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  • 1.
    Barro-Soria, Rene
    et al.
    Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL, USA.
    Liin, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, H. Peter
    Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL, USA.
    Using fluorescence to understand beta subunit-Na-V channel interactions2017In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 149, no 8, p. 757-762Article in journal (Other academic)
    Abstract [en]

    n/a

  • 2.
    Barro-Soria, Rene
    et al.
    University of Miami, FL 33136 USA.
    Ramentol, Rosamary
    University of Miami, FL 33136 USA.
    Liin, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. University of Miami, FL 33136 USA.
    Perez, Marta E.
    University of Miami, FL 33136 USA.
    Kass, Robert S.
    Columbia University, NY 10032 USA.
    Larsson, H. Peter
    University of Miami, FL 33136 USA.
    KCNE1 and KCNE3 modulate KCNQ1 channels by affecting different gating transitions2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 35, p. E7367-E7376Article in journal (Refereed)
    Abstract [en]

    KCNE beta-subunits assemble with and modulate the properties of voltage-gated K+ channels. In the heart, KCNE1 associates with the alpha-subunit KCNQ1 to generate the slowly activating, voltage-dependent potassium current (IKs) in the heart that controls the repolarization phase of cardiac action potentials. By contrast, in epithelial cells from the colon, stomach, and kidney, KCNE3 coassembles with KCNQ1 to form K+ channels that are voltage-independent K+ channels in the physiological voltage range and important for controlling water and salt secretion and absorption. How KCNE1 and KCNE3 subunits modify KCNQ1 channel gating so differently is largely unknown. Here, we use voltage clamp fluorometry to determine how KCNE1 and KCNE3 affect the voltage sensor and the gate of KCNQ1. By separating S4 movement and gate opening by mutations or phosphatidylinositol 4,5-bisphosphate depletion, we show that KCNE1 affects both the S4 movement and the gate, whereas KCNE3 affects the S4 movement and only affects the gate in KCNQ1 if an intact S4-to-gate coupling is present. Further, we show that a triple mutation in the middle of the transmembrane (TM) segment of KCNE3 introduces KCNE1-like effects on the second S4 movement and the gate. In addition, we show that differences in two residues at the external end of the KCNE TM segments underlie differences in the effects of the different KCNEs on the first S4 movement and the voltage sensor-to-gate coupling.

  • 3.
    Benosman, M. M.
    et al.
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Tlemcen Univ, Biomed Engn Dept, Tilimsen 13000, Algeria.
    Bereksi-Reguig, F.
    Tlemcen Univ, Algeria.
    Salerud, Göran
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    STRONG REAL-TIME QRS COMPLEX DETECTION2017In: Journal of Mechanics in Medicine and Biology, ISSN 0219-5194, Vol. 17, no 8, article id 1750111Article in journal (Refereed)
    Abstract [en]

    Heart rate variability (HRV) analysis is used as a marker of autonomic nervous system activity which may be related to mental and/or physical activity. HRV features can be extracted by detecting QRS complexes from an electrocardiogram (ECG) signal. The difficulties in QRS complex detection are due to the artifacts and noises that may appear in the ECG signal when subjects are performing their daily life activities such as exercise, posture changes, climbing stairs, walking, running, etc. This study describes a strong computation method for real-time QRS complex detection. The detection is improved by the prediction of the position of R waves by the estimation of the RR intervals lengths. The estimation is done by computing the intensity of the electromyogram noises that appear in the ECG signals and known here in this paper as ECG Trunk Muscles Signals Amplitude (ECG-TMSA). The heart rate (HR) and ECG-TMSA increases with the movement of the subject. We use this property to estimate the lengths of the RR intervals. The method was tested using famous databases, and also with signals acquired when an experiment with 17 subjects from our laboratory. The obtained results using ECG signals from the MIT-Noise Stress Test Database show a QRS complex detection error rate (ER) of 9.06%, a sensitivity of 95.18% and a positive prediction of 95.23%. This method was also tested against MIT-BIH Arrhythmia Database, the result are 99.68% of sensitivity and 99.89% of positive predictivity, with ER of 0.40%. When applied to the signals obtained from the 17 subjects, the algorithm gave an interesting result of 0.00025% as ER, 99.97% as sensitivity and 99.99% as positive predictivity.

  • 4.
    Bergstrand, Sara
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences.
    Morales, Maria-Aurora
    CNR Inst Clin Physiol, Italy.
    Coppini, Giuseppe
    CNR Inst Clin Physiol, Italy.
    Larsson, Marcus
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Strömberg, Tomas
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    The relationship between forearm skin speed-resolved perfusion and oxygen saturation, and finger arterial pulsation amplitudes, as indirect measures of endothelial function2018In: Microcirculation, ISSN 1073-9688, E-ISSN 1549-8719, Vol. 25, no 2, article id e12422Article in journal (Refereed)
    Abstract [en]

    Objective: Endothelial function is important for regulating peripheral blood flow to meet varying metabolic demands and can be measured indirectly during vascular provocations. In this study, we compared the PAT finger response (EndoPAT) after a 5-minutes arterial occlusion to that from forearm skin comprehensive microcirculation analysis (EPOS). Methods: Measurements in 16 subjects with varying cardiovascular risk factors were carried out concurrently with both methods during arterial occlusion, while forearm skin was also evaluated during local heating. Results: Peak values for EPOS skin Perf(conv) and speed-resolved total perfusion after the release of the occlusion were significantly correlated to the EndoPAT RHI (rho =.68, P = .007 and rho =.60, P = .025, respectively), mainly due to high-speed blood flow. During local heating, EPOS skin oxygen saturation, SO2, was significantly correlated to RHI (rho = .62, P =.043). This indicates that SO2 may have diagnostic value regarding endothelial function. Conclusions: We have demonstrated for the first time a significant relationship between forearm skin microcirculatory perfusion and oxygen saturation and finger PAT. Both local heating and reactive hyperemia are useful skin provocations. Further studies are needed to understand the precise regulation mechanisms of blood flow and oxygenation during these tests.

  • 5.
    Björck, Hanna M.
    et al.
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences.
    Renner, Johan
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, The Institute of Technology.
    Maleki, Shohreh
    Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Sweden.
    Nilsson, Siv F.E.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Kihlberg, Johan
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.
    Folkersen, Lasse
    Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Sweden.
    Karlsson, Matts
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, The Institute of Technology.
    Ebbers, Tino
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Clinical Physiology UHL.
    Eriksson, Per
    Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Sweden.
    Länne, Toste
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Thoracic and Vascular Surgery in Östergötland.
    Characterization of Shear-Sensitive Genes in the NormalRat Aorta Identifies Hand2 as a Major Flow-ResponsiveTranscription Factor2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12Article in journal (Refereed)
    Abstract [en]

    Objective: Shear forces play a key role in the maintenance of vessel wall integrity. Current understanding regarding shear-dependent gene expression is mainly based on in vitro or in vivo observations with experimentally deranged shear, hence reflecting acute molecular events in relation to flow. Our objective was to determine wall shear stress (WSS) in the rat aorta and study flow-dependent vessel wall biology under physiological conditions.

    Methods and Results: Animal-specific aortic WSS magnitude and vector direction were estimated using computational fluid dynamic simulation based on aortic geometry and flow information acquired by MRI. Two distinct flow pattern regions were identified in the normal rat aorta; the distal part of the inner curvature being exposed to low WSS and a non-uniform vector direction, and a region along the outer curvature being subjected to markedly higher levels of WSS and a uniform vector direction. Microarray analysis revealed a strong differential expression between the flow regions, particularly associated with transcriptional regulation. In particular, several genes related to Ca2+-signalling, inflammation, proliferation and oxidative stress were among the most highly differentially expressed.

    Conclusions: Microarray analysis validated the CFD-defined WSS regions in the rat aorta, and several novel flow-dependent genes were identified. The importance of these genes in relation to atherosusceptibility needs further investigation.

  • 6.
    Björnsdotter, Malin
    et al.
    Institute of Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden.
    Löken, Line
    Institute of Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden.
    Olausson, Håkan
    Institute of Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden.
    Vallbo, Åke
    Institute of Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden.
    Wessberg, Johan
    Institute of Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden.
    Somatotopic Organization of Gentle Touch Processing in the Posterior Insular Cortex2009In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 29, no 29, p. 9314-9320Article in journal (Refereed)
    Abstract [en]

    A network of thin (C and A delta) afferents relays various signals related to the physiological condition of the body, including sensations of gentle touch, pain, and temperature changes. Such afferents project to the insular cortex, where a somatotopic organization of responses to noxious and cooling stimuli was recently observed. To explore the possibility of a corresponding body-map topography in relation to gentle touch mediated through C tactile (CT) fibers, we applied soft brush stimuli to the right forearm and thigh of a patient (GL) lacking A beta afferents, and six healthy subjects during functional magnetic resonance imaging (fMRI). For improved fMRI analysis, we used a highly sensitive multivariate voxel clustering approach. A somatotopic organization of the left (contralateral) posterior insular cortex was consistently demonstrated in all subjects, including GL, with forearm projecting anterior to thigh stimulation. Also, despite denying any sense of touch in daily life, GL correctly localized 97% of the stimuli to the forearm or thigh in a forced-choice paradigm. The consistency in activation patterns across GL and the healthy subjects suggests that the identified organization reflects the central projection of CT fibers. Moreover, substantial similarities of the presently observed insular activation with that described for noxious and cooling stimuli solidify the hypothesized sensory-affective role of the CT system in the maintenance of physical well-being as part of a thin-afferent homeostatic network.

  • 7.
    Bäckryd, Emmanuel
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Ghafouri, Bijar
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Larsson, Britt
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Gerdle, Björn
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Plasma pro-inflammatory markers in chronic neuropathic pain: A multivariate, comparative, cross-sectional pilot study2016In: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, no 10, p. 1-5Article in journal (Refereed)
    Abstract [en]

    Background: Caused by a lesion or disease of the somatosensory system, neuropathic pain is notoriously difficult to treat with conventional analgesics. It has been suggested that inflammatory cytokines play a role in the development and maintenance of neuropathic pain. But human studies of these substances are relatively few and partly contradictory. Objectives: To simultaneously investigate the plasma levels of chemokine interleukin 8 (IL-8) and the cytokines IL-6, IL-1, and Granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with peripheral neuropathic pain (most of whom due to failed back surgery syndrome) (n = 14) compared to controls (n = 17). Results: IL-6 was significantly higher in patients than in controls (0.92 ± 0.12 pg/ml vs. 0.57 ± 0.08 pg/ml, p = 0.012). IL-1, IL-8, and GM-CSF levels did not differ between the two groups. A multivariate analysis showed a tendency for patients also to have higher GM-CSF plasma levels than controls. Conclusions: This study found an increased level of IL-6 in plasma in patients with neuropathic pain, but not for the other pro-inflammatory substances investigated. There are several possible confounders not registered or controlled for in this and other studies of neuropathic pain. Implications: Larger studies that take several possible confounders into consideration are needed to further investigate the levels of plasma cytokines in different pain conditions. © 2015 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  • 8.
    Case, Laura K.
    et al.
    NIH, MD 20892 USA.
    Laubacher, Claire M.
    NIH, MD 20892 USA.
    Richards, Emily A.
    NIH, MD 20892 USA.
    Spagnolo, P. A.
    NIAAA, MD USA.
    Olausson, Håkan
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Bushnell, M. Catherine
    NIH, MD 20892 USA.
    Inhibitory rTMS of secondary somatosensory cortex reduces intensity but not pleasantness of gentle touch2017In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 653, p. 84-91Article in journal (Refereed)
    Abstract [en]

    Research suggests that the discriminative and affective aspects of touch are processed differently in the brain. Primary somatosensory cortex is strongly implicated in touch discrimination, whereas insular and prefronal regions have been associated with pleasantness aspects of touch. However, the role of secondary somatosensory cortex (S2) is less clear. In the current study we used inhibitory repetitive transcranial magnetic stimulation (rTMS) to temporarily deactivate S2 and probe its role in touch perception. Nineteen healthy adults received two sessions of 1-Hz rTMS on separate days, one targeting right S2 and the other targeting the vertex (control). Before and after rTMS, subjects rated the intensity and pleasantness of slow and fast gentle brushing of the hand and performed a 2-point tactile discrimination task, followed by fMRI during additional brushing. rTMS to S2 (but not vertex) decreased intensity ratings of fast brushing, without altering touch pleasantness or spatial discrimination. MRI showed a reduced response to brushing in S2 (but not in S1 or insula) after S2 rTMS. Together, our results show that reducing touch evoked activity in S2 decreases perceived touch intensity, suggesting a causal role of S2 in touch intensity perception. Published by Elsevier Ireland Ltd.

  • 9.
    Cibis, Merih
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Ebbers, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Karlsson, Lars
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Carlhäll, Carljohan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Left Atrial 4D Blood Flow Dynamics and Hemostasis following Electrical Cardioversion of Atrial Fibrillation2017In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 8, article id 1052Article in journal (Refereed)
    Abstract [en]

    Background: Electrical cardioversion in patients with atrial fibrillation is followed by a transiently impaired atrial mechanical function, termed atrial stunning. During atrial stunning, a retained risk of left atrial thrombus formation exists, which may be attributed to abnormal left atrial blood flow patterns. 4D Flow cardiovascular magnetic resonance (CMR) enables blood flow assessment from the entire three-dimensional atrial volume throughout the cardiac cycle. We sought to investigate left atrial 4D blood flow patterns and hemostasis during left atrial stunning and after left atrial mechanical function was restored. Methods: 4D Flow and morphological CMR data as well as blood samples were collected in fourteen patients at two time-points: 2-3 h (Time-1) and 4 weeks (Time-2) following cardioversion. The volume of blood stasis and duration of blood stasis were calculated. In addition, hemostasis markers were analyzed. Results: From Time-1 to Time-2: Heart rate decreased (61 +/- 7 vs. 56 +/- 8 bpm, p = 0.01); Maximum change in left atrial volume increased (8 +/- 4 vs. 22 +/- 15%, p = 0.009); The duration of stasis (68 +/- 11 vs. 57 +/- 8%, p = 0.002) and the volume of stasis (14 +/- 9 vs. 9 +/- 7%, p = 0.04) decreased; Thrombin-antithrombin complex (TAT) decreased (5.2 +/- 3.3 vs. 3.3 +/- 2.2it.g/L, p = 0.008). A significant correlation was found between TAT and the volume of stasis (r(2) = 0.69, p amp;lt; 0.001) at Time-1 and between TAT and the duration of stasis (r(2) = 0.34, p = 0.04) at Time-2. Conclusion: In this longitudinal study, left atrial multidimensional blood flow was altered and blood stasis was elevated during left atrial stunning compared to the restored left atrial mechanical function. The coagulability of blood was also elevated during atrial stunning. The association between blood stasis and hypercoagulability proposes that assessment of left atrial 4D flow can add to the pathophysiological understanding of thrombus formation during atrial fibrillation related atrial stunning.

