, Savonia University of Applied Sciences, Kuopio, Finland.
    Korhonen, Rami
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland; Diagnostic Imaging Center, Kuopio University Hospital, Kuopio, Finland.
    A combined experimental atomic force microscopy-based nanoindentation and computational modeling approach to unravel the key contributors to the time-dependent mechanical behavior of single cells2017In: Biomechanics and Modeling in Mechanobiology, ISSN 1617-7959, E-ISSN 1617-7940, Vol. 16, no 1, p. 297-311, article id 27554263Article in journal (Refereed)
    Abstract [en]

    Cellular responses to mechanical stimuli are influenced by the mechanical properties of cells and the surrounding tissue matrix. Cells exhibit viscoelastic behavior in response to an applied stress. This has been attributed to fluid flow-dependent and flow-independent mechanisms. However, the particular mechanism that controls the local time-dependent behavior of cells is unknown. Here, a combined approach of experimental AFM nanoindentation with computational modeling is proposed, taking into account complex material behavior. Three constitutive models (porohyperelastic, viscohyperelastic, poroviscohyperelastic) in tandem with optimization algorithms were employed to capture the experimental stress relaxation data of chondrocytes at 5 % strain. The poroviscohyperelastic models with and without fluid flow allowed through the cell membrane provided excellent description of the experimental time-dependent cell responses (normalized mean squared error (NMSE) of 0.003 between the model and experiments). The viscohyperelastic model without fluid could not follow the entire experimental data that well (NMSE = 0.005), while the porohyperelastic model could not capture it at all (NMSE = 0.383). We also show by parametric analysis that the fluid flow has a small, but essential effect on the loading phase and short-term cell relaxation response, while the solid viscoelasticity controls the longer-term responses. We suggest that the local time-dependent cell mechanical response is determined by the combined effects of intrinsic viscoelasticity of the cytoskeleton and fluid flow redistribution in the cells, although the contribution of fluid flow is smaller when using a nanosized probe and moderate indentation rate. The present approach provides new insights into viscoelastic responses of chondrocytes, important for further understanding cell mechanobiological mechanisms in health and disease.

  • 317.
    Fong, Gloria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Influence of neuromodulators and mechanical loading on pathological cell and tissue characteristics in tendinosis2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Tendinosis is a painful chronic, degenerative condition characterized by objective changes in the tissue structure of a tendon. Hallmark features in tendinosis tendons include increased number of cells (hypercellularity), extracellular matrix (ECM) degradation and disorganized collagen. The progression of these pathological changes seen in tendinosis is neither well characterized nor fully understood.

    Studies have suggested that there are biochemical and mechanical elements involved in tendinosis. From a biochemical perspective, studies have shown that the tendon cells, tenocytes, produce a number of neuronal signal substances/neuromodulators, such as substance P (SP) and acetylcholine (ACh), traditionally thought to be confined to the nervous system. Furthermore, it has been shown that the expression of these neuromodulators is elevated in tendinosis tendons as compared to normal healthy tendons. Interestingly, studies on other tissue types have revealed that both SP and ACh can induce tissue changes seen in tendinosis, such as hypercellularity and collagen disorganization. From a mechanical angle, it has been suggested that overload of tendons, including extensive strain on the primary tendon cells (tenocytes), causes the degenerative processes associated with tendinosis. In vivo studies have shown that in overloaded tendons, the presence of neuromodulators is elevated, not least SP, which also precedes the development of the tissue changes seen in tendinosis. This further supports the importance of combining biochemical factors and mechanical factors in the pathogenesis of tendinosis.

    Hypotheses: In this thesis project, we hypothesize: 1) that neuromodulators, such as SP and ACh when stimulating their preferred receptors, the neurokinin 1 (NK-1 R) and muscarinic receptors (mAChRs), respectively, can cause increased tenocyte proliferation; 2) that the effects of SP and ACh on tenocyte proliferation converge mechanistically via a shared signalling pathway; 3) that mechanical loading of tenocytes results in increased production of SP by the tenocytes; and 4) that SP enhances collagen remodelling by tenocytes via NK-1 R.

    Model system: In vitro studies offer insight into the function of healthy tendon matrix and the etiology of tendinopathy. Using a cell culture model of human primary tendon cells, highly controlled experiments were performed in this thesis project to study a subset of biological and mechanical parameters that are implicated in tendinosis. The FlexCell® Tension System was used to study the influence of mechanical loading on tenocytes. As well, a collagen gel contraction assay was used to examine the intrinsic ability of tenocytes to reorganise type I collagen matrices under the influence of the neuromodulator SP.

    Results: The studies showed that exogenous administration of SP and ACh results in increased tenocyte proliferation that is mediated via activation of the ERK1/2 mitogenic pathway when the preferred receptors of SP and ACh, the NK-1 R and mAChRs, respectively, are stimulated. Furthermore, the studies resulted in the novel finding that SP and ACh both converge mechanistically via transforming growth factor (TGF)-β1 and that a negative feedback mechanism is present in which TGF-β1 downregulates the expression of mAChRs and NK-1 R. The studies also showed that SP can increase collagen remodelling and upregulate expression of genes related to tendinosis. Finally, it was established that tenocytes are mechanoresponsive by showing that cyclic mechanical loading increases the expression of SP by human tenocytes.

    Conclusions: This thesis work concludes that stimulation of NK-1 R and mAChRs results in proliferation of human tenocytes, which both involve the ERK1/2 signalling pathway. It also shows that SP and ACh converge mechanistically via TGF-β1 in their contribution to tenocyte proliferation. The role of hypercellularity in tendinosis tissue is unknown. Possibly, it has different roles at different stages of the disease. The findings also show that SP increases collagen remodelling, suggesting that increased SP not only results in hypercellularity but also contributes to the collagen morphology in tendinosis.