  • 10.
    De Basso, Rachel
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences.
    Influence of Genetics and Mechanical Properties on Large Arteries in Man2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Arterial pathology is the major contributor to cardiovascular diseases and mortality. The mechanical properties of arteries are independent factors for cardiovascular disease and mortality, where genetics influence the structure of the arterial wall, which may result in change in arterial stiffness. The aims of this thesis were to study the mechanical properties of the popliteal artery (PA) in healthy subjects and the influence of angiotensin-converting enzyme (ACE) polymorphism and Fibrillin-1 (FBN1) polymorphism on large arteries. Further, the impact of FBN1 polymorphism on cardiovascular morbidity and mortality was investigated.

    The PA is, after the abdominal aorta, the most common site of aneurysmal development. The PA was studied in healthy subject with ultrasound and the diameter increased and the distensibility decreased with age, with men having lower distensibility than women. This seems not to be the behavior of a true muscular artery but rather of a central elastic artery such as the aorta, and might have implications for the susceptibility to aneurysm formation, as well as the association of dilating disease between the PA and the aorta. The wall stress in the PA was low and unaffected by age, probably caused by a compensatory remodeling response with an increase in wall thickness. This indicates that other mechanisms than wall stress contribute to the process of pathological dilatation in the PA.

    The ACE D allele may be associated with abdominal aortic aneurysm. Elderly men with the ACE D allele were associated with increased abdominal aortic stiffness compared to men carrying the I/I genotype. This suggests that the ACE D allele impairs arterial wall integrity, and in combination with local hemodynamic and other genetic factors it may have a roll in aneurysm formation.

    The FBN1 2/3 genotype has been associated with increased systolic blood pressure. The FBN1 2/3 genotype in middle-aged men was associated with increased abdominal aortic stiffness and blood pressure which indicates an increased risk for developing cardiovascular disease. The increased presence of plaque in the carotid artery of middle-aged men with the FBN1 2/3 genotype indicates a pathological arterial wall remodeling with a more pronounced atherosclerotic burden, but did however not affect the risk of cardiovascular events and/or death in this population. This relationship needs to be studied further.

    List of papers
    1. The popliteal artery, an unusual muscular artery with wall properties similar to the aorta: Implications for susceptibility to aneurysm formation?
    Open this publication in new window or tab >>The popliteal artery, an unusual muscular artery with wall properties similar to the aorta: Implications for susceptibility to aneurysm formation?
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    2004 (English)In: Journal of Vascular Surgery, ISSN 0741-5214, E-ISSN 1097-6809, Vol. 39, no 4, p. 836-842Article in journal (Refereed) Published
    Abstract [en]

    Objective: The popliteal artery is, after the aorta, the most common site for aneurysm formation. Why the popliteal artery is more susceptible than other peripheral muscular arteries is unknown. An important factor may be differences in arterial wall composition as compared with other peripheral muscular arteries, which in turn affect wall properties. These are however unknown. We studied the mechanical wall properties of the popliteal artery in healthy subjects. Material and Methods: An ultrasound echo-tracking system was used to measure pulsatile changes in popliteal diameter in 108 healthy subjects (56 female, 52 male, age range, 9-82 years). In combination with blood pressure, stiffness (β), strain, cross-sectional artery wall compliance coefficient (CC), and distensibility coefficient (DC) were calculated. Intima-media thickness (IMT) was registered with a Philips P700 ultrasound scanner. Results: The popliteal diameter increased with age, and was larger in male subjects than in female subjects (P < .001). Fractional diameter change (strain) decreased with age (P < .001), and strain values were lower in male subjects than in female subjects (P < .01). Accordingly, stiffness increased with age (P < .001), with higher stiffness values in male subjects (P < .01). DC decreased with age (P < .001), with lower DC values in male subjects (P < .01). CC decreased with age, with no difference between genders (P < .001). IMT increased with age (P < .001), with higher IMT values in male subjects (P < .001). The increase in IMT did not affect distensibility. Conclusion: The wall properties of the popliteal artery are affected by age and gender, not only with an increase in diameter, but also with an age-related decrease in distensibility, with male subjects having lower distensibility than in female subjects. This seems not to be the behavior of a true muscular artery, but of a central elastic artery, such as the aorta, and might have implications for susceptibility to arterial dilatation, as well as the association of aneurysm formation between the aorta and the popliteal artery.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-24039 (URN)10.1016/j.jvs.2003.12.005 (DOI)3595 (Local ID)3595 (Archive number)3595 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
    2. Low wall stress in popliteal artery – other mechanisms responsible for the predilection of aneurysmal dilatation?
    Open this publication in new window or tab >>Low wall stress in popliteal artery – other mechanisms responsible for the predilection of aneurysmal dilatation?
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Introduction: The popliteal artery (PA) is, after aorta, the most common site for aneurysm formation. Why the PA is more susceptible than other peripheral muscular arteries is unknown. We hypothesised that the wall composition, which in turn affects wall properties, as well as the circumferential wall stress imposed on the arterial wall, might differ compared to other muscular arteries. The aim was to study the circumferential wall stress of the PA in healthy subjects with the adjacent muscular common femoral artery (CFA) as a comparison.

    Material and Methods: Ninety-four healthy subjects were included in this study (45 males, range 10-78 years and 49 females, range 10-83 years). The lumen diameter (LD) and intima-media thickness (IMT) in the PA and CFA were investigated with a Philips P700 ultrasound device. Together with blood pressure the circumferential wall stress was defined according to the law of Laplace adjusted for IMT.

    Results: The diameter increased with age in both PA and CFA (P<.001), with males having larger diameter than females (P<.001). IMT increased with age in both PA and CFA (P<.001), with higher IMT values in males only in PA (P<0.001). The calculated wall stress was unchanged with age in both arteries, but lower in PA than in CFA in both male and female subjects (P<0.001).

    Conclusion: This study shows that the popliteal and common femoral artery wall stress is maintained during ageing, probably due to compensatory remodeling response with an increase in arterial wall thickness. However, the stress imposed on the popliteal artery wall is quite low, indicating that other mechanisms than wall stress contribute to the process of pathological arterial dilatation in the popliteal artery.

    National Category
    Physiology
    Identifiers
    urn:nbn:se:liu:diva-86142 (URN)
    Available from: 2012-12-07 Created: 2012-12-07 Last updated: 2018-01-12
    3. Impaired abdominal aortic wall integrity in elderly men carrying the angiotensin-converting enzyme D allele
    Open this publication in new window or tab >>Impaired abdominal aortic wall integrity in elderly men carrying the angiotensin-converting enzyme D allele
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    2011 (English)In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 42, no 3, p. 309-316Article in journal (Refereed) Published
    Abstract [en]

    Objective: A genetic polymorphism in the angiotensin-converting enzyme gene (ACE I/D polymorphism) has been associated with abdominal aortic aneurysm and a link between aortic aneurysm and aortic stiffness has been suggested. The aim of this study was to explore the links between ACE I/D polymorphism, circulating ACE, and abdominal aortic wall integrity as reflected by abdominal aortic wall stiffness.

    Material: The study population consisted of 406 subjects (212 men and 194 women) aged 70-88 years.

    Methods: The mechanical properties of the abdominal aorta were determined 3-4 cm proximal to the aortic bifurcation using a Wall Track System. ACE-genotype was determined by PCR followed by gel electrophoresis, and circulating ACE level was measured by ELISA.

    Results: Men carrying the ACE D allele had lower distensibility coefficient than II carriers (ID/DD 8.09 vs II 10.38, P=0.017). Multiple regression analyses showed additional associations between the ACE D allele and increased stiffness β as well as reduced cross-sectional compliance.

    Conclusion: This study showed that men carrying the ACE D allele have stiffer abdominal aortas compared to II carriers. Deranged abdominal aortic stiffness indicates impaired vessel wall integrity, which along with other local predisposing factors, may be of importance in aneurysmal disease.

    Place, publisher, year, edition, pages
    Elsevier, 2011
    Keywords
    Aorta; Arterial stiffness; Distensibility; Gene polymorphism; Mechanical properties
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-67213 (URN)10.1016/j.ejvs.2011.04.010 (DOI)000295061800007 ()
    Available from: 2011-04-04 Created: 2011-04-04 Last updated: 2017-12-11Bibliographically approved
    4. Influence of fibrillin-1 genotype on the aortic stiffness in men
    Open this publication in new window or tab >>Influence of fibrillin-1 genotype on the aortic stiffness in men
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    2005 (English)In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 99, no 3, p. 1036-1040Article in journal (Refereed) Published
    Abstract [en]

    Aortic stiffness is a predictor of cardiovascular mortality. The mechanical properties of the arterial wall depend on the connective tissue framework, with variation in fibrillin-1 and collagen I genes being associated with aortic stiffness and/or pulse pressure elevation. The aim of this study was to investigate whether variation in fibrillin-1 genotype was associated with aortic stiffness in men. The mechanical properties of the abdominal aorta of 79 healthy men (range 28-81 yr) were investigated by ultrasonographic phase-locked echo tracking. Fibrillin-1 genotype, characterized by the variable tandem repeat in intron 28, and collagen type I alpha 1 genotype characterized by the 2,064 OT polymorphism, were determined by using DNA from peripheral blood cells. Three common fibrillin-1 genotypes, 2-2, 2-3, and 2-4, were observed in 50 (64%), 10 (13%), and 11 (14%) of the men, respectively. Those of 2-3 genotype had higher pressure strain elastic modulus and aortic stiffness compared with men of 2-2 or 2-4 genotype (P = 0.005). Pulse pressure also was increased in the 2-3 genotype (P = 0.04). There was no significant association between type 1 collagen genotype and aortic stiffness in this cohort. In conclusion, the fibrillin-1 2-3 genotype in men was associated with increased aortic stiffness and pulse pressure, indicative of an increased risk for cardiovascular disease. Copyright © 2005 the American Physiological Society.

    Keywords
    blood pressure, collagen, elastin, mechanics
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-29056 (URN)10.1152/japplphysiol.00554.2004 (DOI)14310 (Local ID)14310 (Archive number)14310 (OAI)
    Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2017-12-13
    5. Increased carotid plaque burden in men with the Fibrillin-1 2/3 genotype
    Open this publication in new window or tab >>Increased carotid plaque burden in men with the Fibrillin-1 2/3 genotype
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    2014 (English)In: Clinical and experimental pharmacology & physiology, ISSN 0305-1870, E-ISSN 1440-1681, Vol. 41, no 9, p. 637-642Article in journal (Refereed) Published
    Abstract [en]

    Objective: Fibrillin-1 is an important constituent of the vascular wall and earlier studies have indicated an effect of the Fibrillin-1 (FBN1) 2/3 genotype on blood pressure as well as aortic stiffness in men. The aim was to determine if the FBN1 2/3 genotype was associated with presence of carotid plaque and incident cardiovascular morbidity and mortality in middle-aged subjects.

    Material and Method: The FBN1 genotype was characterized in 5765 subjects (2424 men, 3341 women; aged 45-69 years) recruited from the Malmö Diet and Cancer Study Cardiovascular Cohort, Sweden. Plaque occurrence and intima media thickness (IMT) of the carotid artery were assessed by ultrasound. Incidence of first cardiovascular events (myocardial infarction and stroke) and cause-specific mortality was monitored during a mean of 13.2 years follow-up.

    Results: The most common FBN1 genotypes were 2/2, 2/3 and 2/4 which accounted for 92.2% (n=5317) of the subjects. There were no differences between the three genotypes regarding age, blood pressure, glucose, lipids, smoking habits, CCA diameter and IMT in men and women. Presence of plaque in the carotid artery was higher in men with genotype 2/3 as compared to the 2/2 and 2/4 genotypes, (55% vs. 46% and 50%, p=0.007). No similar difference was observed in women. No significant relationship was observed between FBN1 genotypes and incidence of CVD or all-cause mortality.

    Conclusions: The increased prevalence of plaque in the carotid artery of middle-aged men with FBN1 2/3 genotype indicates a pathological arterial wall remodeling with a more pronounced atherosclerotic burden. 

    Place, publisher, year, edition, pages
    Wiley-Blackwell, 2014
    Keywords
    IMT, cardiovascular risk, blood pressure, arterial wall, human
    National Category
    Physiology
    Identifiers
    urn:nbn:se:liu:diva-86143 (URN)10.1111/1440-1681.12259 (DOI)000344348100004 ()24837032 (PubMedID)
    Available from: 2012-12-07 Created: 2012-12-07 Last updated: 2018-01-12Bibliographically approved
  • 11.
    De Basso, Rachel
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Hedblad, Bo
    Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
    Carlson, Joyce
    Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
    Persson, Margaretha
    Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
    Östling, Gerd
    Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
    Länne, Toste
    Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Thoracic and Vascular Surgery. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Increased carotid plaque burden in men with the Fibrillin-1 2/3 genotype2014In: Clinical and experimental pharmacology & physiology, ISSN 0305-1870, E-ISSN 1440-1681, Vol. 41, no 9, p. 637-642Article in journal (Refereed)
    Abstract [en]

    Objective: Fibrillin-1 is an important constituent of the vascular wall and earlier studies have indicated an effect of the Fibrillin-1 (FBN1) 2/3 genotype on blood pressure as well as aortic stiffness in men. The aim was to determine if the FBN1 2/3 genotype was associated with presence of carotid plaque and incident cardiovascular morbidity and mortality in middle-aged subjects.

    Material and Method: The FBN1 genotype was characterized in 5765 subjects (2424 men, 3341 women; aged 45-69 years) recruited from the Malmö Diet and Cancer Study Cardiovascular Cohort, Sweden. Plaque occurrence and intima media thickness (IMT) of the carotid artery were assessed by ultrasound. Incidence of first cardiovascular events (myocardial infarction and stroke) and cause-specific mortality was monitored during a mean of 13.2 years follow-up.

    Results: The most common FBN1 genotypes were 2/2, 2/3 and 2/4 which accounted for 92.2% (n=5317) of the subjects. There were no differences between the three genotypes regarding age, blood pressure, glucose, lipids, smoking habits, CCA diameter and IMT in men and women. Presence of plaque in the carotid artery was higher in men with genotype 2/3 as compared to the 2/2 and 2/4 genotypes, (55% vs. 46% and 50%, p=0.007). No similar difference was observed in women. No significant relationship was observed between FBN1 genotypes and incidence of CVD or all-cause mortality.

    Conclusions: The increased prevalence of plaque in the carotid artery of middle-aged men with FBN1 2/3 genotype indicates a pathological arterial wall remodeling with a more pronounced atherosclerotic burden. 

  • 12.
    De Basso, Rachel
    et al.
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences.
    Åstrand, Håkan
    Department of Vascular Surgery, Jönköping Hospital, Jönköping, Sweden.
    Rydén Ahlgren, Åsa
    Clinical Physiology and Nuclearmedicine Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Sandgren, Thomas
    Department of Surgery, Capio Lundby Hospital, Gothenburg, Sweden.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Thoracic and Vascular Surgery in Östergötland.
    Low wall stress in popliteal artery – other mechanisms responsible for the predilection of aneurysmal dilatation?Manuscript (preprint) (Other academic)
    Abstract [en]

    Introduction: The popliteal artery (PA) is, after aorta, the most common site for aneurysm formation. Why the PA is more susceptible than other peripheral muscular arteries is unknown. We hypothesised that the wall composition, which in turn affects wall properties, as well as the circumferential wall stress imposed on the arterial wall, might differ compared to other muscular arteries. The aim was to study the circumferential wall stress of the PA in healthy subjects with the adjacent muscular common femoral artery (CFA) as a comparison.

    Material and Methods: Ninety-four healthy subjects were included in this study (45 males, range 10-78 years and 49 females, range 10-83 years). The lumen diameter (LD) and intima-media thickness (IMT) in the PA and CFA were investigated with a Philips P700 ultrasound device. Together with blood pressure the circumferential wall stress was defined according to the law of Laplace adjusted for IMT.

    Results: The diameter increased with age in both PA and CFA (P<.001), with males having larger diameter than females (P<.001). IMT increased with age in both PA and CFA (P<.001), with higher IMT values in males only in PA (P<0.001). The calculated wall stress was unchanged with age in both arteries, but lower in PA than in CFA in both male and female subjects (P<0.001).

    Conclusion: This study shows that the popliteal and common femoral artery wall stress is maintained during ageing, probably due to compensatory remodeling response with an increase in arterial wall thickness. However, the stress imposed on the popliteal artery wall is quite low, indicating that other mechanisms than wall stress contribute to the process of pathological arterial dilatation in the popliteal artery.

  • 13.
    Dezsi, Livia
    et al.
    Szegedi Tudomanyegyet, Altalonos Orvostudomanyi Kar, Szent Gyorgyi Albert Klinikai Kozpont, Neurol Klin, Szeged, Hungary.
    Danielsson, Olof
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Gati, Istvan
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Timea Varga, Edina
    Szegedi Tudomanyegyet, Altalonos Orvostudomanyi Kar, Szent Gyorgyi Albert Klinikai Kozpont, Neurol Klin, Szeged, Hungary.
    Vecsei, Laszlo
    Szegedi Tudomanyegyet, Altalonos Orvostudomanyi Kar, Szent Gyorgyi Albert Klinikai Kozpont, Neurol Klin, Szeged, Hungary.
    Inclusion body myositis - a rarely recognized disorder2013In: Ideggyogyaszati Szemle - Clinical Neuroscience, ISSN 0019-1442, Vol. 66, no 3-4, p. 89-101Article, review/survey (Refereed)
    Abstract [en]

    Inclusion body myositis is the most common disabling inflammatory myopathy in the elderly. It is more frequent in men and after the age of 50 years. Inflammatory and degenerative features coexist. There is a T-cell mediated autoimmunity driven by in situ clonally expanded cytotoxic CD8-positive T-cells invading non-necrotic muscle fibres expressing MHC-I antigen. The hallmarks of degeneration are the deposition of protein aggregates and the formation of vesicles. The course of the disease is slow and the diagnosis is usually set after several years. The muscle weakness and wasting is assymetric, affecting predominantly distal muscles of the upper extremity and proximal muscles of the legs. The signs and clinical course can be characteristic, but the diagnosis is established by muscle biopsy. less thanbrgreater than less thanbrgreater thanThere is currently no evidence based effective treatment for sIBM. Prednisone, azathioprine, methotrexate, cyclosporine and IFN-beta failed. Oxandrolon did not improve symptoms. Treatment with intravenous immunglobuline (IVIG) induced in some patients a transient improvement of swallowing and of muscle strenght, but the overall study results were negative. less thanbrgreater than less thanbrgreater thanA T-cell depleting monoclonal antibody (alemtuzumab), in a small uncontrolled study slowed down disease progression for a six-month period. Repeated muscle biopsies showed the reduction of T-cells in the muscle and the suppression of some degeneration associated molecules. An effective therapeutic mean should act on both aspects of the pathomechanism, on the inflammatory and the degenerative processes as well.

  • 14.
    Droog Tesselaar, Erik
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Health Sciences.
    Assessment of microvascular function by use of transdermal iontophoresis: methodological aspects2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Assessment of the microcirculation is of major importance in understanding the physiology of the vasculature and in assessing te vascular effects of pathological conditions such as diabetes, hypertension and sepsis. Transdermal iontophoresis can be used to non‐invasively introduce vasoactive drugs into the skin. The response to these drugs of the local cutaneous microvasculature can be measured by laser Doppler flowmetry methods. Although these techniques have been used together for over two decades, there are still important methodological issues to be resolved. This work is aimed at optimizing transdermal iontophoresis as a tool for microvascular assessment by focusing on the main methdological issues: non‐specific vasodilatation, drug delivery protocols and analysis of blood flow data.

    Non‐specific vasodilatation, an increase blood flow during iontophoresis of non‐vasoactive compounds, is an important problem as it interferes with the response to the administered drug. By investigating this effect in healthy volunteers, we found that the extent of the non‐specific response differs between the positive and negative electrode and that it is dependent on the voltage over the skin andon the ionic strength of the vehicle in which the drug is dissolved. We also found that the extent of the non‐specific response could be reduced by applying local anesthetics and by pre‐treatment with antihistamine drugs. These results suggest that non‐specific effects could be mediated by depolarization or hyperpolarisation of cells, triggering neural and histamine related mechanisms that finally lead to vasodilatation of the local microvasculature.

    To prevent non‐specific effects from occurring during the experiments, our results show that the current strength and the total electric charge during iontophoresis should be limited to 0.02 mA and12 mC, respectively. Furthermore, drug solutions at physiological ionic strengths should be used. Under these conditions, adequate responses to the most commonly used drugs, acetylcholine (ACh) and sodium nitroprusside (SNP), are obtained while no significant non‐specific vasodilatation occurs.

    The results of our investigations show that blood responses to ACh and SNP applied by a single iontophoretic pulse can well be escribed by conventional dose‐response models, which enables a more powerful analysis and comparison between drugs or possibly patient groups as compared with conventional aalysis methods. Finally, we have incorporated drug transport and physiological response to the local drug concentration during iontophoresis of vasoactve drugs into a single model. Validation of this model using measured responses to ACh and SNP shows that the commonly used assumption that the local drug concentration during iontophoresis is linearly proportional to the electric charge may not be valid.

    List of papers
    1. Nonspecific vasodilatation during transdermal iontophoresis: the effect of voltage over the skin
    Open this publication in new window or tab >>Nonspecific vasodilatation during transdermal iontophoresis: the effect of voltage over the skin
    2003 (English)In: Microvascular research, ISSN 0026-2862, Vol. 65, no 3, p. 172-178Article in journal (Refereed) Published
    Abstract [en]

    We used laser Doppler perfusion imaging (LDPI) to study nonspecific vasodilatation during iontophoresis. In iontophoresis studies, nonspecific vasodilatation occurs as a result either of galvanic currents or of the applied voltage over the skin. We made dose–response measurements to study the effect of ionic strength of the vehicle on the nonspecific vasodilatation during iontophoresis of sodium chloride and deionized water, while we monitored the voltage over the skin. We found that anodal and cathodal ionotophoresis induced a voltage over the skin that was dependent on the ionic strength of the test solution. The nonspecific vasodilatation during anodal iontophoresis was less pronounced than during cathodal iontophoresis, and was independent of the voltage over the skin. The nonspecific vasodilatation in cathodal iontophoresis was related to the voltage over the skin, and was possibly mediated by depolarization of local sensory nerves. In experiments using cathodal iontophoresis, therefore, the ionic strengths of the vehicle and the drug are important when vasoactive drugs are examined, as the nonspecific vasodilatation needs to be controlled for. As the vasodilatation that we observed was heterogeneously distributed within the area of iontophoresis, LDPI may provide more accurate measurements than conventional laser Doppler perfusion monitoring.

    Keywords
    Microcirculation, Skin, Laser-Doppler, Depolarization, Hyperpolarization
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14456 (URN)10.1016/S0026-2862(03)00002-5 (DOI)
    Available from: 2007-05-04 Created: 2007-05-04 Last updated: 2009-02-19
    2. Role of histamine release in nonspecific vasodilatation during anodal and cathodal iontophoresis
    Open this publication in new window or tab >>Role of histamine release in nonspecific vasodilatation during anodal and cathodal iontophoresis
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    2004 (English)In: Microvascular research, ISSN 0026-2862, Vol. 67, no 2, p. 192-196Article in journal (Refereed) Published
    Abstract [en]

    Nonspecific vasodilatation during iontophoresis is an important confounding factor in experimental pharmacology. In this investigation, we studied the involvement of sensory nerves and histamine-related reactions in causing nonspecific vasodilatation in a model of anodal and cathodal iontophoresis of sodium chloride. Firstly, we applied a mixture of local anesthetic (EMLA) cream to confirm its suppressive effect on nonspecific vasodilatation and to measure its efficacy in three different dosages (duration: 1, 2, and 3 h). We then investigated the role of histamine in nonspecific vasodilatation by giving an oral antihistamine drug (cetirizine) to subjects who had and had not been given EMLA. We found substantial suppression of the nonspecific vasodilatation in all EMLA-treated groups (all dosages) compared with untreated controls (with suppression rates of 60–65%). Dosage had no significant effect. A further suppression of nonspecific vasodilatation was seen after oral cetirizine during anodal and cathodal iontophoresis in both EMLA-treated and untreated groups. The antihistamine effect was most pronounced during anodal iontophoresis. These results suggest a histaminergic increase in perfusion that may be independent of neurogenic mechanisms and depend on polarity (anode or cathode). Local nerve blocks (EMLA) together with cetirizine may therefore be used to reduce nonspecific vasodilatation in both anodal and cathodal iontophoresis.

    Keywords
    Microcirculation, Iontophoresis, Nonspecific vasodilatation, EMLA, Cetirizine, Histamine, Laser Doppler
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14457 (URN)10.1016/j.mvr.2003.12.002 (DOI)
    Available from: 2007-05-04 Created: 2007-05-04 Last updated: 2009-08-18
    3. A protocol for iontophoresis of acetylcholine and sodium nitroprusside that minimises nonspecific vasodilatory effects
    Open this publication in new window or tab >>A protocol for iontophoresis of acetylcholine and sodium nitroprusside that minimises nonspecific vasodilatory effects
    2004 (English)In: Microvascular research, ISSN 0026-2862, Vol. 67, no 2, p. 197-202Article in journal (Refereed) Published
    Abstract [en]

    Iontophoresis of vasoactive substances is a promising tool for studying pharmacological aspects of the (patho)physiology of the microvasculature. However, nonspecific microvascular responses are a common problem in most protocols used. We studied the effect of current density (mA/cm2), charge density (mC/cm2), drug concentration (mass %) and vehicle concentration (M) on the nonspecific vasodilatation during iontophoresis of sodium chloride, acetylcholine (ACh) and sodium nitroprusside (SNP).

    We found that nonspecific vasodilatation depended on current density and charge density in both anodal and cathodal iontophoresis. The responses to ACh and SNP were dependent on current density, charge density and drug concentration. We found that by limiting current density (<0.01 mA/cm2) and charge density (<7.8 mC/cm2) and with adjusted concentrations for drugs and vehicles, it is possible to prevent nonspecific effects during iontophoresis of ACh and SNP, while maximum drug effects (plateaus in the dose–response curves) are still obtained. These new findings are important for future iontophoresis studies in which vasoactive drugs are used to assess microvascular function because the presented approach has advantages compared to older techniques, which mainly have attempted to suppress or compensate for the nonspecific responses during iontophoresis by the use of local anaesthetics or the measurement of drug-minus-vehicle responses, both of which present well-known experimental shortcomings.

    Keywords
    Microcirculation, Skin, Laser Doppler, Nonspecific vasodilatation, Sodium chloride, Acetylcholine, Nitroprusside
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14458 (URN)10.1016/j.mvr.2003.12.003 (DOI)
    Available from: 2007-05-04 Created: 2007-05-04 Last updated: 2009-08-17
    4. Assessment of microvascular function by study of the dose‐response effects of iontophoretically applied drugs (acetylcholine and sodium nitroprusside): Methods and comparison with in vitro studies
    Open this publication in new window or tab >>Assessment of microvascular function by study of the dose‐response effects of iontophoretically applied drugs (acetylcholine and sodium nitroprusside): Methods and comparison with in vitro studies
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    2007 (English)In: Microvascular Research, ISSN 0026-2862, E-ISSN 1095-9319, Vol. 73, no 2, p. 143-149Article in journal (Refereed) Published
    Abstract [en]

    Current knowledge about vascular function stems mainly from pharmacological in vitro studies using mounted vascular strips on a strain gauge. We know of no paper that has systematically examined the possibility of assessing the conventional dose–response effects of iontophoresis and laser Doppler investigation of vasoactive substances and compared those relations to data obtained from strips mounted on a strain gauge.

    We used the vasoactive substances acetylcholine (endothelium dependent) and sodium nitroprusside (endothelium independent) and an antagonist (atropine) to enable further investigations in the receptor physiology of iontophoresis.

    Dose–response curves from the iontophoresis experiments showed close similarity to those obtained by vascular strips mounted on a strain gauge. The coefficient of variation (CV) of the dose–response factors found in iontophoresis (both inter and intra experimental variability) was low. The iontophoretic effective dose of 50% (ED50) for acetylcholine and nitroprusside had only CVs of 25% and 26%, respectively, compared with 71% and 77% for the vascular strips. Acetylcholine-induced response was antagonized by iontophoresis of atropine. Contrary to expectations, this antagonism was not competitive.

    The results show that iontophoresis in combination with laser Doppler technology produces reproducible and reliable dose–response curves that picture the vascular effects of vasoactive drugs.

    Keywords
    Microvascular circulation, Endothelium, Dose–response, Iontophoresis, Laser doppler
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14459 (URN)10.1016/j.mvr.2006.10.004 (DOI)
    Available from: 2007-05-04 Created: 2007-05-04 Last updated: 2017-12-13Bibliographically approved
    5. A time–response model for analysis of drug transport and blood flow response during iontophoresis of acetylcholine and sodium nitroprusside
    Open this publication in new window or tab >>A time–response model for analysis of drug transport and blood flow response during iontophoresis of acetylcholine and sodium nitroprusside
    2009 (English)In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 46, no 4, p. 270-277Article in journal (Refereed) Published
    Abstract [en]

    Background/Aims: The analysis of blood flow responses to iontophoresis of vasoactive drugs is often limited to evaluation of maximum responses. In this study, a time-response model is proposed for the blood flow responses to vasoactive drugs applied by iontophoresis.

    Methods: The microvascular bed is represented as a single compartment with a zero-order influx of the drugs from the electrode and a first-order clearance due to diffusion and blood flow. The blood flow response to the local drug dose is described using the Emax model.