  • 318.
    Fong, Gloria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Backman, Ludvig
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Andersson, Gustav
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Scott, Alexander
    Vancouver Coastal Health and Research Institute.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Human tenocytes are stimulated to proliferate by acetylcholine through an EGFR signalling pathway2013In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 351, no 3, p. 465-475Article in journal (Refereed)
    Abstract [en]

    Studies of human patellar and Achilles tendons have shown that primary tendon fibroblasts (tenocytes) not only have the capacity to produce acetylcholine (ACh) but also express muscarinic ACh receptors (mAChRs) through which ACh can exert its effects. In patients with tendinopathy (chronic tendon pain) with tendinosis, the tendon tissue is characterised by hypercellularity and angiogenesis, both of which might be influenced by ACh. In this study, we have tested the hypothesis that ACh increases the proliferation rate of tenocytes through mAChR stimulation and have examined whether this mechanism operates via the extracellular activation of the epidermal growth factor receptor (EGFR), as shown in other fibroblastic cells. By use of primary human tendon cell cultures, we identified cells expressing vimentin, tenomodulin and scleraxis and found that these cells also contained enzymes related to ACh synthesis and release (choline acetyltransferase and vesicular acetylcholine transporter). The cells furthermore expressed mAChRs of several subtypes. Exogenously administered ACh stimulated proliferation and increased the viability of tenocytes in vitro. When the cells were exposed to atropine (an mAChR antagonist) or the EGFR inhibitor AG1478, the proliferative effect of ACh decreased. Western blot revealed increased phosphorylation, after ACh stimulation, for both EGFR and the extracellular-signal-regulated kinases 1 and 2. Given that tenocytes have been shown to produce ACh and express mAChRs, this study provides evidence of a possible autocrine loop that might contribute to the hypercellularity seen in tendinosis tendon tissue.

  • 319.
    Fong, Gloria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Centre for Hip Health and Mobility, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.
    Backman, Ludvig J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Scott, Alex
    Centre for Hip Health and Mobility, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    The Effects of Substance P and Acetylcholine on Human Tenocyte Proliferation Converge Mechanistically via TGF-β12017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 3, article id e0174101Article in journal (Refereed)
    Abstract [en]

    Previous in vitro studies on human tendon cells (tenocytes) have demonstrated that the exogenous administration of substance P (SP) and acetylcholine (ACh) independently result in tenocyte proliferation, which is a prominent feature of tendinosis. Interestingly, the possible link between SP and ACh has not yet been explored in human tenocytes. Recent studies in other cell types demonstrate that both SP and ACh independently upregulate TGF-β1 expression via their respective receptors, the neurokinin 1 receptor (NK-1R) and muscarinic ACh receptors (mAChRs). Furthermore, TGF-β1 has been shown to downregulate NK-1R expression in human keratocytes. The aim of this study was to examine if TGF-β1 is the intermediary player involved in mediating the proliferative pathway shared by SP and ACh in human tenocytes. The results showed that exogenous administration of SP and ACh both caused significant upregulation of TGF-β1 at the mRNA and protein levels. Exposing cells to TGF-β1 resulted in increased cell viability of tenocytes, which was blocked in the presence of the TGFβRI/II kinase inhibitor. In addition, the proliferative effects of SP and ACh on tenocytes were reduced by the TGFβRI/II kinase inhibitor; this supports the hypothesis that the proliferative effects of these signal substances are mediated via the TGF-β axis. Furthermore, exogenous TGF-β1 downregulated NK-1R and mAChRs expression at both the mRNA and protein levels, and these effects were negated by simultaneous exposure to the TGFβRI/II kinase inhibitor, suggesting a negative feedback loop. In conclusion, the results indicate that TGF-β1 is the intermediary player through which the proliferative actions of both SP and ACh converge mechanistically.

  • 320.
    Fong, Gloria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Backman, Ludvig J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Hart, David A.
    Vancouver Coastal Hlth & Res Inst, Ctr Hip Hlth & Mobil, Vancouver, BC, Canada.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    McCormack, Bob
    Vancouver Coastal Hlth & Res Inst, Ctr Hip Hlth & Mobil, Vancouver, BC, Canada.
    Scott, Alex
    Univ British Columbia, Dept Phys Therapy, Vancouver, BC V5Z 1M9, Canada.
    Substance P enhances collagen remodeling and MMP-3 expression by human tenocytes2013In: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 31, no 1, p. 91-98Article in journal (Refereed)
    Abstract [en]

    The loss of collagen organization is considered a hallmark histopathologic feature of tendinosis. At the cellular level, tenocytes have been shown to produce signal substances that were once thought to be restricted to neurons. One of the main neuropeptides implicated in tendinosis, substance P (SP), is known to influence collagen organization, particularly after injury. The aim of this study was to examine the influence of SP on collagen remodeling by primary human tendon cells cultured in vitro in three-dimensional collagen lattices. We found that SP stimulation led to an increased rate of collagen remodeling mediated via the neurokinin-1 receptor (NK-1 R), the preferred cell receptor for SP. Gene expression analysis showed that SP stimulation resulted in significant increases in MMP3, COL3A1 and ACTA2 mRNA levels in the collagen lattices. Furthermore, cyclic tensile loading of tendon cell cultures along with the administration of exogenous SP had an additive effect on MMP3 expression. Immunoblotting confirmed that SP increased MMP3 protein levels via the NK-1 R. This study indicates that SP, mediated via NK-1 R, increases collagen remodeling and leads to increased MMP3 mRNA and protein expression that is further enhanced by cyclic mechanical loading.

  • 321.
    Forsberg, Simon
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Development of a real-time approach to inter-individual interaction An experimental paradigm of cooperation and competition to use with functional brain imaging2012Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 322.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Differentiation of heart Purkinje fibres: an immuno- and enzyme histochemical and ultrastructural study1982Doctoral thesis, comprehensive summary (Other academic)
  • 323.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    New data favouring that neurotrophins are of importance in arthritis2009In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 11, no 4, p. 122-Article in journal (Other academic)
    Abstract [en]

    Neurotrophins are important in inflammation. In an article in Arthritis Research & Therapy, Barthel and collaborators give new information on the existence of neurotrophin production in the synovial tissue of arthritic joints. These findings, together with other recent findings, stress that neurotrophins should be considered important factors in arthritis. This is reinforced by the facts that they are also produced by articular chondrocytes and that receptors for these are present in the synovial tissue and on chondrocytes. The importance of neurotrophins in joints should be further studied, including examinations on the efficacy of interfering with their effects in arthritis.

  • 324.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Presence of ChAT mRNA and a very marked alpha 7nAChR immunoreaction in the synovial lining layer of the knee joint2012In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 91, no 21-22, p. 1043-1047Article in journal (Refereed)
    Abstract [en]

    Aims: The aim was to examine if there is evidence of acetylcholine (ACh) production within the synovial lining layer and to examine the pattern of alpha 7nAChR expression in the layer. This layer is of relevance clinically as it becomes thickened in response to both rheumatoid arthritis (RA) and osteoarthritis (OA) and as it has been shown to produce proteases that are involved in the cartilage destruction. Main methods: Synovial tissue specimens from the knee joint of patients with RA and OA undergoing prosthetic surgery were examined. In situ hybridization and immunohistochemistry were used for the evaluation of ChAT reaction patterns. Immunohistochemistry was utilized for demonstration of activity of alpha 7nAChR. Key findings: There were ChAT mRNA reactions in the synovial lining layer of both patient categories. On the other hand, no ChAT immunoreactions were detected in the layer. There was a very marked alpha 7nAChR immunoreaction. Significance: There is a potential for ACh production within the synovial lining layer as there are ChAT mRNA reactions. However, the level of ACh production is apparently very low. It is thus possible that there is a down-regulation of ACh production but an apparent upregulation in expression level of alpha 7nAChR. Based on the knowledge that the non-neuronal cholinergic system can have anti-inflammatory effects, the low level of ACh production in the synovial lining layer can be a drawback for the arthritic joints. (C) 2012 Elsevier Inc. All rights reserved.