    Results: The model accurately describes the blood flow responses to acetylcholine and sodium nitroprusside during a single iontophoretic current pulse. There is a significant clearance out of the microvascular bed during iontophoresis which depends on the type of drug administered.

    Conclusion: The model enables an accurate estimation of response parameters such as ED50 and maximum response, even if the true maximum blood flow is not obtained. The results suggest that due to clearance from the microvascular bed, the local drug dose during a single pulse of current is not linearly proportional to current strength multiplied by pulse duration.

    Place, publisher, year, edition, pages
    Basel, Switzerland: S. Karger, 2009
    Keywords
    Time-response model, Iontophoresis, Laser Doppler flowmetry, Acetylcholine, Sodium nitroprusside
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14460 (URN)10.1159/000176042 (DOI)000267091200002 ()
    Available from: 2007-05-04 Created: 2007-05-04 Last updated: 2017-12-13Bibliographically approved
  • 15.
    Dyverfeldt, Petter
    et al.
    University of California, San Francisco, USA.
    Hope, Michael D.
    University of California, San Francisco, USA.
    Tseng, Elaine E.
    University of California, San Francisco, USA.
    Saloner, David
    University of California, San Francisco, USA.
    Magnetic Resonance Measurement of Turbulent Kinetic Energy for the Estimation of Irreversible Pressure Loss in Aortic Stenosis2013In: JACC Cardiovascular Imaging, ISSN 1936-878X, E-ISSN 1876-7591, Vol. 6, no 1, p. 64-71Article in journal (Refereed)
    Abstract [en]

    Objectives

    The authors sought to measure the turbulent kinetic energy (TKE) in the ascending aorta of patients with aortic stenosis and to assess its relationship to irreversible pressure loss.

    Background

    Irreversible pressure loss caused by energy dissipation in post-stenotic flow is an important determinant of the hemodynamic significance of aortic stenosis. The simplified Bernoulli equation used to estimate pressure gradients often misclassifies the ventricular overload caused by aortic stenosis. The current gold standard for estimation of irreversible pressure loss is catheterization, but this method is rarely used due to its invasiveness. Post-stenotic pressure loss is largely caused by dissipation of turbulent kinetic energy into heat. Recent developments in magnetic resonance flow imaging permit noninvasive estimation of TKE.

    Methods

    The study was approved by the local ethics review board and all subjects gave written informed consent. Three-dimensional cine magnetic resonance flow imaging was used to measure TKE in 18 subjects (4 normal volunteers, 14 patients with aortic stenosis with and without dilation). For each subject, the peak total TKE in the ascending aorta was compared with a pressure loss index. The pressure loss index was based on a previously validated theory relating pressure loss to measures obtainable by echocardiography.

    Results

    The total TKE did not appear to be related to global flow patterns visualized based on magnetic resonance–measured velocity fields. The TKE was significantly higher in patients with aortic stenosis than in normal volunteers (p < 0.001). The peak total TKE in the ascending aorta was strongly correlated to index pressure loss (R2 = 0.91).

    Conclusions

    Peak total TKE in the ascending aorta correlated strongly with irreversible pressure loss estimated by a well-established method. Direct measurement of TKE by magnetic resonance flow imaging may, with further validation, be used to estimate irreversible pressure loss in aortic stenosis.

  • 16.
    Dyverfeldt, Petter
    et al.
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences. Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, The Institute of Technology.
    Sigfridsson, Andreas
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, The Institute of Technology.
    Escobar Kvitting, John-Peder
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Ebbers, Tino
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences. Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, The Institute of Technology.
    Quantification of intravoxel velocity standard deviation and turbulence intensity by generalizing phase-contrast MRI2006In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 56, no 4, p. 850-858Article in journal (Refereed)
    Abstract [en]

    Turbulent flow, characterized by velocity fluctuations, is a contributing factor to the pathogenesis of several cardiovascular diseases. A clinical noninvasive tool for assessing turbulence is lacking, however. It is well known that the occurrence of multiple spin velocities within a voxel during the influence of a magnetic gradient moment causes signal loss in phase-contrast magnetic resonance imaging (PC-MRI). In this paper a mathematical derivation of an expression for computing the standard deviation (SD) of the blood flow velocity distribution within a voxel is presented. The SD is obtained from the magnitude of PC-MRI signals acquired with different first gradient moments. By exploiting the relation between the SD and turbulence intensity (TI), this method allows for quantitative studies of turbulence. For validation, the TI in an in vitro flow phantom was quantified, and the results compared favorably with previously published laser Doppler anemometry (LDA) results. This method has the potential to become an important tool for the noninvasive assessment of turbulence in the arterial tree.

  • 17.
    Ebbers, Tino
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, The Institute of Technology. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Clinical Physiology UHL.
    Flow Imaging: Cardiac Applications of 3D Cine Phase-Contrast MRI2011In: Current Cardiovascular Imaging Reports, ISSN 1941-9074, Vol. 4, no 2, p. 127-133Article, review/survey (Refereed)
    Abstract [en]

    Global and regional blood flow dynamics are of pivotal importance to cardiac function. Fluid mechanical forces can affect hemolysis and platelet aggregation, as well as myocardial remodeling. In recent years, assessment of blood flow patterns based on time-resolved, three-dimensional, three-directional phase-contrast MRI (3D cine PC MRI) has become possible and rapidly gained popularity. Initially, this technique was mainly known for its intuitive and appealing visualizations of the cardiovascular blood flow. Most recently, the technique has begun to go beyond compelling images toward comprehensive and quantitative assessment of blood flow. In this article, cardiac applications of 3D cine PC MRI data are discussed, starting with a review of the acquisition and analysis techniques, and including descriptions of promising applications of cardiac 3D cine PC MRI for the clinical evaluation of myocardial, valvular, and vascular disorders.

  • 18.
    Ekström, Andreas
    Linköping University, Department of Physics, Chemistry and Biology.
    Effects of the NO donors Sodium Nitroprusside andS-nitrosoglutathione on oxygen consumption and embryonic organ growth in the domestic broiler chicken,Gallus gallus domesticus.2010Independent thesis Basic level (degree of Bachelor), 15 credits / 22,5 HE creditsStudent thesis
    Abstract [en]

    Nitric oxide (NO) is an important chemical factor that controls vascular tone in the cardiovascular system. NO is a vasodilatory molecule that plays a role in blood pressure and blood flow regulation as well as vessel formation and tissue cell proliferation. NO influences the flow by which nutrients and other metabolites required for growth are transported to the tissues. The aim of this study was to investigate if NO, through mediation by the NO donors Sodium Nitroprusside (SNP) and S-Nitrosoglutathione (GSNO) affect growth and oxygen consumption of prenatal broiler chicken. The results indicate that, although the treatments did not have clear significant effects on the embryos or the organs examined, a slight delay in development can be observed in the GSNO treatment embryos. The study could not conclude, however, if this was due to effects of NO donors

  • 19.
    Elander, Louise
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Prostaglandin E2 in Brain-mediated Illness Responses2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    We are unceasingly exposed to potentially harmful microorganisms. The battle against threatening infectious agents includes activation of both the innate and of the adaptive immune systems. Illness responses are elicited and include inflammation, fever, decreased appetite, lethargy and increased sensitivity to painful stimuli in order to defeat invaders. While many of these signs of disease are controlled by the central nervous system, it has remained an enigma how signals from the peripheral immune system reach the brain through its blood-brain barrier, which precludes macromolecules, including cytokines, from diffusing into the brain parenchyma.

    Previous findings indicate the existence of a pathway across the blood-brain barrier, which includes binding of the cytokine interleukin-1 (IL-1) to its receptor in the brain vessels, thereby inducing the production of the prostaglandin E2 (PGE2) synthesizing enzymes cyclooxygenase-2 (Cox-2) and microsomal prostaglandin E synthase-1 (mPGES-1), which ultimately synthesize PGE2. PGE2 subsequently binds to any of the four prostaglandin E2 (EP) -receptors. Previous results from our laboratory have suggested that this pathway plays a critical role in the febrile response to infectious stimuli. The present thesis aims at further investigating the molecular events underlying immune-to-brain signalling, with special emphasis on fever, hypothalamic-pituitary-adrenal (HPA) -axis activation and anorexia and their connection to signalling molecules of the cytokine and prostaglandin families, respectively.

    In paper I, the molecular processes linking the proinflammatory cytokine interleukin-6 (IL-6) and PGE2 in the febrile response were investigated. Both IL-6 and PGE2 have been shown to be critical players in the febrile response, although the molecular connections are not known, i.e. if IL-6 exerts its effects up- or downstream of PGE2. Mice deficient in IL-6 were unable to respond to bacterial lipopolysaccharide (LPS) with a febrile response, but displayed similar induction of Cox-2 and mPGES-1, and similar concentrations of PGE2 in the cerebrospinal fluid as wild-type mice. Paradoxically, the IL-6 deficient mice responded with a dose-dependent elevation of body temperature in response to intracerebroventricularly injected PGE2. Furthermore, IL-6 per se was not pyrogenic when injected peripherally in mice, and did not cause increased levels of PGE2 in cerebrospinal fluid. IL-6 deficient mice were not refractory to the action of PGE2 because of excess production of some hypothermia-producing factor, since administration of a Cox-2 inhibitor in LPS-challenged IL-6 deficient mice did not unmask any hypothermic response, and neutralization of tumor necrosis factor α (TNFα), associated with hypothermia, did not produce fever in LPS-challenged IL-6 deficient mice. These data indicate that IL-6 rather than exerting its effects up- or down-stream of PGE2 affects some process in parallel to PGE2, perhaps by influencing the diffusion and binding of PGE2 onto its target neurons.

    In papers II and III, we injected the proinflammatory cytokine IL-1β in free-fed wild-type mice, in mice with a deletion of the gene encoding mPGES-1, or in mice deficient in the EP1, EP2 and EP3. Food intake was continuously measured during their active period, revealing that mPGES-1 deficient mice were almost completely resistant to anorexia induced by IL-1β. However, all of the investigated EP receptor deficient mice exhibited a normal profound anorexic response to IL-1β challenge, suggesting that the EP4 is the critical receptor that mediates IL-1β-induced anorexia. We also investigated the role of mPGES-1 in anorexia induced by lipopolysaccharide (LPS) in mPGES-1 deficient mice. The profound anorexic response after LPS-challenge was similar in mPGES-1 deficient and wild-type mice. To further investigate the anorectic behaviour after LPS injection, we pre-starved the animals for 22 hours before injecting them with LPS. In this paradigm, the anorexia was less profound in mPGES-1 knock-out mice. Our results suggest that while the inflammatory anorexia elicited by peripheral IL-1β seems largely to be dependent on mPGES-1-mediated PGE2 synthesis, similar to the febrile response, the LPS-induced anorexia is independent of this mechanism in free-fed mice but not in pre-starved animals.

    In papers IV and V, the role of prostanoids for the immune-induced HPA-axis response was investigated in mice after genetic deletion or pharmacological inhibition of prostanoid-synthesizing enzymes, including Cox-1, Cox-2, and mPGES-1. The immediate LPS-induced release of ACTH (adrenocorticotropic hormone and corticosteroids was critically dependent on Cox-1 derived prostanoids and occurred independently of Cox-2 and mPGES-1 derived PGE2. In contrast, the delayed HPA-axis response was critically dependent on immune-induced PGE2, synthesized by Cox-2 and mPGES-1, and occurred independently of Cox-1 derived enzymes. In addition, in the mPGES-1 deficient mice, the synthesis of CRH hnRNA and mRNA was decreased in the paraventricular nucleus of the hypothalamus after LPS-challenge, indicating that the delayed hormone secretion was mediated by PGE2-induced gene-transcription of CRH in the hypothalamus. The expression of the c-fos gene and Fos protein, an index of synaptic activation, was maintained in the paraventricular nucleus and its brainstem afferents both after unselective and Cox-2 selective inhibition as well as in Cox-1, Cox-2, and mPGES-1 knock-out mice. This suggests that the immune-induced neuronal activation of autonomic relay nuclei occurs independently of prostanoid synthesis and that it is insufficient for eliciting stress hormone release.

    List of papers
    1. The Role of Interleukin-6 in Lipopolysaccharide-Induced Fever by Mechanisms Independent of Prostaglandin E-2
    Open this publication in new window or tab >>The Role of Interleukin-6 in Lipopolysaccharide-Induced Fever by Mechanisms Independent of Prostaglandin E-2
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    2009 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 150, no 4, p. 1850-1860Article in journal (Refereed) Published
    Abstract [en]

    Fever has been shown to be elicited by prostaglandin E-2 (PGE(2)) binding to its receptors on thermoregulatory neurons in the anterior hypothalamus. The signals that trigger PGE(2) production are thought to include proinflammatory cytokines, such as IL-6. However, although the presence of IL-6 is critical for fever, IL- 6 by itself is not or only weakly pyrogenic. Here we examined the relationship between IL-6 and PGE(2) in lipopolysaccharide (LPS)-induced fever. Immune-challenged IL- 6 knockout mice did not produce fever, in contrast to wild-type mice, but the expression of the inducible PGE(2)-synthesizing enzymes, cyclooxygenase-2 and microsomal prostaglandin E synthase-1, was similarly up-regulated in the hypothalamus of both genotypes, which also displayed similarly elevated PGE(2) levels in the cerebrospinal fluid. Nevertheless, both wild-type and knockout mice displayed a febrile response to graded concentrations of PGE(2) injected into the lateral ventricle. There was no major genotype difference in the expression of IL-1 beta and TNF alpha or their receptors, and pretreatment of IL- 6 knockout mice with soluble TNF alpha receptor ip or intracerebroventricularly or a cyclooxygenase-2 inhibitor ip did not abolish the LPS unresponsiveness. Hence, although IL- 6 knockout mice have both an intact PGE(2) synthesis and an intact fever-generating pathway downstream of PGE(2), endogenously produced PGE(2) is not sufficient to produce fever in the absence of IL-6. The findings suggest that IL- 6 controls some factor(s) in the inflammatory cascade, which render(s) IL- 6 knockout mice refractory to the pyrogenic action of PGE(2), or that it is involved in the mechanisms that govern release of synthesized PGE(2) onto its target neurons.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17620 (URN)10.1210/en.2008-0806 (DOI)
    Available from: 2009-04-07 Created: 2009-04-06 Last updated: 2017-12-13
    2. IL-1β and LPS induce anorexia by distinct mechanisms differentially dependent on microsomal prostaglandin E synthase-1
    Open this publication in new window or tab >>IL-1β and LPS induce anorexia by distinct mechanisms differentially dependent on microsomal prostaglandin E synthase-1
    2007 (English)In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 292, no 1, p. R258-R267Article in journal (Refereed) Published
    Abstract [en]