  • 325.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Recent studies using an overuse animal model show that signal substances are highly involved in muscle derangement and muscle inflammation2013In: Proceedings of the International Congress on Sports Science Research and Technology Support / [ed] Jan Cabri, Pedro Pezarat Correia, João Barreiros, SciTePress, 2013, Vol. 1, p. 64-70p. 64-70Conference paper (Other academic)
    Abstract [en]

    Muscle overuse is a frequent condition accompanying sports-related activities. There is a lack of knowledge concerning the importance of signal substances in situations when overuse leads to markedly affected muscle structure and muscle inflammation. Recent observations on signal substance systems for the muscle tissue in situations with muscle overuse, noted via the use of a rabbit model, are therefore here focused on. The signal substance systems are the tachykinin system, the TNF-alpha system and the glutamate system. The studies have shown that all three systems are involved in the myositis/muscle derangement processes that occur. A central finding is the notion that signal substances in all three systems become locally produced in the muscle tissue and that there is a marked presence of receptors for these in the inflammatory/affected muscle tissue. The relevance of the findings in relation to what is known for the systems and possibilities in treatment regimens are discussed. Th e findings suggest that signal substances, more than what has been previously considered, should be taken into consideration as factors of relevance in situations when overuse leads to structural derangement and muscle inflammation.

  • 326.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The Cholinergic System Can Be of Unexpected Importance in Osteoarthritis2012In: Priciples of Osteoarthritis, Its definition, character, derivation and modality-related recognition / [ed] Rotschild BM, InTech, 2012, p. 461-472Chapter in book (Refereed)
    Abstract [en]

    The main belief is that joints such as the knee and ankle joints are not innervated by nerves with a cholinergic function. That includes  the assumption that these joints are not innervated by the vagus nerve (van Maanen et al., 2009a, see also Grimsholm et al., 2008). Accordingly, there is actually no morphologic proof of a cholinergic innervation of the knee joint, nor of the ankle joint. Despite this fact, it is shown that electrical and pharmacological stimulation of the vagus nerve has a diminishing effect on carragenan-induced paw inflammation in rats (Borovikova et al., 2000a) and that interference with the effects of the vagus nerve leads to effects on the knee joint arthritis as seen experimentally (van Maanen et al., 2009b). There are also other findings which  show the potential effects that interference with vagal effects has on joint inflammation. These will be discussed below. It is actually strange that interference with cholinergic effects, as via manpulations of the vagus nerve, has effects in knee joint inflamed synovium without presence of a vagal nerve innervation. One possibility is that the effects are indirect, via an occurrence of vagal effects on other sites such as the spleen (Huston et  al., 2006, see also van Maanen et al., 2009a). However, another possibility is that there is  a non-neuronal production of acetylcholine (ACh) within the synovial tissue itself. This has actually been shown to be the case (Grimsholm et al., 2008) (see  further in paragraph 3).

  • 327.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Andersson, Gustav
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Further proof of the existence of a non-neuronal cholinergic system in the human Achilles tendon: Presence of the AChR alpha 7 receptor in tendon cells and cells in the peritendinous tissue2015In: International Immunopharmacology, ISSN 1567-5769, E-ISSN 1878-1705, Vol. 29, no 1, p. 195-200Article in journal (Refereed)
    Abstract [en]

    Human tendon cells have the capacity for acetylcholine (ACh) production. It is not known if the tendon cells also have the potential for ACh breakdown, nor if they show expression of the nicotinic acetylcholine receptor AChR alpha 7 (alpha 7nAChR). Therefore, tendon tissue specimens from patients with midportion Achilles tendinopathy/tendinosis and from normal midportion Achilles tendons were examined. Reaction for the degradative enzyme acetylcholinesterase (AChE) was found in some tenocytes in only a few tendinopathy tendons, and was never found in those of control tendons. Tenocytes displayed more regularly alpha 7nAChR immunoreactivity. However, there was a marked heterogeneity in the degree of this reaction within and between the specimens. alpha 7nAChR immunoreactivity was especially pronounced for tenocytes showing an oval/widened appearance. There was a tendency that the magnitude of alpha 7nAChR immunoreactivity was higher in tendinopathy tendons as compared to control tendons. A stronger alpha 7nAChR immunoreactivity than seen for tenocytes was observed for the cells in the peritendinous tissue. It is likely that the alpha 7nAChR may be an important part of an auto-and paracrine loop of non-neuronal ACh that is released from the tendon cells. The effects may be related to proliferative and blood vessel regulatory functions as well as features related to collagen deposition. ACh can furthermore be of importance in leading to anti-inflammatory effects in the peritendinous tissue, a tissue nowadays considered to be of great relevance for the tendinopathy process. Overall, the findings show that tendon tissue, a tissue known to be devoid of cholinergic innervation, is a tissue in which there is a marked non-neuronal cholinergic system.

  • 328.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Bjur, Dennis
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Norrgård, Örjan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Dalén, Tore
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novel information on the non-neuronal cholinergic system in orthopedics provides new possible treatment strategies for inflammatory and degenerative diseases2009In: Orthopedic Reviews, ISSN 2035-8237, Vol. 1, no 1, p. 39-46Article in journal (Refereed)
    Abstract [en]

    Anti-cholinergic agents are used in thetreatment of several pathological conditions.Therapy regimens aimed at up-regulatingcholinergic functions, such as treatment withacetylcholinesterase inhibitors, are also currentlyprescribed. It is now known that not onlyis there a neuronal cholinergic system but alsoa non-neuronal cholinergic system in variousparts of the body. Therefore, interference withthe effects of acetylcholine (ACh) broughtabout by the local production and release ofACh should also be considered. Locally producedACh may have proliferative, angiogenic,wound-healing, and immunomodulatory functions.Interestingly, cholinergic stimulationmay lead to anti-inflammatory effects. Withinthis review, new findings for the locomotorsystem of a more widespread non-neuronalcholinergic system than previously expectedwill be discussed in relation to possible newtreatment strategies. The conditions discussedare painful and degenerative tendon disease(tendinopathy/tendinosis), rheumatoid arthritis,and osteoarthritis.