    Recent work demonstrated that the febrile response to peripheral immune stimulation with proinflammatory cytokine IL-1β or bacterial wall lipopolysaccharide (LPS) is mediated by induced synthesis of prostaglandin E2 by the terminal enzyme microsomal prostaglandin E synthase-1 (mPGES-1). The present study examined whether a similar mechanism might also mediate the anorexia induced by these inflammatory agents. Transgenic mice with a deletion of the Ptges gene, which encodes mPGES-1, and wild-type controls were injected intraperitoneally with IL-1β, LPS, or saline. Mice were free fed, and food intake was continuously monitored with an automated system for 12 h. Body weight was recorded every 24 h for 4 days. The IL-1β induced anorexia in wild-type but not knock-out mice, and so it was almost completely dependent on mPGES-1. In contrast, LPS induced anorexia of the same magnitude in both phenotypes, and hence it was independent of mPGES-1. However, when the mice were prestarved for 22 h, LPS induced anorexia and concomitant body weight loss in the knock-out animals that was attenuated compared with the wildtype controls. These data suggest that IL-1β and LPS induce anorexia by distinct immune-to-brain signaling pathways and that the anorexia induced by LPS is mediated by a mechanism different from the fever induced by LPS. However, nutritional state and/or motivational factors also seem to influence the pathways for immune signaling to the brain. Furthermore, both IL-1β and LPS caused reduced meal size but not meal frequency, suggesting that both agents exerted an anhedonic effect during these experimental conditions. Copyright © 2007 the American Physiological Society.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-40485 (URN)10.1152/ajpregu.00511.2006 (DOI)53365 (Local ID)53365 (Archive number)53365 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
    3. Prostaglandin E2 receptors in IL-1β induced anorexia
    Open this publication in new window or tab >>Prostaglandin E2 receptors in IL-1β induced anorexia
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Anorexia in response to immune challenge by Interleukin-1β (IL-1β) has been shown to be dependent on Prostaglandin E2 (PGE2) produced by the inducible enzyme microsomal prostaglandin E synthase-1 (mPGES-1). However, it is not known which of the four known PGE2 receptors EP1-4, encoded by the genes Ptger 1-4, that mediates the PGE2-induced anorexia. Here we examined food intake in mice deficient in EP1, EP2 and EP3, respectively, during normal conditions and following treatment with IL-1β. Neither of the gene deletions affected baseline food intake, and all the three genotypes displayed anorexia following IL-1β injection, similar to wild type mice. Previous work has demonstrated that the EP3 receptor is critical for the generation of fever, and that EP1 and EP3 receptors mediate inflammationinduced activation of the hypothalamic-pituitary-adrenal (HPA) axis. The present data, showing intact anorexigenic responses in EP1 and EP3 deficient mice, as well as in mice with deletion of the EP2 receptor, hence suggest that PGE2-elicited acute phase responses are mediated by distinct set or sets of PGE2-receptors.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-53910 (URN)
    Available from: 2010-02-11 Created: 2010-02-11 Last updated: 2010-02-11Bibliographically approved
    4. Inducible Prostaglandin E-2 Synthesis Interacts in a Temporally Supplementary Sequence with Constitutive Prostaglandin-Synthesizing Enzymes in Creating the Hypothalamic-Pituitary-Adrenal Axis Response to Immune Challenge
    Open this publication in new window or tab >>Inducible Prostaglandin E-2 Synthesis Interacts in a Temporally Supplementary Sequence with Constitutive Prostaglandin-Synthesizing Enzymes in Creating the Hypothalamic-Pituitary-Adrenal Axis Response to Immune Challenge
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    2009 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 29, no 5, p. 1404-1413Article in journal (Refereed) Published
    Abstract [en]

    Inflammation-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis has been suggested to depend on prostaglandins, but the prostaglandin species and the prostaglandin-synthesizing enzymes that are responsible have not been fully identified. Here, we examined HPA axis activation in mice after genetic deletion or pharmacological inhibition of prostaglandin E-2-synthesizing enzymes, including cyclooxygenase-1 (Cox-1), Cox-2, and microsomal prostaglandin E synthase-1 (mPGES-1). After immune challenge by intraperitoneal injection of lipopolysaccharide, the rapid stress hormone responses were intact after Cox-2 inhibition and unaffected by mPGES-1 deletion, whereas unselective Cox inhibition blunted these responses, implying the involvement of Cox-1. However, mPGES-1-deficient mice showed attenuated transcriptional activation of corticotropin-releasing hormone (CRH) that was followed by attenuated plasma concentrations of adrenocorticotropic hormone and corticosterone. Cox-2 inhibition similarly blunted the delayed corticosterone response and further attenuated corticosterone release in mPGES-1 knock-out mice. The expression of the c-fos gene, an index of synaptic activation, was maintained in the paraventricular hypothalamic nucleus and its brainstem afferents both after unselective and Cox-2 selective inhibition as well as in Cox-1, Cox-2, and mPGES-1 knock-out mice. These findings point to a mechanism by which ( 1) neuronal afferent signaling via brainstem autonomic relay nuclei and downstream Cox-1-dependent prostaglandin release and ( 2) humoral, CRH transcription-dependent signaling through induced Cox-2 and mPGES-1 elicited PGE(2) synthesis, shown to occur in brain vascular cells, play distinct, but temporally supplementary roles for the stress hormone response to inflammation.

    Keywords
    CRH, ACTH, corticosterone, mPGES-1, LPS, Fos
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-16849 (URN)10.1523/JNEUROSCI.5247-08.2009 (DOI)
    Available from: 2009-02-21 Created: 2009-02-20 Last updated: 2017-12-13
    5. Cyclooxygenase-1 mediates the immediate corticosterone response to peripheral immune challenge induced by lipopolysaccharide
    Open this publication in new window or tab >>Cyclooxygenase-1 mediates the immediate corticosterone response to peripheral immune challenge induced by lipopolysaccharide
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    2010 (English)In: Neuroscience letters, ISSN 1872-7972, Vol. 470, no 1, p. 10-2Article in journal (Refereed) Published
    Abstract [en]

    Immune-induced activation of the hypothalamus-pituitary-adrenal axis is mediated by cyclooxygenase derived prostaglandins. Here we examined the role of cyclooxygenase-1 in this response, by using genetically modified mice as well as pharmacological inhibition. We found that mice with a deletion of the gene encoding cyclooxygenase-1, in contrast to wild type mice, did not show increased plasma corticosterone at 1h after immune challenge by peripheral injection of bacterial wall lipopolysaccharide, whereas the corticosterone levels were similarly elevated in both genotypes at 6h post-injection. Pretreatment of mice with the selective cyclooxygenase-1 inhibitor SC-560, given orally, likewise inhibited the rapid corticosterone response. These findings, taken together with our recent demonstration that the delayed stress hormone response to immune challenge is dependent on cyclooxygenase-2, show that the two cyclooxygenase isoforms play distinct, but temporally supplementary roles for the stress hormone response to inflammation.

    Keywords
    Corticosterone; Hypothalamus–pituitary–adrenal axis; Mouse; Cyclooxygenase; Lipopolysaccharide
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-53911 (URN)10.1016/j.neulet.2009.12.036 (DOI)000274947500003 ()20034541 (PubMedID)
    Available from: 2010-02-11 Created: 2010-02-11 Last updated: 2010-03-12
  • 20.
    Ericsson, Elin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Tesselaar, Erik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Sjöberg, Folke
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Effect of Electrode Belt and Body Positions on Regional Pulmonary Ventilation- and Perfusion-Related Impedance Changes Measured by Electric Impedance Tomography2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 6, p. e0155913-Article in journal (Refereed)
    Abstract [en]

    Ventilator-induced or ventilator-associated lung injury (VILI/VALI) is common and there is an increasing demand for a tool that can optimize ventilator settings. Electrical impedance tomography (EIT) can detect changes in impedance caused by pulmonary ventilation and perfusion, but the effect of changes in the position of the body and in the placing of the electrode belt on the impedance signal have not to our knowledge been thoroughly evaluated. We therefore studied ventilation-related and perfusion-related changes in impedance during spontaneous breathing in 10 healthy subjects in five different body positions and with the electrode belt placed at three different thoracic positions using a 32-electrode EIT system. We found differences between regions of interest that could be attributed to changes in the position of the body, and differences in impedance amplitudes when the position of the electrode belt was changed. Ventilation-related changes in impedance could therefore be related to changes in the position of both the body and the electrode belt. Perfusion-related changes in impedance were probably related to the interference of major vessels. While these findings give us some insight into the sources of variation in impedance signals as a result of changes in the positions of both the body and the electrode belt, further studies on the origin of the perfusion-related impedance signal are needed to improve EIT further as a tool for the monitoring of pulmonary ventilation and perfusion.

  • 21.
    Farnebo, Simon
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Plastic Surgery, Hand Surgery and Burns. Linköping University, Faculty of Health Sciences.
    Zettersten, Erik
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Samuelsson, Anders
    Linköping University, Department of Medical and Health Sciences, Anesthesiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Intensive Care UHL. Östergötlands Läns Landsting, Sinnescentrum, Department of Anaesthesiology and Surgery UHL.
    Sjöberg, Folke
    Linköping University, Department of Clinical and Experimental Medicine, Burn Center. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Plastic Surgery, Hand surgery UHL. Östergötlands Läns Landsting, Sinnescentrum, Department of Anaesthesiology and Surgery UHL.
    Assessment of blood flow changes in human skin by microdialysis urea clearance2011In: Microcirculation, ISSN 1073-9688, E-ISSN 1549-8719, Vol. 18, no 3, p. 198-204Article, review/survey (Refereed)
    Abstract [en]

    Objective: The aim of this study was to evaluate the urea clearance technique for the measurement of drug-induced blood flow changes in human skin, and compare it with two non-invasive techniques: polarization light spectroscopy and laser Doppler perfusion imaging.

    Methods: Fifteen microdialysis catheters were placed intracutaneously on the volar aspect of the forearms of healthy human subjects, and were perfused with nitroglycerine, noradrenaline, and again nitroglycerine, to induce local tissue hyperaemia, hypoperfusion, and hyperaemia, respectively.

    Results: Urea clearance, but not the other techniques, detected the changes in blood flow during all three periods of altered flow.  The last hyperaemic response was detected by all three methods.

    Conclusion: Urea clearance can be used as a relatively simple method to estimate blood flow changes during microdialysis of vasoactive substances, in particular when the tissue is preconditioned in order to enhance the contrast between baseline and the responses to the provocations. Our results support that, in the model described, urea clearance was superior to the optical methods as it detected both the increases and decrease in blood flow, and the returns to baseline between these periods.

  • 22.
    Folmli, Brookes
    et al.
    Faculty of Health Science and Medicine, Bond University, Gold Coast, Queensland, Australia.
    Turman, Bulent
    Faculty of Health Science and Medicine, Bond University, Gold Coast, Queensland, Australia.
    Johnson, Peter
    Faculty of Health Science and Medicine, Bond University, Gold Coast, Queensland, Australia.
    Abbott, Allan
    Linköping University, Department of Medical and Health Sciences, Division of Physiotherapy. Linköping University, Faculty of Medicine and Health Sciences. Faculty of Health Science and Medicine, Bond University, Gold Coast, Queensland, Australia.
    Dose-response of somatosensory cortex repeated anodal transcranial direct current stimulation on vibrotactile detection: A randomized sham controlled trial2018In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598Article in journal (Refereed)
    Abstract [en]

    This randomized sham-controlled trial investigated anodal transcranial direct current stimulation (tDCS) over the somatosensory cortex contralateral to hand dominance for dose-response (1mA-20 minutes x 5 days) effects on vibrotactile detection thresholds (VDT). VDT was measured before and after tDCS on days 1,3&5 for low (30hz) and high (200hz) frequency vibrations on the dominant and non-dominant hands in 29 healthy adults (mean age = 22.86; 15 males, 14 females). Only the dominant hand 200Hz VDT displayed statistically significant medium effect size improvement for mixed model analysis of variance time x group interaction for active tDCS compared to sham. Post Hoc contrasts were statistically significant for dominant hand 200Hz VDT on day 5 after tDCS compared to day 1 before tDCS , day 1 after tDCS and day 3 before tDCS. There was a linear dose-response improvement with dominant hand 200Hz VDT mean difference decreasing from day 1 before tDCS peaking at -15.5% (SD=34.9%) on day 5 after tDCS. Both groups showed learning effect trends over time for all VDT test conditions but only the non-dominant hand 30Hz VDT was statistically significant (p=0.03) though Post Hoc contrasts were non-significant after Sidak adjustment. No adverse effects for tDCS were reported. In conclusion, anodal tDCS 1mA-20 minutes x 5 days on the dominant sensory cortex can modulate a linear improvement of dominant hand high frequency VDT but not for low frequency or non-dominant hand VDT.

    The full text will be freely available from 2019-05-05 13:17
  • 23.
    Franzén, Stephanie
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    The role of hypoxia for the development of diabetic nephropathy: Temporal relationship and involvement of endothelin receptor signaling2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Diabetic nephropathy is one of the most common causes of end stage renal disease and develops in approximately one third of all diabetes patients. Disease progression is characterized by deteriorating glomerular filtration rate and escalating urinary albumin/protein excretion; both are used as clinical markers for disease progression. Recently, it has been proposed that intrarenal hypoxia is a unifying mechanism for chronic kidney disease, including diabetic nephropathy. Several mechanistic pathways have been linked to the development of intrarenal hypoxia and diabetic nephropathy including increased angiotensin II signaling, oxidative stress and hyperglycemia per se. Furthermore, pathological endothelin signaling has recently immerged as a possible contributing factor for chronic kidney disease and diabetic nephropathy. The overall aims of this thesis were therefore to determine the temporal relationship between development of intrarenal hypoxia and kidney disease as well as elucidate the potential link between endothelin signaling, intrarenal hypoxia and kidney disease in experimental insulinopenic diabetes.

    It is well established that different mouse strains have different susceptibility for kidney and cardiovascular disease. The first step was therefore to compare four commonly used mouse strains with regards to development of kidney disease after onset of insulinopenic diabetes. From the results of this study, we concluded that the NMRI mouse strain has a disease progression closest to the human disease and this strain was chosen in the subsequent studies in mice.

    The next step was to adapt and optimize a suitable method for repetitive measurements of intrarenal oxygen tension during the course of disease development. Electron paramagnetic resonance (EPR) oximetry had previously been used in tumor biology and was now adapted and optimized for measurements of kidney oxygenation in our diabetic mouse model. EPR oximetry in normoglycemic control mice recorded cortical oxygen tension values similar to previous reports using invasive techniques. Surprisingly, intrarenal hypoxia developed already within the first 72h after induction of hyperglycemia and persisted throughout the two-week study period. Importantly, this was well before albuminuria developed.