  • 329.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Bjur, Dennis
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Den kroniskt smärtande senan - histopatologi.2007In: Idrottsskador - frontlinjen inom behandling och rehablitering, p. 267-274Article in journal (Refereed)
    Abstract [en]

    I denna artikel belyses de morfologiska förändringar man ser i Achilles- och patellarsena vid tendinos. Fokus riktas inte minst på nya fynd avseende utseenden för sencellerna (tenocyterna). Vidare ges en kortfattad beskrivning av vad man idag känner till avseende nervrelaterade aspekter för dessa senor hos människa. Det är sannolikt att kunskap om dessa är viktig för att man rätt ska förstå de smärtsymptom som föreligger vid tendinos och även de effekter som nyare tids behandlingar har vid dessa kroniska smärttillstånd.

  • 330.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Bjur, Dennis
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Förändringar i kroniskt smärtande sena.2006In: Svensk Idrottsforskning: Organ för Centrum för Idrottsforskning, ISSN 1103-4629, Vol. 25, no 3, p. 8-10Article in journal (Refereed)
    Abstract [en]

    Vad känner man till om de förändringar som sker i en kroniskt smärtande sena?

    Hur ser sencellerna ut och hur påverkas nerverna vid tendinos? I denna sammanställning kommer de förändringar man ser i Akilles- och patellarsena vid tendinos att belysas. Fokus riktas inte minst på nya fynd avseende utseenden för sencellerna (tenocyterna). Vidare ges en kortfattad beskrivning av vad man idag känner till avseende nervrelaterade aspekter för dessa senor hos människa. Det är sannolikt att kunskap om dessa är viktig för att man rätt ska förstå de smärtsymptom som föreligger vid tendinos och även de effekter som nyare tids behandlingar har vid dessa kroniska smärttillstånd.

  • 331.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Anatomi.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Vascular NK-1 receptor occurrence in normal and chronic painful Achilles and patellar tendons: studies on chemically unfixed as well as fixed specimens.2005In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 126, no 3, p. 173-181Article in journal (Refereed)
    Abstract [en]

    It is not known as to whether the Achilles and patellar tendons contain neurokinin-1 (NK-1) receptors. This is a drawback when considering the fact that pain symptoms are frequent in these and as recent studies show that the pain symptoms might be cured via interference with blood vessel function. In the present study, the human Achilles and patellar tendons were examined concerning immunohistochemical expression of the NK-1 receptor. Chemically unfixed and fixed specimens, TRITC and PAP stainings and a battery of NK-1 receptor antibodies, including antibodies against the C-terminus and the N-terminal region, were utilized. NK-1 receptor immunoreaction could be detected in inner parts of the walls of large blood vessels and in the walls of small blood vessels. To some extent, NK-1 immunoreaction was also detectable in small nerve fascicles and in tenocytes. It was found to be of utmost importance to apply both chemically unfixed and fixed specimens. The use of chemically unfixed tissue was found advantageous in order to depict the immunoreactions in the blood vessel walls. The observations represent new findings and are of relevance as substance P (SP) is known to be of importance where neurogenic angiogenesis contributes to diseases and as SP on the whole has profound effects concerning blood vessel regulation.

  • 332.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Grimsholm, Ola
    University of Gothenburg.
    Dalén, Tore
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Measurements in the Blood of BDNF for RA Patients and in Response to Anti-TNF Treatment Help Us to Clarify the Magnitude of Centrally Related Pain and to Explain the Relief of This Pain upon Treatment2011In: International Journal of Inflammation, ISSN 2042-0099, E-ISSN 2042-0099, Vol. 2011, p. 650685-Article, review/survey (Refereed)
    Abstract [en]

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin with functions related to neuronal survival/proliferation processes and inflammation. BDNF is also an important central pain mediator. The levels of BDNF have been found to be high for RA patients with severe disease and to become lowered in response to anti-TNF treatment. New information says that the levels of BDNF in the blood parallel the BDNF concentrations in the brain and that BDNF can pass the blood-brain barrier. Furthermore, most of the circulating BDNF is produced in the brain. Habitual and regular exercise, in contrast to temporary exercise, does also lead to a lowering of BDNF blood levels. Both anti-TNF treatment and habitual and regular exercise do have pain-relieving effects. It might be that the pain-relieving effect of anti-TNF treatment is related to an affection of central neuronal regions, hereby influencing BDNF production. Measurements of BDNF in the blood help us to clarify the magnitude of centrally related pain for RA patients and help us to explain the relief of this pain in response to anti-TNF treatment.

  • 333.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Renström, Lina
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Purdam, Craig
    Gaida, James E.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. School of Primary Health Care, Monash University, Frankston, Australia.
    TNF-Alpha in the Locomotor System beyond Joints: High Degree of Involvement in Myositis in a Rabbit Model.2012In: International Journal of Rheumatology, ISSN 1687-9260, E-ISSN 1687-9279, Vol. 2012, p. 637452-Article in journal (Refereed)
    Abstract [en]

    The importance of TNF-alpha in arthritis is well documented. It may be that TNF-alpha is also markedly involved in muscle inflammation (myositis). An animal model where this can be investigated is needed. A newly developed rabbit myositis model involving pronounced muscle overuse and local injections of substances having proinflammatory effects was therefore used in the present study. The aim was to investigate the patterns of TNF-alpha expression in the developing myositis and to evaluate the usefulness of this myositis model for further TNF-alpha research. Human rheumatoid arthritis (RA) synovial tissue was examined as a reference. TNF-alpha immunoexpression and TNF-alpha mRNA, visualized via in situ hybridization, were detected in cells in the inflammatory infiltrates of the affected muscle (soleus muscle). Coexistence of TNF-alpha and CD68 immunoreactions was noted, suggesting that the TNF-alpha reactive cells are macrophages. Expression of TNF-alpha mRNA was also noted in muscle fibers and blood vessel walls in areas with inflammation. These findings demonstrate that TNF-alpha is highly involved in the myositis process. The model can be used in further studies evaluating the importance of TNF-alpha in developing myositis.