    The final part of this thesis was to investigate the role of endothelin signaling for the intrarenal hypoxia in a diabetic rat model. Endothelin 1 signals via two distinctly different receptor-mediated pathways. In normal physiology, endothelin 1 binding to endothelin receptor type A (ETA) induces vasoconstriction, which can be blocked by the specific ETA antagonist BQ123, whereas endothelin 1 binding to endothelin receptor type B (ETB) induces nitric oxide-dependent vasodilation. ETB receptors can be selectively activated by Sarafotoxin 6c. The results from blocking ETA and activating ETB receptors demonstrated that endothelin 1 signaling via ETA receptors contributes to intrarenal hypoxia in the rat diabetic kidney, and that ETB stimulation significantly reduces the diabetes-induced intrarenal hypoxia. The beneficial effects on kidney oxygen availability in diabetes by ETA blockade or ETB stimulation were mainly linked to hemodynamic improvements rather than direct effects on kidney oxygen consumption or oxidative stress status.

    In conclusion, by applying EPR oximetry in a mouse model of insulinopenic diabetes mimicking the human disease, we demonstrated intrarenal hypoxia already within the first couple of days after the onset of hyperglycemia, which is well before detectable signs of kidney disease development. Furthermore, blockade of ETA or activation of ETB receptors significantly reduced intrarenal hypoxia in the diabetic kidney. These results demonstrate involvement of ETA receptor signaling in diabetes-induced intrarenal hypoxia and ETA blockade or ETB activation might provide new therapeutical targets to reduce kidney hypoxia and disease progression in diabetes.

    List of papers
    1. Differences in susceptibility to develop parameters of diabetic nephropathy in four mouse strains with type 1 diabetes
    Open this publication in new window or tab >>Differences in susceptibility to develop parameters of diabetic nephropathy in four mouse strains with type 1 diabetes
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    2014 (English)In: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, ISSN 1931-857X, Vol. 306, no 10, p. F1171-F1178Article in journal (Refereed) Published
    Abstract [en]

    One-third of diabetes mellitus patients develop diabetic nephropathy, and with underlying mechanisms unknown it is imperative that diabetic animal models resemble human disease. The present study investigated the susceptibility to develop diabetic nephropathy in four commonly used and commercially available mouse strains with type 1 diabetes to determine the suitability of each strain. Type 1 diabetes was induced in C57Bl/6, NMRI, BALB/c, and 129Sv mice by alloxan, and conscious glomerular filtration rate, proteinuria, and oxidative stress levels were measured in control and diabetic animals at baseline and after 5 and 10 wk. Histological alterations were analyzed using periodic acid-Schiff staining. Diabetic C57Bl/6 displayed increased glomerular filtration rate, i.e., hyperfiltration, whereas all other parameters remained unchanged. Diabetic NMRI developed the most pronounced hyperfiltration as well as increased oxidative stress and proteinuria but without glomerular damage. Diabetic BALB/c did not develop hyperfiltration but presented with pronounced proteinuria, increased oxidative stress, and glomerular damage. Diabetic 129Sv displayed proteinuria and increased oxidative stress without glomerular hyperfiltration or damage. However, all strains displayed intras-train correlation between oxidative stress and proteinuria. In conclusion, diabetic C57Bl/6 and NMRI both developed glomerular hyperfiltration but neither presented with histological damage, although NMRI developed low-degree proteinuria. Thus these strains may be suitable when investigating the mechanism causing hyperfiltration. Neither BALB/c nor 129Sv developed hyperfiltration although both developed pronounced proteinuria. However, only BALB/c developed detectable histological damage. Thus BALB/c may be suitable when studying the roles of proteinuria and histological alterations for the progression of diabetic nephropathy.

    Place, publisher, year, edition, pages
    American Physiological Society, 2014
    Keywords
    C57Bl/6; NMRI; BALB/c; 129Sv; diabetic nephropathy; kidney function
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-108808 (URN)10.1152/ajprenal.00595.2013 (DOI)000336846400007 ()
    Available from: 2014-07-07 Created: 2014-07-06 Last updated: 2016-03-09
    2. Repetitive Measurements of Intrarenal Oxygenation In Vivo Using L Band Electron Paramagnetic Resonance
    Open this publication in new window or tab >>Repetitive Measurements of Intrarenal Oxygenation In Vivo Using L Band Electron Paramagnetic Resonance
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    2014 (English)In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 812, p. 135-141Article in journal (Refereed) Published
    Abstract [en]

    Intrarenal oxygenation is heterogeneous with oxygen levels normally being highest in the superficial cortex and lowest in the inner medulla. Reduced intrarenal oxygenation has been implied in the pathology of several kidney diseases. However, there is currently no method available to repetitively monitor regional renal oxygenation using minimally invasive procedures. We therefore evaluated implantable lithium phthalocyanine (LiPc) probes, which display a close correlation between EPR line width and oxygen availability. LiPc probes were implanted in the kidney cortex and medulla in the same mouse and sEPR spectra were acquired using a L band scanner during inhalation of air (21 % oxygen) or a mixture of air and nitrogen (10 % oxygen). In order to separate the signals from the two probes, a 1 G/cm gradient was applied and the signals were derived from 40 consecutive sweeps. Peak-to-peak comparison of the EPR line was used to convert the signal to an approximate oxygen tension in MATLAB. Kidney cortex as well as medullary oxygenation was stable over the 45 day period (cortex 56 +/- 7 mmHg and medulla 43 +/- 6 mmHg). However, 10 % oxygen inhalation significantly reduced oxygenation in both cortex (56 +/- 6 to 34 +/- 2 mmHg n = 15 p less than 0.05) and medulla (42 +/- 5 to 29 +/- 3 mmHg n = 7 p less than 0.05). In conclusion, L band EPR using LiPc probes implanted in discrete intrarenal structures can be used to repetitively monitor regional renal oxygenation. This minimally invasive method is especially well suited for conditions of reduced intrarenal oxygenation since this increases the signal intensity which facilitates the quantification of the EPR signal to absolute oxygenation values.

    Place, publisher, year, edition, pages
    Kluwer Academic Publishers, 2014
    Keywords
    Kidney; LiPc; L-Band EPR; NMRI mice; Oxygenation
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-113035 (URN)10.1007/978-1-4939-0620-8_18 (DOI)000345121200019 ()24729225 (PubMedID)978-1-4939-0620-8; 978-1-4939-0583-6 (ISBN)
    Conference
    41st Annual Meeting of the International-Society-on-Oxygen-Transport-to-Tissue (ISOTT)
    Available from: 2015-01-09 Created: 2015-01-08 Last updated: 2017-12-05
    3. Pronounced kidney hypoxia precedes albuminuria in type 1 diabetic mice
    Open this publication in new window or tab >>Pronounced kidney hypoxia precedes albuminuria in type 1 diabetic mice
    Show others...
    2016 (English)In: American Journal of Physiology, ISSN 0002-9513, E-ISSN 2163-5773, Vol. 310, no 9, p. F807-F809Article in journal (Refereed) Published
    Abstract [en]

    Intrarenal tissue hypoxia has been proposed as a unifying mechanism for the development of chronic kidney disease, including diabetic nephropathy. However, hypoxia has to be present before the onset of kidney disease in order to be the causal mechanism. In order to establish if hypoxia precedes the onset of diabetic nephropathy, we implemented a minimally invasive electron paramagnetic resonance oximetry technique using implanted oxygen sensing probes for repetitive measurements of in vivo kidney tissue oxygen tensions in mice. Kidney cortex oxygen tensions were measured before and up to 15 days after the induction of insulinopenic diabetes in male mice and compared to normoglycemic controls. On day 16, urinary albumin excretions and conscious glomerular filtration rates were determined in order to define the temporal relationship between intrarenal hypoxia and disease development. Diabetic mice developed pronounced intrarenal hypoxia three days after the induction of diabetes, which persisted throughout the study period. On day 16, diabetic mice had glomerular hyperfiltration, but normal urinary albumin excretion. In conclusion, intrarenal tissue hypoxia in diabetes precedes albuminuria thereby being a plausible cause for the onset and progression of diabetic nephropathy.

    Place, publisher, year, edition, pages
    American Physiological Society Journals, 2016
    Keywords
    nephropathy, diabetes, hypoxia, EPR
    National Category
    Physiology
    Identifiers
    urn:nbn:se:liu:diva-125526 (URN)10.1152/ajprenal.00049.2016 (DOI)000375115700001 ()
    Note

    The status of this article was previous Manuscript.

    Funding agencies: Swedish Research Council; Swedish Heart Lung Foundation; Swedish Diabetes Foundation

    Available from: 2016-02-26 Created: 2016-02-25 Last updated: 2018-01-10Bibliographically approved
    4. Endothelin type A receptor inhibition normalises intrarenal hypoxia in rats used as a model of type 1 diabetes by improving oxygen delivery
    Open this publication in new window or tab >>Endothelin type A receptor inhibition normalises intrarenal hypoxia in rats used as a model of type 1 diabetes by improving oxygen delivery
    2015 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no 10, p. 2435-2442Article in journal (Refereed) Published
    Abstract [en]

    Aims/hypothesis Intrarenal tissue hypoxia, secondary to increased oxygen consumption, has been suggested as a unifying mechanism for the development of diabetic nephropathy. Increased endothelin-1 signalling via the endothelin type A receptor (ETA-R) has been shown to contribute to the development of chronic kidney disease, but its role in kidney oxygen homeostasis is presently unknown. Methods The effects of acute ETA-R inhibition (8 nmol/l BQ-123 for 30-40 min directly into the left renal artery) on kidney function and oxygen metabolism were investigated in normoglycaemic control and insulinopenic male Sprague Dawley rats (55 mg/kg streptozotocin intravenously 2 weeks before the main experiment) used as a model of type 1 diabetes. Results Local inhibition of ETA-R in the left kidney did not affect BP in either the control or the diabetic rats. As previously reported, diabetic rats displayed increased kidney oxygen consumption resulting in tissue hypoxia in both the kidney cortex and medulla. The inhibition of ETA-Rs restored normal kidney tissue oxygen availability in the diabetic kidney by increasing renal blood flow, but did not affect oxygen consumption. Furthermore, ETA-R inhibition reduced the diabetes-induced glomerular hyperfiltration and increased the urinary sodium excretion. Kidney function in normoglycaemic control rats was largely unaffected by BQ-123 treatment, although it also increased renal blood flow and urinary sodium excretion in these animals. Conclusions/interpretation Acutely reduced intrarenal ETA-R signalling results in significantly improved oxygen availability in the diabetic kidney secondary to elevated renal perfusion. Thus, the beneficial effects of ETA-R inhibition on kidney function in diabetes may be due to improved intrarenal oxygen homeostasis.

    Place, publisher, year, edition, pages
    SPRINGER, 2015
    Keywords
    BQ-123; Diabetic nephropathy; Endothelin type; A receptor; Hypoxia; Kidney function; Rats
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-122101 (URN)10.1007/s00125-015-3690-9 (DOI)000361538600027 ()26173672 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council; Swedish Diabetes Foundation; Family Ernfors Fund

    Available from: 2015-10-19 Created: 2015-10-19 Last updated: 2017-12-01
    5. Intrarenal activation of endothelin type B receptors improve intrarenal oxygenation in type 1 diabetic rats
    Open this publication in new window or tab >>Intrarenal activation of endothelin type B receptors improve intrarenal oxygenation in type 1 diabetic rats
    (English)Manuscript (preprint) (Other academic)
    Keywords
    nephropathy, diabetes, hypoxia, endothelin, sarafotoxin 6c
    National Category
    Physiology
    Identifiers
    urn:nbn:se:liu:diva-125525 (URN)
    Note

    About one third of patients with type 1 diabetes develop kidney damage. The mechanism is largely unknown, but intrarenal hypoxia has been proposed as a unifying mechanism for chronic kidney disease including diabetic nephropathy. The endothelin system has recently been demonstrated to regulate oxygen availability in the diabetic kidney via a pathway involving endothelin type A receptors (ETA-R). These receptors mainly mediate vasoconstriction and tubular sodium retention, and inhibition of ETA-R improves intrarenal oxygenation in the diabetic kidney. Endothelin type B receptors (ETB-R) have been reported to have opposite effects on vascular tone and tubular sodium handling. However, the role of ETB-R in kidney oxygen homeostasis is unknown.

    The effects of acute intrarenal ETB-R activation (Sarafotoxin 6c for 30-40 minutes; 0.78 pmol h-1 directly into the renal artery) on kidney function and oxygen metabolism were investigated in normoglycemic control and insulinopenic male Sprague Dawley rats administered streptozotocin (55 mg kg-1) two weeks before the acute experiments.

    Intrarenal activation of ETB-R improved oxygenation of the hypoxia diabetic kidney. However, neither effects on the diabetes-induced increased kidney oxygen consumption nor alterations in parameters related to tubular sodium transport could explain the improved oxygenation in the diabetic kidney after ETB-R activation. Rather, the improved kidney oxygenation was due to hemodynamic effects increasing oxygen delivery.

    In conclusion, increased ETB-R signaling in the diabetic kidney improves tissue oxygenation due to increased oxygen delivery as a result of increased total renal blood flow.

    Available from: 2016-02-25 Created: 2016-02-25 Last updated: 2018-01-10
  • 24.
    Franzén, Stephanie
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Fasching, Angelica
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Intrarenal activation of endothelin type B receptors improve intrarenal oxygenation in type 1 diabetic ratsManuscript (preprint) (Other academic)
  • 25.
    Franzén, Stephanie
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Pihl, Liselotte
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Khan, Nadeem
    Gustafsson, Håkan
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Norrköping/Finspång. Linköping University, Faculty of Medicine and Health Sciences.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Pronounced kidney hypoxia precedes albuminuria in type 1 diabetic mice2016In: American Journal of Physiology, ISSN 0002-9513, E-ISSN 2163-5773, Vol. 310, no 9, p. F807-F809Article in journal (Refereed)
    Abstract [en]

    Intrarenal tissue hypoxia has been proposed as a unifying mechanism for the development of chronic kidney disease, including diabetic nephropathy. However, hypoxia has to be present before the onset of kidney disease in order to be the causal mechanism. In order to establish if hypoxia precedes the onset of diabetic nephropathy, we implemented a minimally invasive electron paramagnetic resonance oximetry technique using implanted oxygen sensing probes for repetitive measurements of in vivo kidney tissue oxygen tensions in mice. Kidney cortex oxygen tensions were measured before and up to 15 days after the induction of insulinopenic diabetes in male mice and compared to normoglycemic controls. On day 16, urinary albumin excretions and conscious glomerular filtration rates were determined in order to define the temporal relationship between intrarenal hypoxia and disease development. Diabetic mice developed pronounced intrarenal hypoxia three days after the induction of diabetes, which persisted throughout the study period. On day 16, diabetic mice had glomerular hyperfiltration, but normal urinary albumin excretion. In conclusion, intrarenal tissue hypoxia in diabetes precedes albuminuria thereby being a plausible cause for the onset and progression of diabetic nephropathy.

  • 26.
    Fredly, Siv
    et al.
    Department of Neonatal Intensive Care, Oslo University Hospital, Ullevål, Oslo, Norway / Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
    Fugelseth, Drude
    Department of Neonatal Intensive Care, Oslo University Hospital, Ullevål, Oslo, Norway / Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
    Nygaard, Cathrine S
    Department of Neonatal Intensive Care, Oslo University Hospital, Ullevål, Oslo, Norway.
    Salerud, Göran
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering.
    Stiris, Tom
    Department of Neonatal Intensive Care, Oslo University Hospital, Ullevål, Oslo, Norway / Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
    Kvernebo, Knut
    Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway / Department of Cardiothoracic Surgery, Oslo University Hospital, Ullevål, Oslo, Norway.
    Noninvasive assessments of oxygen delivery from the microcirculation to skin in hypothermia-treated asphyxiated newborn infants2016In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 76, no 6, p. 902-906Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Therapeutic hypothermia (TH) has become standard treatment for severe and moderate hypoxic-ischemic neonatal encephalopathy (HIE). Our group has developed an optically based, noninvasive concept of assessing the capacity for oxygen delivery from the microcirculation to the cells of a tissue under investigation. The hypothesis was that mechanisms of reduced oxygen delivery due to reduced metabolism in cooled asphyxiated neonates could be characterized with this concept.

    METHODS:

    The skin of 28 asphyxiated newborn infants was studied on days 1 and 3 during TH and on day 4 following rewarming with laser Doppler perfusion measurements (LDPM), computer-assisted video microscopy (CAVM), and diffuse reflectance spectroscopy (DRS). Twenty-five healthy neonates served as a control group.

    RESULTS:

    The LDPM decreased during cooling (P < 0.01). Functional capillary density was higher both during and following TH compared with control infants (P < 0.01). Capillary flow velocities were reduced during TH (P < 0.05). The heterogeneity of the flow velocities was larger in the HIE infants than in the control infants. Tissue oxygen extraction was higher during TH (P < 0.01).

    CONCLUSION:

    This study indicates that assessments of skin microvascular density, capillary flow velocity, and oxygen extraction can be used to characterize reduced oxygen delivery to cells during TH

  • 27.
    Fyrenius, Anna
    Linköping University, Department of Medicine and Health Sciences, Clinical Physiology . Linköping University, Faculty of Health Sciences.
    Dynamiskt lärande: En ämnesdidaktisk avhandling om fysiologiska fenomen och läkarstudentens lärande2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    It is well known that the outcome of teaching and learning in higher education is often unsatisfactory. Earlier studies have shown that medical students often have a surface approach to their studies and that misconceptions of fundamental physiological phenomena are common. The aim of this thesis is to support educational practice in medicine, particularly in medical physiology. The thesis can be categorised as subject matter-specific education research, which means that questions about teaching and learning are closely linked to the subject studied. The researcher should be well acquainted with the subject in question. The subject area dealt with in this thesis is physiological phenomena related to cardiovascular pressure-flow relations.

    The thesis consists of studies of 3-dimensional intra cardiac pressure-flow phenomena in the heart (studies 1 and 2) and studies of how students conceive of and develop an understanding of physiological phenomena related to blood pressure and blood pressure regulation (studies 3 and 4).

    Flow in the left atrium as well as inflow-patterns to the left ventricle were studied. The 3-dimensional method elucidates vortical flow phenomena which were previously unknown. The findings could contribute to increasing physicians and technicians understanding of flow phenomena in the diagnosis and assessment of heart disease and to the further development of diagnostic methods. In the studies of learning and understanding of physiological phenomena, the findings point to new aspects of a deep approach to learning, which have to do with the students’ ability to change perspective and adopt a variety of learning strategies to a phenomenon (Moving) versus a tendency to hold on to one explanatory model (Holding). The study also investigates the students’ ability to identify and apply fundamental physiological principles as well as how they conceive of the importance of detailed knowledge for understanding of physiology. The findings point to differences in the students’ conceptions of physiological principles. A problemising approach, which includes not only causally described relations, indicates a more complex conception of physiological phenomena. The study shows aspects of understanding which are seldom assessed in examinations.

    The findings indicate a connection between the students’ approaches to learning and the quality of their understanding of fundamental physiological principles. In the thesis, teaching interventions are proposed in order to stimulate dynamic learning and a learning environment where students are not afraid to challenge their conceptions in order to acquire a rich and nuanced picture of physiological phenomena.

    List of papers
    1. Three-dimensional flow in the human left atrium
    Open this publication in new window or tab >>Three-dimensional flow in the human left atrium
    Show others...
    2001 (English)In: Heart, ISSN 1355-6037, Vol. 86, no 4, p. 448-455Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Abnormal flow patterns in the left atrium in atrial fibrillation or mitral stenosis are associated with an increased risk of thrombosis and systemic embolisation; the characteristics of normal atrial flow that avoid stasis have not been well defined.

    OBJECTIVES: To present a three dimensional particle trace visualisation of normal left atrial flow in vivo, constructed from flow velocities in three dimensional space.

    METHODS: Particle trace visualisation of time resolved three dimensional magnetic resonance imaging velocity measurements was used to provide a display of intracardiac flow without the limitations of angle sensitivity or restriction to imaging planes. Global flow patterns of the left atrium were studied in 11 healthy volunteers.

    RESULTS: In all subjects vortical flow was observed in the atrium during systole and diastolic diastasis (mean (SD) duration of systolic vortex, 280 (77) ms; and of diastolic vortex, 256 (118) ms). The volume incorporated and recirculated within the vortices originated predominantly from the left pulmonary veins. Inflow from the right veins passed along the vortex periphery, constrained between the vortex and the atrial wall.

    CONCLUSIONS: Global left atrial flow in the normal human heart comprises consistent patterns specific to the phase of the cardiac cycle. Separate paths of left and right pulmonary venous inflow and vortex formation may have beneficial effects in avoiding left atrial stasis in the normal subject in sinus rhythm.

    Keywords
    atrium, blood flow, magnetic resonance imaging, haemodynamics
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14554 (URN)10.1136/heart.86.4.448 (DOI)
    Available from: 2007-06-04 Created: 2007-06-04 Last updated: 2016-03-14
    2. Pitfalls in Doppler evaluation of diastolic function: insights from three-dimensional magnetic resonance imaging
    Open this publication in new window or tab >>Pitfalls in Doppler evaluation of diastolic function: insights from three-dimensional magnetic resonance imaging
    Show others...
    1999 (English)In: Journal of the American Society of Echocardiography, ISSN 0894-7317, E-ISSN 1097-6795, Vol. 12, no 10, p. 817-826Article in journal (Refereed) Published
    Abstract [en]

    Ultrasound-Doppler assessment of diastolic function is subject to velocity errors caused by angle sensitivity and a fixed location of the sample volume. We used 3-dimensional phase contrast magnetic resonance imaging (MRI) to evaluate these errors in 10 patients with hypertension and in 10 healthy volunteers. The single (Doppler) and triple (MRI) component velocity was measured at early (E) and late (A) inflow along Doppler-like sample lines or 3-dimensional particle traces generated from the MRI data. Doppler measurements underestimated MRI velocities by 9.4% ± 8.6%; the effect on the E/A ratio was larger and more variable. Measuring early and late diastolic inflows from a single line demonstrated the error caused by their 3-dimensional spatial offset. Both errors were minimized by calculating the E/A ratio from maximal E and A values without constraint to a single line. Alignment and spatial offset are important sources of error in Doppler diastolic parameters. Improved accuracy may be achieved with the use of maximal E and A velocities from wherever they occur in the left ventricle.

    Place, publisher, year, edition, pages
    Amsterdam: Elsevier Science B.V., 1999
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14555 (URN)10.1016/S0894-7317(99)70186-0 (DOI)83255200007 ()10511650 (PubMedID)
    Available from: 2007-06-04 Created: 2007-06-04 Last updated: 2017-12-13
    3. Student approaches to achieving understanding ― Approaches to learning revisited
    Open this publication in new window or tab >>Student approaches to achieving understanding ― Approaches to learning revisited
    2007 (English)In: Studies in Higher Education, ISSN 0307-5079, Vol. 32, no 2, p. 149-165Article in journal (Refereed) Published
    Abstract [en]

    This article presents a phenomenographic study that investigates students' approaches to achieving understanding. The results are based on interviews, addressing physiological phenomena, with 16 medical students in a problem-based curriculum. Four approaches—sifting, building, holding and moving—are outlined. The holding and moving approaches describe variations in deep-level processing. The moving approach is characterised by an intention to continuously refine understanding in an open-ended process. The student strives for a change in perspective and deliberately creates actions that are rich in variation and challenge. The holding approach is characterised by an intention to reach a final goal. This is achieved by high degrees of structure and control in the learning act. Understanding is sometimes sealed, 'held on to' and can be threatened by new input and other students' viewpoints. The study also shows how students deal with details when constructing understanding of wholes.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14556 (URN)10.1080/03075070701267194 (DOI)
    Available from: 2007-06-04 Created: 2007-06-04 Last updated: 2018-02-06
    4. Students' conceptions of underlying principles in medical physiology: An interview study of medical students understanding in a PBL curriculum
    Open this publication in new window or tab >>Students' conceptions of underlying principles in medical physiology: An interview study of medical students understanding in a PBL curriculum
    2007 (English)In: Advances in Physiology Education, ISSN 1043-4046, E-ISSN 1522-1229, Vol. 31, p. 364-369Article in journal (Refereed) Published
    Abstract [en]

    Medical physiology is known to be a complex area where students develop significant errors in conceptual understanding. Students’ knowledge is often bound to situational descriptions rather than underlying principles. This study explores how medical students discern and process underlying principles in physiology. Indepth interviews, where students elaborated on principles related to blood pressure and blood pressure regulation, were carried out with 16 medical students in a problem-based learning curriculum. A qualitative, phenomenographic approach was used, and interviews were audiotaped, transcribed, qualitatively analyzed, and categorized. Four categories were outlined. The underlying principles were conceived as follows: 1) general conditions for body function at a specified time point, 2) transferable phenomena between organ systems and time points, 3) conditionally transferable phenomena between organ systems and time points, and 4) cognitive constructions of limited value in medical physiology. The results offers insights into students’ thinking about underlying principles in physiology and suggest how understanding can be challenged to stimulate deep-level processing of underlying principles rather than situational descriptions of physiology. A complex conception of underlying principles includes an ability to problemize phenomena beyond long causal reasoning chains, which is often rewarded in traditional examinations and tests. Keywords for problemized processing are as follows: comparisons, differences, similarities, conditions, context, relevance, multiple sampling, connections, and dependencies.

    Keywords
    general models, phenomenography, problem-based learning
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14557 (URN)10.1152/advan.00108.2006 (DOI)
    Available from: 2007-06-04 Created: 2007-06-04 Last updated: 2017-12-13
  • 28.
    Gerdle, Björn
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Molander, Peter
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Stenberg, Gunilla
    Department of Community Medicine and Rehabilitation, Physiotherapy, Umeå University, Umeå, Sweden.
    Stålnacke, Britt-Marie
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Enthoven, Paul
    Linköping University, Department of Medical and Health Sciences, Division of Physiotherapy. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care. 5 Department of Community Medicine and Rehabilitation, Rehabilitation Medicine, Umeå University, Umeå, Sweden.
    Weak outcome predictors of multimodal rehabilitation at one-year follow-up in patients with chronic pain-a practice based evidence study from two SQRP centres.2016In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 17, no 1, article id 490Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: For patients with chronic pain, the heterogeneity of clinical presentations makes it difficult to identify patients who would benefit from multimodal rehabilitation programs (MMRP). Yet, there is limited knowledge regarding the predictors of MMRP's outcomes. This study identifies predictors of outcome of MMRPs at a 12-month follow-up (FU-12) based on data from the Swedish Quality Registry for Pain Rehabilitation (SQRP).

    METHODS: Patients with chronic pain from two clinical departments in Sweden completed the SQRP questionnaires-background, pain characteristics, psychological symptoms, function, activity/participation, health and quality of life-on three occasions: 1) during their first visit; 2) immediately after the completion of their MMRP; and 3) 12 months after completing the MMRP (n = 227). During the FU-12, the patients also retrospectively reported their global impressions of any changes in their perception of pain and their ability to handle their life situation in general.

    RESULTS: Significant improvements were found for pain, psychological symptoms, activity/participation, health, and quality of life aspects with low/medium strong effects. A general pattern was observed from the analyses of the changes from baseline to FU-12; the largest improvements in outcomes were significantly associated with poor situations according to their respective baseline scores. Although significant regressors of the investigated outcomes were found, the significant predictors were weak and explained a minor part of the variation in outcomes (15-25%). At the FU-12, 53.6% of the patients reported that their pain had decreased and 80.1% reported that their life situation in general had improved. These improvements were associated with high education, low pain intensity, high health level, and work importance (only pain perception). The explained variations were low (9-11%).

    CONCLUSIONS: Representing patients in real-world clinical settings, this study confirmed systematic reviews that outcomes of MMRP are associated with broad positive effects. A mix of background and baseline variables influenced the outcomes investigated, but the explained variations in outcomes were low. There is still a need to develop standardized and relatively simple outcomes that can be used to evaluate MMRP in trials, in clinical evaluations at group level, and for individual patients.

  • 29.
    Grams, Morgan
    et al.
    John Hopkins University.
    Sang, Yingying
    John Hopkins University.
    Coresh, Josef
    John Hopkins University.
    Ballew, Shoshana
    John Hopkins University.
    Matsushita, Kunihiro
    John Hopkins University.
    Greene, Tom
    University of Utah.
    Levey, Adrew S
    Tufts Medical Center.
    Molnar, Miklos Z
    University of Tennessee Health Science Center.
    Szabó, Zoltán
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Decline in Estimated Glomerular Filtration Rate After Acute Kidney Injury: A Surrogate Endpoint?2015In: ASN (American Society of Nephrology), 2015, Vol. 26Conference paper (Refereed)
    Abstract [en]

    Background: Often a transient condition, acute kidney injury (AKI) is not currently accepted as an endpoint for drug registration trials by the US FDA. We sought to determine whether an intermediate-term change in eGFR after AKI has a sufficiently strong relationship with subsequent ESRD to serve as an alternative endpoint in clinical trials of AKI preventionand/or treatment.

    Methods: We evaluated 161,185 US veterans who underwent major surgery between2004-2011. Post-surgical AKI was defined by the KDIGO creatinine criteria;decline in eGFR was calculated from pre-hospitalization value to two time-points post-discharge (60-days, 90-days) and related to ESRD and mortality using Cox proportional hazards regression.

    Results: In-hospital mortality varied by AKI status, ranging from 1% for patients without AKI to 35% for those with dialysis-requiring AKI. An eGFR decline of ³30% at 60-days was relatively frequent: 2.5%, 9.7%, 17.2%, and 28.6% in those with no AKI, Stage 1 AKI, Stage 2 AKI, and Stage 3 AKI, respectively. There was a graded relationship between eGFR decline at 60-days and risk of ESRD in persons both with and without AKI (Figure). Compared to stable eGFR/no in-hospital AKI, the adjusted hazard ratio (HR) of ESRD associated with a 30% decline at 60-days after AKI was 6.42 (95% CI: 4.8-8.7). Risks for mortality associated with eGFR decline were smaller: the HR for 30% decline 60-days after in-hospital AKI was 1.59 (95% CI: 1.46-1.73). Risk relationships were similar at 90-days.