  • 334.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    In mid-portion Achilles tendinosis the plantaris tendon shows the same tendinosis-like morphological features and expression of the non-neuronal cholinergic system as the Achilles tendon itself2013In: International journal of experimental pathology (Print), ISSN 0959-9673, E-ISSN 1365-2613, Vol. 94, no 4, p. A3-A3Article in journal (Other academic)
  • 335.
    Fossati-Jimack, Liliane
    et al.
    University of Geneva.
    Azeredo da Silveira, Samareh
    University of Geneva.
    Moll, Thomas
    University of Geneva.
    Kina, Tatsuo
    Kyoto University.
    Kuypers, Frans A
    Children's Hospital Oakland Research Institute, Oakland, California.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Reininger, Luc
    Institut National de la Santé et de la Recherche Médicale U 399, Marseille.
    Izui, Shozo
    University of Geneva.
    Selective increase of autoimmune epitope expression on aged erythrocytes in mice: implications in anti-erythrocyte autoimmune responses2002In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 18, no 1, p. 17-25Article in journal (Refereed)
    Abstract [en]

    We investigated the impact of changes occurring during red blood cell (RBC) ageing on the RBC-binding activity of pathogenic anti-erythrocyte monoclonal antibodies derived from autoimmune-prone New Zealand black (NZB) mice. As assessed by flow cytometric analysis on in vivo biotinylated RBCs, all five NZB-derived anti-RBC mAb exhibited more efficient binding to aged RBCs than to young RBCs, and resulted in a selective elimination of more aged RBCs from the circulating blood. In addition, treatment of RBCs with proteases markedly enhanced the binding of all five anti-RBC mAb, raising the possibility that increased exposure of autoimmune epitopes on aged RBCs may be in part, a result of contacts with proteolytic enzymes during the lifetime of circulating RBCs. In marked contrast, the binding activity of mAb raised in non-autoimmune animals against antigens expressed on RBCs, such as CD44, CD47, CD147 and TER-119, was either decreased or unchanged with RBC ageing, and these epitopes, except for that recognized by anti-CD47 mAb, were highly sensitive to mild treatment with proteases. Our data unravel the unique molecular feature of RBC epitopes involved in autoimmune haemolytic anaemia, suggesting that membrane alterations in aged RBCs might play a significant role in the development of the autoantibody response to RBCs.

  • 336.
    Francis, Monika K.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Holst, Mikkel R.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Vidal-Quadras, Maite
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Henriksson, Sara
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Santarella-Mellwig, Rachel
    Sandblad, Linda
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Endocytic membrane turnover at the leading edge is driven by a transient interaction between Cdc42 and GRAF12015In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 128, no 22, p. 4183-4195Article in journal (Refereed)
    Abstract [en]

    Changes in cell morphology require coordination of plasma membrane turnover and cytoskeleton dynamics, processes that are regulated by Rho GTPases. Here, we describe how a direct interaction between the Rho GTPase Cdc42 and the GTPase activating protein (GAP) GRAF1, facilitate rapid cell surface turnover at the leading edge. Both Cdc42 and GRAF1 were required for fluid phase uptake and regulated the generation of transient GRAF1-coated endocytic carriers, distinct from clathrin coated vesicles. GRAF1 was found to transiently assemble at discrete Cdc42-enriched punctae at the plasma membrane resulting in a corresponding decrease in Cdc42 microdomain association. However, Cdc42 captured in its active state was, via a GAP domain mediated interaction, localised together with GRAF1 on accumulated internal structures derived from the cell surface. Correlative fluorescence and electron tomography microscopy revealed that these structures were clusters of small membrane carriers affected in their endosomal processing. We conclude that a transient interaction between Cdc42 and GRAF1 drives endocytic turnover and controls the transition essential for endosomal maturation of plasma membrane internalised by this mechanism.

  • 337.
    Francis, Monika K.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Krupp, Nikolai
    Blomberg, Jeanette
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Behrmann, Elmar
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    GRAF1 sculpts membrane through a regulated oligomerisation reactionManuscript (preprint) (Other academic)
  • 338.
    Franzén, Lars
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sundström, Staffan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Karlsson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Gustafsson, Hans
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Littbrand, Bo
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Fractionated irradiation and early changes in noradrenaline induced potassium efflux(86Rb+) in rat parotid gland1992In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 31, no 3, p. 359-364Article in journal (Refereed)
    Abstract [en]

    The effects of fractionated irradiation on the electrolyte fluid secretion from rat parotid gland were studied. Secretion was measured as noradrenaline stimulated potassium efflux in vitro with Rb-86+ as tracer for potassium. The irradiation was delivered either as a five-day schedule (total dose 20, 25, 30, 35, 40, 45 Gy) or a two-day schedule (total dose 24, 32 Gy). The noradrenaline stimulated efflux was decreased in comparison with contralateral controls 10 days after the last irradiation. The effect was dose-dependent. Based on the data available, alpha/beta ratio of the used system was calculated to about 20 Gy, which corresponds to other results regarding early radiation effects.

  • 339.
    Frias, Barbara
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Merighi, Adalberto
    Capsaicin, Nociception and Pain2016In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 21, no 6, article id 797Article, review/survey (Refereed)
    Abstract [en]

    Capsaicin, the pungent ingredient of the hot chili pepper, is known to act on the transient receptor potential cation channel vanilloid subfamily member 1 (TRPV1). TRPV1 is involved in somatic and visceral peripheral inflammation, in the modulation of nociceptive inputs to spinal cord and brain stem centers, as well as the integration of diverse painful stimuli. In this review, we first describe the chemical and pharmacological properties of capsaicin and its derivatives in relation to their analgesic properties. We then consider the biochemical and functional characteristics of TRPV1, focusing on its distribution and biological effects within the somatosensory and viscerosensory nociceptive systems. Finally, we discuss the use of capsaicin as an agonist of TRPV1 to model acute inflammation in slices and other ex vivo preparations.

  • 340.
    Fridén, Jan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. the Department of Physiology III, Karolinska Institutet, Stockholm, Sweden.
    Exercise-induced muscle soreness: a qualitative and quantitative study of human muscle morphology and function1983Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Exercise-induced muscle soreness is characterized by stiffness, tenderness and pain during active movements and weakness of the affected musculature the days after unusually or particularly heavy work. The most pronounced subjective symptoms do not arise immediately but rather between a couple of hours to some days after the exercise (a delayed-onset of muscle soreness), the intensity of pain is greatest about 48 hours after the work. A particular association exists between muscle soreness and eccentric contractions. Despite the fact that muscle soreness is a well known phenomenon in the sphere of sports as well as working life, the pathophysiological mechanisms underlying this are still not understood.

    In the present study a detailed analysis of human muscle fibre population structure after high tension work (eccentric exercise) that gave rise to muscle soreness, was carried out. The objective was to elucidate how fibres of different types are influenced by repeated muscle contractions reaching extreme tension levels using qualitative and quantitative light and electron microscopic techniques. It was hoped that such morphological analysis would provide a basis for discussion of possible causes for muscle soreness. The muscle function after the work was measured by isokinetic methods.

    To improve the basis for the ultrastructural analysis the fibre populations in untrained and en­durance trained human m. vastus lateralis of age-matched individuals were classified into different fibre type groups according to their ultrastructure. The selective glycogen depletion from Type 1 fibres seen after long term submaximal work, visualized electron microscopically with PA-TSC-SP staining, substantiated the usefulness of the appearance of the M-band to differentiate between fibre types. Stereological data showed that neither volume density of mitochondria nor of lipid droplets provide sufficient criteria to differentiate between fibre types.

    After an eccentric exercise regimen sore muscles (m. soleus or m. vastus lateralis) showed disturb­ances of the cross striated band pattern. Fibres with disorganized myofibrillar material made up 1/3, 1/2 and 1/10 of the analysed material, 1 hour, 3 and 6 days after exercise, respectively. The myofibril­lar lesions were preferably localized in the Z-band. This showed streaming, broadening and sometimes total disruption. The Type 2 fibres were most affected.

    The reduction of strength was greatest with the most rapid contractions. Strength remained de­creased the period when the structural damage was most pronounced. Eight weeks of eccentric muscle training reduced all the above negative effects.

    The results indicate that the Z-disc constitute the weak link in the myofibrillar contractile chain at high muscle tensions. It is suggested that the myofibrillar lesions are a direct result of mechanical tearing. Rupture of myofibrils is thought to result in formation of protein components and a con- sequental release of protein bound ions that via osmosis result in oedema and soreness. Training, using eccentric contractions over a long period of time leads to adaptations at the fibre level by a reorgani­zation of the contractile apparatus as well as an optimization of nervous coordination.

  • 341. Fridén, Jan
    et al.
    Pontén, Eva
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Department of Orthopaedics, Uppsala University, Uppsala, Sweden.
    Lieber, Richard L
    Effect of muscle tension during tendon transfer on sarcomerogenesis in a rabbit model2000In: Journal of Hand Surgery-American Volume, ISSN 0363-5023, E-ISSN 1531-6564, Vol. 25, no 1, p. 138-143Article in journal (Refereed)
    Abstract [en]

    Sarcomere number change was investigated in an animal model of tendon transfer. In 9 adult New Zealand white rabbits, the flexor digitorum longus muscle was cut distally and transferred and woven into the tibialis anterior tendon. Ankles were then immobilized for 3 weeks in 75 degrees flexion. Transferred flexor digitorum longus muscles were harvested and complete architectural analysis was performed. Sarcomere lengths were measured using laser diffraction. Serial sarcomere number in transferred flexor digitorum longus fibers was a strong function of the sarcomere length at the time of transfer. A highly significant negative correlation between these 2 parameters was approximated by a linear relationship. Based on this finding, we conclude that serial sarcomere number is significantly affected by the degree of stretch during the transfer itself. This could easily compromise the purpose of surgical tendon transfer by reducing the procedure to little more than a tenodesis.

  • 342.
    Frykholm, Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Klijn, Peter
    Saey, Didier
    van Hees, Hieronymus W. H.
    Stål, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Sandström, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Sörlin, Ann
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Maltais, François
    Nyberg, Andre
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Effect and feasibility of non-linear periodized resistance training in people with COPD: study protocol for a randomized controlled trial2019In: Trials, ISSN 1745-6215, E-ISSN 1745-6215, Vol. 20, no 1, article id 6Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In people with chronic obstructive pulmonary disease (COPD), limb-muscle dysfunction is one of the most troublesome systemic manifestations of the disease, which at the functional level is evidenced by reduced strength and endurance of limb muscles. Improving limb-muscle function is an important therapeutic goal of COPD management, for which resistance training is recommended. However, current guidelines for resistance training in COPD mainly focus on improving muscle strength which only reflects one aspect of limb-muscle function and does not address the issue of reduced muscle endurance. The latter is of importance considering that the reduction in limb-muscle endurance often is greater than that of muscle weakness, and also, limb-muscle endurance seems to be closer related to walking capacity as well as arm function than to limb-muscle strength within this group of people. Thus, strategies targeting multiple aspects of the decreased muscle function are warranted to increase the possibility for an optimal effect for the individual patient. Periodized resistance training, which represents a planned variation of resistance training variables (i.e., volume, intensity, frequency, etc.), is one strategy that could be used to target limb-muscle strength as well as limb-muscle endurance within the same exercise regimen.

    METHODS: This is an international, multicenter, randomized controlled trial comparing the effect and feasibility of non-linear periodized resistance training to traditional non-periodized resistance training in people with COPD. Primary outcomes are dynamic limb-muscle strength and endurance. Secondary outcomes include static limb-muscle strength and endurance, functional performance, quality of life, dyspnea, intramuscular adaptations as well as the proportion of responders. Feasibility of the training programs will be assessed and compared on attendance rate, duration, satisfaction, drop-outs as well as occurrence and severity of any adverse events.

    DISCUSSION: The proposed trial will provide new knowledge to this research area by investigating and comparing the feasibility and effects of non-linear periodized resistance training compared to traditional non-periodized resistance training. If the former strategy produces larger physiological adaptations than non-periodized resistance training, this project may influence the prescription of resistance training in people with COPD.

    TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03518723 . Registered on 13 April 2018.

  • 343.
    Fuchs, Gabriel
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Berg, Niclas
    Eriksson, Anders
    Wittberg, Lisa Prahl
    Detection of Thrombosis in the Extracorporeal Membrane Oxygenation Circuit by Infrasound: Proof of Concept2017In: Artificial Organs, ISSN 0160-564X, E-ISSN 1525-1594, Vol. 41, no 6, p. 573-579Article in journal (Refereed)
    Abstract [en]

    As of today, there exist no reliable, objective methods for early detection of thrombi in the extracorporeal membrane oxygenators (ECMO) system. Within the ECMO system, thrombi are not always fixed to a certain component or location in the circuit. Thus, clot fragments of different shapes and consistencies may circulate and give rise to vibrations and sound generation. By bedside sound measurements and additional laboratory experiments (although not detailed herein), we found that the presence of particles (clots or aggregates and fragments of clots) can be detected by analyzing the strength of infra-sound (< 20 Hz) modes of the spectrum near the inlet and outlet of the centrifugal pump in the ECMO circuit. For the few patients that were considered in this study, no clear false positive or negative examples were found when comparing the spectral approach with clinical observations. A laboratory setup provided insight to the flow in and out of the pump, confirming that in the presence of particles a low-amplitude low-frequency signal is strongly amplified, enabling the identification of a clot.

  • 344.
    Fytagoridis, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Sjöberg, Richard
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Åström, Mattias
    Fredricks, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Effects of deep brain stimulation in the caudal Zona incerta on verbal fluency2013In: Stereotactic and Functional Neurosurgery, ISSN 1011-6125, E-ISSN 1423-0372, Vol. 91, no 1, p. 24-29Article in journal (Refereed)
    Abstract [en]

    Background: Deep brain stimulation (DBS) of the caudal zona incerta (cZi) is a relatively unexplored and promising treatment in patients with severe essential tremor (ET). Preliminary data further indicate that the ability to produce language may be slightly affected by the treatment.

    Objective: To evaluate the effects on verbal fluency following cZi DBS in patients with ET.

    Method: Seventeen consecutive patients who had undergone DBS of the cZi for ET were tested regarding verbal fluency before surgery, 3 days after surgery and after 1 year. Ten patients were also evaluated by comparing performance on versus off stimulation after 1 year.

    Results: The total verbal fluency score decreased slightly, but significantly, from 22.7 (SD = 10.9) before surgery to 18.1 (SD = 7.5) 3 days after surgery (p = 0.036). After 1 year the score was nonsignificantly decreased to 20.1 (SD = 9.7, p = 0.2678). There was no detectable difference between stimulation on and off after 1 year.

    Conclusion: There was a tendency of an immediate and mostly transient postoperative decline in verbal fluency following cZi DBS for ET. In some of the patients this reduction was, however, more pronounced and also sustained over time.

  • 345.
    Gaida, J
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. School of Primary Health Care, Monash University, Melbourne, Australia.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Cook, J
    School of Primary Health Care, Monash University, Melbourne, Australia.
    Decreased tumour necrosis factor alpha (tnf-a) in serum of patients with achilles tendinopathy: further evidence against the role of inflammation in the chronic stage2014In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 48, no 7, p. 597-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Altered expression of several cytokines and growth factors has been shown in biopsies of tendinopathy tissue. Biopsy studies are however challenged by capacity to obtain i) healthy tissue for comparison, ii) multiple samples to monitor cytokine dynamics, and iii) tissue from recent onset tendinopathy. An alternative is to study cytokines in blood samples. Whether cytokines in blood samples reflect tissue levels and the degree of tendinopathy is unknown.

    OBJECTIVE: To measure serum concentration of six cytokines and growth factors suggested to have a role in tendon response to load among individuals with chronic Achilles tendinopathy and controls.

    DESIGN: In this cross-sectional study, serum cytokine concentrations were measured from fasting blood samples on the BioPlex-200.

    SETTING: Sports Medicine Unit, Umeå University.

    PARTICIPANTS: Participants were recreationally active individuals. Achilles tendinopathy (n=22) was diagnosed on clinical criteria and confirmed with ultrasound examination. The control group (n=10) had no history of tendon pain and had normal ultrasound findings.

    INDEPENDENT VARIABLES: Serum concentration of tumour necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), basic fibroblast growth factor (bFGF), platelet derived growth factor BB (PDGF-BB), interferon gamma (IFN-γ), and vascular-derived endothelial growth factor (VEGF) were the independent variables.

    MAIN OUTCOME MEASUREMENTS: A diagnosis of Achilles tendinopathy (yes/no) was defined as the key outcome variable prior to data collection.

    RESULTS: TNF-α concentration was lower in the tendinopathy group than the control group (P=.018); there were no other group differences.

    CONCLUSIONS: The observations indicate a lowering of the TNF-α concentration in the chronic phase of Achilles tendinopathy. As TNF-α levels are elevated in chronic inflammatory conditions, this reinforces that chronic Achilles tendinopathy is not an inflammatory disorder. Collecting a blood sample to study disease biomarkers leaves the tendon intact and therefore this design can be used to study cytokine dynamics with multiple sampling during disease progression and recovery.

  • 346.
    Gaida, James E.
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. University of Canberra Research Institute for Sport and Exercise (UCRISE); Discipline of Physiotherapy, University of Canberra.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Institute of Sport Exercise and Health, University College Hospital London.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Cook, Jill L.
    A pilot study on biomarkers for tendinopathy: lower levels of serum TNF-alpha and other cytokines in females but not males with Achilles tendinopathy2016In: BMC Sports Science Medicine and Rehabilitation, ISSN 2052-1847, Vol. 8, article id 5Article in journal (Refereed)
    Abstract [en]

    Background: Achilles tendinopathy is a painful musculoskeletal condition that is common among athletes, and which limits training capacity and competitive performance. The lack of biomarkers for tendinopathy limits research into risk factors and also the evaluation of new treatments. Cytokines and growth factors involved in regulating the response of tendon cells to mechanical load have potential as biomarkers for tendinopathy. Methods: This case-control study compared serum concentration of cytokines and growth factors (TNF-alpha, IL-1 beta, bFGF, PDFG-BB, IFN-gamma, VEGF) between individuals with chronic Achilles tendinopathy and controls. These were measured in fasting serum from 22 individuals with chronic Achilles tendinopathy and 10 healthy controls. Results were analysed in relation to gender and physical activity pattern. Results: TNF-alpha concentration was lower in the entire tendinopathy group compared with the entire control group; none of the other cytokines were significantly different. TNF-alpha levels were nevertheless highly correlated with the other cytokines measured, in most of the subgroups. Analysed by gender, TNF-alpha and PDGF-BB concentrations were lower in the female tendinopathy group but not the male tendinopathy group. A trend was seen for lower IL-1 beta in the female tendinopathy group. Physical activity was correlated with TNF-alpha, PDGF-BB and IL-1 beta to varying extents for control subgroups, but not for the female tendinopathy group. No correlations were seen with BMI or duration of symptoms. Conclusions: This pilot study indicates a lower level of TNF-alpha and PDGF-BB, and to some extent IL-1 beta among females, but not males, in the chronic phase of Achilles tendinopathy. It is suggested that future studies on tendinopathy biomarkers analyse male and female data separately. The lack of correlation between cytokine level and physical activity in the female tendinopathy group warrants further study.

  • 347.
    Gaida, James Edmund
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine. University of Canberra, Canberra, ACT, Australia ; University of Canberra Research Institute for Sport and Exercise (UCRISE), Canberra, ACT, Australia.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine. Institute of Sport Exercise and Health, University College Hospital London, London, UK.
    Scott, A.
    Mousavizadeh, R.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Apolipoprotein A1 distribution pattern in the human Achilles tendon2018In: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, E-ISSN 1600-0838, Vol. 28, no 5, p. 1506-1513Article in journal (Refereed)
    Abstract [en]

    Metabolic factors such as cholesterol appear to play an important role in the development of Achilles tendinopathy. There is, however, no morphologic proof explaining the link between high cholesterol and tendinopathy. As apolipoprotein A1 (Apo-A1) is essential for reverse cholesterol transport, it may be related to cholesterol overload in tendon. Nothing is known about Apo-A1 expression in tendon tissue. We examined the distribution of Apo-A1 protein in biopsies from normal and tendinopathy-affected human Achilles tendons, and APOA1 mRNA production from cultured human hamstring tenocytes. Specific immunoreactions for Apo-A1 were detected. The tenocytes showed specific Apo-A1 immunoreactions. These reactions were usually distinct in the tendinopathy specimens. While the tendinopathy specimens often showed granular/small deposit reactions, the slender tenocytes of control specimens did not show this pattern. The magnitude of Apo-A1 immunoreactivity was especially marked in the tendinopathy specimens, as there is a high number of tenocytes. Reactions were also seen in the walls of blood vessels located within the tendon tissue proper of both the normal and tendinopathy tendons and within the peritendinous/fatty tissue of the tendinopathy tendons. The reactions were predominantly in the form of deposit reactions within the smooth muscle layer of the vessel walls. Cultured hamstring tenocytes produced APOA1 mRNA. We demonstrated the presence of Apo-A1 in human tendon tissue. This suggests there may be a link between Achilles tendinopathy and cholesterol metabolism. We hypothesize that Apo-A1 may be important for tenocyte and blood vessel function within tendons.

  • 348.
    Gaida, James Edmund
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Bagge, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Purdam, Craig
    Cook, Jill
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Evidence of the TNF-α system in the human Achilles tendon: expression of TNF-α and TNF receptor at both protein and mRNA levels in the tenocytes2012In: Cells Tissues Organs, ISSN 1422-6405, E-ISSN 1422-6421, Vol. 196, no 4, p. 339-352Article in journal (Refereed)
    Abstract [en]

    Understanding adaption to load is essential for prevention and treatment of tendinopathy/tendinosis. Cytokine release in response to load is one mechanism involved in mechanotransduction. The cytokine tumor necrosis factor alpha (TNF-α) is implicated in tendinosis and can induce apoptotic effects via tumor necrosis factor receptor 1 (TNFR1). The complete absence of information concerning the TNF-α system in Achilles tendon is a limitation as mid-portion Achilles tendinosis is very frequent. Purpose: To examine expression patterns of TNF-α and its two receptors (TNFR1 and TNFR2) in human Achilles tendinosis and control tissue and to biochemically confirm the presence of TNF-α in tendinosis tissue. Methods: TNF-α and TNFR1 mRNA were detected via in situ hybridization. TNF-α, TNFR1, and TNFR2 were demonstrated immunohistochemically. Apoptosis markers were utilized. ELISA was used to detect TNF-α. Results: TNF-α and TNFR1 mRNA was detected in tenocytes of both tendinosis and control tendons. Tenocytes from both groups displayed specific immunoreactions for TNF-α, TNFR1, and TNFR2. The widened/rounded tenocytes of tendinosis samples exhibited the most intense immunoreactions. Apoptosis was detected in only a subpopulation of the tenocytes in tendinosis tissue. TNF-α was measurable in tendinosis tissue. Inflammatory cells were not seen. Conclusion: This is the first evidence of the existence of the TNF-α system in the human Achilles tendon. Findings are confirmed at mRNA and protein levels as well as biochemically. The TNF-α system was in principle confined to the tenocytes. The connection between tenocyte morphology and the expression pattern of TNF-α, TNFR1, and TNFR2 suggests that the TNF-α system may be involved in tenocyte activation in Achilles tendinosis.

  • 349. Gardai, Shyra J
    et al.
    McPhillips, Kathleen A
    Frasch, S Courtney
    Janssen, William J
    Starefeldt, Anna
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Murphy-Ullrich, Joanne E
    Bratton, Donna L
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Michalak, Marek
    Henson, Peter M
    Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte2005In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 123, no 2, p. 321-334Article in journal (Refereed)
    Abstract [en]

    Apoptotic-cell removal is critical for development, tissue homeostasis, and resolution of inflammation. Although many candidate systems exist, only phosphatidylserine has been identified as a general recognition ligand on apoptotic cells. We demonstrate here that calreticulin acts as a second general recognition ligand by binding and activating LDL-receptor-related protein (LRP) on the engulfing cell. Since surface calreticulin is also found on viable cells, a mechanism preventing inadvertent uptake was sought. Disruption of interactions between CD47 (integrin-associated protein) on the target cell and SIRPalpha (SHPS-1), a heavily glycosylated transmembrane protein on the engulfing cell, permitted uptake of viable cells in a calreticulin/LRP-dependent manner. On apoptotic cells, CD47 was altered and/or lost and no longer activated SIRPalpha. These changes on the apoptotic cell create an environment where "don't eat me" signals are rendered inactive and "eat me" signals, including calreticulin and phosphatidylserine, congregate together and signal for removal.

  • 350. Garrett, Douglas D.
    et al.
    Nagel, Irene E.
    Preuschhof, Claudia
    Burzynska, Agnieszka Z.
    Marchner, Janina
    Wiegert, Steffen
    Jungehuelsing, Gerhard J.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Villringer, Arno
    Li, Shu-Chen
    Heekeren, Hauke R.
    Baeckman, Lars
    Lindenberger, Ulman
    Amphetamine modulates brain signal variability and working memory in younger and older adults2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 24, p. 7593-7598Article in journal (Refereed)
    Abstract [en]

    Better-performing younger adults typically express greater brain signal variability relative to older, poorer performers. Mechanisms for age and performance-graded differences in brain dynamics have, however, not yet been uncovered. Given the age-related decline of the dopamine (DA) system in normal cognitive aging, DA neuromodulation is one plausible mechanism. Hence, agents that boost systemic DA [such as d-amphetamine (AMPH)] may help to restore deficient signal variability levels. Furthermore, despite the standard practice of counterbalancing drug session order (AMPH first vs. placebo first), it remains understudied how AMPH may interact with practice effects, possibly influencing whether DA up-regulation is functional. We examined the effects of AMPH on functional-MRI-based blood oxygen level-dependent (BOLD) signal variability (SDBOLD) in younger and older adults during a working memory task (letter n-back). Older adults expressed lower brain signal variability at placebo, but met or exceeded young adult SDBOLD levels in the presence of AMPH. Drug session order greatly moderated change-change relations between AMPH-driven SDBOLD and reaction time means (RTmean) and SDs (RTSD). Older adults who received AMPH in the first session tended to improve in RTmean and RTSD when SDBOLD was boosted on AMPH, whereas younger and older adults who received AMPH in the second session showed either a performance improvement when SDBOLD decreased (for RTmean) or no effect at all (for RTSD). The present findings support the hypothesis that age differences in brain signal variability reflect aging-induced changes in dopaminergic neuromodulation. The observed interactions among AMPH, age, and session order highlight the state-and practice-dependent neurochemical basis of human brain dynamics.

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