    Conclusions: A 30% decline in eGFR from pre-hospitalization baseline to 60-days or 90-days after an episode of AKI may be an acceptable surrogate endpoint in trials of AKI prevention and/or treatment.

  • 30.
    Granseth, Björn
    et al.
    MRC Laboratory of Molecular Biology, Cambridge.
    Lagnado, Leon
    MRC Laboratory of Molecular Biology, Cambridge.
    The role of endocytosis in regulating the strength of hippocampal synapses2008In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 586, p. 5969-5982Article in journal (Refereed)
    Abstract [en]

    The readily releasable pool of vesicles (RRP) varies in size during synaptic activity and is replenished by recruitment from the reserve pool as well as vesicle retrieval after fusion. To investigate which of these steps is rate limiting in supplying vesicles to the RRP, we measured the effects of changes in temperature in cultured hippocampal neurons, where higher average rates of release can be maintained as the temperature is increased. Using a pHluorin-based reporter of exocytosis and endocytosis (sypHy), we find that changes in temperature between 25 degrees C and 35 degrees C do not significantly alter the rate of recruitment from the reserve pool. In contrast, the time constant of endocytosis fell from approximately 17 s at 25 degrees C to approximately 10 s at 35 degrees C (Q(10) = 1.7), while the time constant of vesicle reacidification fell from approximately 5.5 s to approximately 1 s (Q(10) = 5.5). A kinetic model of the vesicle cycle constructed using measured parameters was found to describe variations in vesicle release rate observed during long trains of spikes as well as recovery from synaptic depression after bursts of activity. These results indicate that endocytosis operating with time constants of 10-15 s is the rate-limiting process determining replenishment of the RRP during long-term activity. A fast mode of vesicle retrieval could not be detected at any temperature, nor was it necessary to invoke such a mechanism to account for use-dependent changes in synaptic release probability.

  • 31.
    Granseth, Björn
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Odermatt, Benjamin
    Medical Research Council, Cambridge.
    Royle, Stephen J.
    University of Liverpool.
    Lagnado, Leon
    Medical Research Council, Cambridge.
    Comment on "The Dynamic Control of Kiss-and-Run and Vesicular Reuse Probed with Single Nanoparticles": in Science(ISSN 0036-8075) vol 325, issue 5947, pp 14992009In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 323, no 5947, p. 1499-Article in journal (Other academic)
    Abstract [en]

    Zhang et al. (Research Articles, 13 March 2009, p. 1448) reported that synaptic vesicles usually release neurotransmitter through a kiss-and-run mechanism occurring within 1 second but that full collapse of the vesicles becomes more prevalent with repeated stimuli. We report that the kinetics of vesicle retrieval do not change during a stimulus train, with endocytosis occurring in 10 to 15 seconds.

  • 32.
    Grimby-Ekman, Anna
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Health Metrics, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden Occupational and Environmental Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden .
    Ghafouri, Bijar
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Sandén, H
    Occupational and Environmental Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden..
    Larsson, Britt
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Gerdle, Björn
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Different DHEA-S Levels and Response Patterns in Individuals with Chronic Neck Pain, Compared with a Pain Free Group-a Pilot Study.2017In: Pain medicine (Malden, Mass.), ISSN 1526-2375, E-ISSN 1526-4637, Vol. 18, no 5, p. 846-855Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To test, in this pilot study, whether DHEA-S (Dehydroepiandrosterone, sulfated form) plasma levels are lower among persons with chronic neck pain, compared to control persons, and to investigate the DHEA-S response after a physical exercise.

    SUBJECTS: Included were 12 persons with chronic neck pain and eight controls without present pain, all 18 and 65 years of age. Exclusion criteria for both groups were articular diseases or tendinosis, fibromyalgia, systemic inflammatory and neuromuscular diseases, pain conditions due to trauma, or severe psychiatric diseases.

    DESIGN AND METHODS: The participants arm-cycled on an ergometer for 30 minutes. Blood samples were taken before, 60 minutes, and 150 minutes after this standardized physical exercise.

    RESULTS: The estimated plasma DHEA-S levels at baseline were 2.0 µmol/L (95% confidence interval [CI] 1.00; 4.01) in the pain group and 4.1 µmol/L (95% CI2.0; 8.6) in the control group, adjusted for sex, age, body mass index (BMI), and Shirom-Melamed Burnout Questionnaire (SMBQ), with a ratio of 0.48 (P = 0.094).The total DHEA-S (AUCG) in the pain group were 183 min*µmol/L lower than in the control group (P = 0.068). For the response to the exercise (AUCI), the difference between the pain group and the control group was 148 min*µmol/L (P = 0.011).

    CONCLUSIONS: In this pilot study, the plasma DHEA-S levels appeared to be lower among the persons with chronic neck pain, compared with the control group. It was indicated that DHEA-S decreased during the physical exercise in the control group, and either increased or was unaffected in the chronic pain group.

  • 33.
    Gurevich-Panigrahi, Tatiana
    et al.
    BioApplication Enterprises, Winnipeg, Canada.
    Wiechec, Emilia
    Manitoba Institute of Cell Biology, CancerCare Manitoba; Department of Human Genetics, University of Aarhus, Aarhus, Denmark.
    Panigrahi, Soumya
    Department of Immunology, Lerner Research Institute, Cleveland, USA.
    Los, Marek Jan
    Interfaculty Institute for Biochemistry, University of Tübingen, Germany; BioApplications Enterprises, Winnipeg, MB, Canada.
    Obesity: Pathophysiology and Clinical2009In: Current Medicinal Chemistry, ISSN 0929-8673, E-ISSN 1875-533X, Vol. 16, no 4, p. 506-521Article in journal (Refereed)
    Abstract [en]

    Obesity is an increasingly serious socioeconomic and clinical problem. Between 1/4 - 1/3 of population in the developed countries can be classified as obese. Four major etiological factors for development of obesity are genetic determinants, environmental factors, food intake and exercise. Obesity increases the risk of the development of various pathologic conditions including: insulin-resistant diabetes mellitus, cardiovascular disease, non-alcoholic fatty liver disease, endocrine problems, and certain forms of cancer. Thus, obesity is a negative determinant for longevity. In this review we provide broad overview of pathophysiology of obesity. We also discuss various available, and experimental therapeutic methods. We highlight functions of adipocytes including fat storing capacity and secretory activity resulting in numerous endocrine effects like leptin, IL-6, adiponectin, and resistin. The anti-obesity drugs are classified according to their primary action on energy balance. Major classes of these drugs are: appetite suppressants, inhibitors of fat absorption (i.e. orlistat), stimulators of thermogenesis and stimulators of fat mobilization. The appetite suppressants are further divided into noradrenergic agents, (i.e. phentermine, phendimetrazine, benzphetamine, diethylpropion), serotoninergic agents (i.e. dexfenfluramine), and mixed noradrenergic-serotoninergic agents (i.e. sibutramine). Thus, we highlight recent advances in the understanding of the central neural control of energy balance, current treatment strategies for obesity and the most promising targets for the development of novel anti-obesity drugs.

  • 34.
    Ha, Hojin
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Kangwon Natl Univ, South Korea.
    Ziegler, Magnus
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Welander, Martin
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Bjarnegård, Niclas
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Carlhäll, Carljohan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Lindenberger, Marcus
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ebbers, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Dyverfeldt, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Age-Related Vascular Changes Affect Turbulence in Aortic Blood Flow2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 36Article in journal (Refereed)
    Abstract [en]

    Turbulent blood flow is implicated in the pathogenesis of several aortic diseases but the extent and degree of turbulent blood flow in the normal aorta is unknown. We aimed to quantify the extent and degree of turbulece in the normal aorta and to assess whether age impacts the degree of turbulence. 22 young normal males (23.7 +/- 3.0 y.o.) and 20 old normal males (70.9 +/- 3.5 y.o.) were examined using four dimensional flow magnetic resonance imaging (4D Flow MRI) to quantify the turbulent kinetic energy (TKE), a measure of the intensity of turbulence, in the aorta. All healthy subjects developed turbulent flow in the aorta, with total TKE of 3-19 mJ. The overall degree of turbulence in the entire aorta was similar between the groups, although the old subjects had about 73% more total TKE in the ascending aorta compared to the young subjects (young = 3.7 +/- 1.8 mJ, old = 6.4 +/- 2.4 mJ, p amp;lt; 0.001). This increase in ascending aorta TKE in old subjects was associated with age-related dilation of the ascending aorta which increases the volume available for turbulence development. Conversely, age-related dilation of the descending and abdominal aorta decreased the average flow velocity and suppressed the development of turbulence. In conclusion, turbulent blood flow develops in the aorta of normal subjects and is impacted by age-related geometric changes. Non-invasive assessment enables the determination of normal levels of turbulent flow in the aorta which is a prerequisite for understanding the role of turbulence in the pathophysiology of cardiovascular disease.

  • 35.
    Hammerman, Malin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Blomgran, Parmis
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Ramstedt, Sandra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping. Linköping University, Faculty of Health Sciences.
    COX-2 inhibition impairs mechanical stimulation of early tendon healing in rats by reducing the response to microdamage2015In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 119, no 5, p. 534-540Article in journal (Refereed)
    Abstract [en]

    Early tendon healing can be stimulated by mechanical loading and inhibited by cyclooxygenase (COX) inhibitors (nonsteroidal anti-inflammatory drugs). Therefore, we investigated if impairment of tendon healing by a COX-2 inhibitor (parecoxib) is related to loading. Because loading might infer microdamage, which also stimulates healing, we also investigated if this effect is inhibited by parecoxib. The Achilles tendon was transected in 114 rats. Three degrees of loading were used: full loading, partial unloading, and unloading (no unloading, Botox injections in the plantar flexor muscles, or Botox in combination with tail suspension). For each loading condition, the rats received either parecoxib or saline. In a second experiment, rats were unloaded with Botox, and the tendon was subjected to microdamage by needling combined with either saline or parecoxib. Mechanical testing day 7 showed that there was a significant interaction between loading and parecoxib for peak force at failure (P less than 0.01). However, logarithmic values showed no significant interaction, meaning that we could not exclude that the inhibitory effect of parecoxib was proportionate to the degree of loading. Microbleeding was common in the healing tissue, suggesting that loading caused microdamage. Needling increased peak force at failure (P less than 0.01), and this effect of microdamage was almost abolished by parecoxib (P less than 0.01). Taken together, this suggests that COX-2 inhibition impairs the positive effects of mechanical loading during tendon healing, mainly by reducing the response to microdamage.

  • 36.
    Hope, Michael D.
    et al.
    University of California, San Francisco, USA.
    Dyverfeldt, Petter
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping. University of California, San Francisco, USA.
    Thoracic Aorta Disease: Flow Evaluation by MR2013In: MRI and CT of the Cardiovascular System / [ed] Charles B Higgins; Albert de Roos, Philadelphia, PA: Lippincott Williams & Wilkins, 2013, 3, p. -676Chapter in book (Other academic)
    Abstract [en]

    Leave no disease undetected with MRI and CT of the Cardiovascular System, your definitive guide to magnetic resonance and computed tomography for cardiovascular health. Authored by a collaboration of international experts, this vivid, four-color third edition imparts the latest technologies in a rapidly advancing field. With topics that range from anatomy, to MR in infants and children, to risk assessment in ischemic heart disease  this text includes seven new chapters to reflect the rising tide of technological discovery as it pertains to cardiology.  Thanks to its expert analysis, procedural guide to implementation, and profound understanding of the recent advances in cardiovascular imagining, MRI and CT of the Cardiovascular System gives you all the tools necessary for powerful screening, diagnosis, and  cardiovascular care. Features:

    --New chapters reflecting  technological discoveries in cardiology  --Color illustrations for heightened clarity --Companion website with fully searchable text --Units organized by pathology and disease detection --Fully updated information on application of MR and CT--Up-to-date analysis of emerging multi-detector CT

  • 37.
    Hope, Michael D.
    et al.
    University of California, San Francisco, USA.
    Dyverfeldt, Petter
    University of California, San Francisco, USA.
    Acevedo-Bolton, Gabriel
    University of California, San Francisco, USA.
    Wrenn, Jarrett
    University of California, San Francisco, USA.
    Foster, Elyse
    University of California, San Francisco, USA.
    Tseng, Elaine
    University of California, San Francisco, USA.
    Saloner, David
    University of California, San Francisco, USA.
    Post-stenotic dilation: evaluation of ascending aortic dilation with 4D flow MR imaging2012In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 156, no 2, p. e40-e42Article in journal (Other academic)
  • 38.
    Hope, Michael D.
    et al.
    University of California, San Francisco, USA.
    Sedlic, Tony
    University of California, San Francisco, USA.
    Dyverfeldt, Petter
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. University of California, San Francisco, USA.
    Cardiothoracic Magnetic Resonance Flow Imaging2013In: Journal of thoracic imaging, ISSN 0883-5993, E-ISSN 1536-0237, Vol. 28, no 4, p. 217-230Article in journal (Refereed)
    Abstract [en]

    Multidimensional blood flow imaging with magnetic resonance has rapidly evolved over the last decade. The technique, often referred to as 4-dimensional (4D) flow, can now reliably image the heart and principal vessels of the chest in ≤15 minutes. In addition to dynamic 3D flow visualization, a range of unique quantitative hemodynamic markers can be calculated from 4D flow data. In this review article, we describe some of the more promising of these hemodynamic markers, including pulse wave velocity, pressure, turbulent kinetic energy, wall shear stress, and flow eccentricity. Evaluation of a range of cardiothoracic disorders has been explored with 4D flow, and many applications have been proposed. We also review the potential clinical applications of 4D flow in 4 broad contexts: the aorta, the pulmonary artery, acquired heart disease, and complex congenital heart disease. Promising preliminary results will be highlighted, including the use of abnormal systolic blood flow to risk-stratify patients for progressive valve-related aortic disease, turbulent kinetic energy to directly assess the hemodynamic impact of a stenotic lesion, and altered intracardiac flow to identify early heart failure. We discuss ongoing research efforts in the context of the larger clinical goals of 4D flow: the use of unique hemodynamic markers to (1) identify cardiovascular disease processes early in their course before clinical manifestation so that preemptive treatment can be undertaken; (2) refine the assessment of cardiovascular disease so as to better identify optimal medical or surgical therapies; and (3) enhance the evaluation and monitoring of the hemodynamic impact of different treatment options.

  • 39.
    Hursti, Timo J
    et al.
    Uppsala Universitet.
    Börjeson, Sussanne
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Nursing Science. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Hellström, Per M
    Karolinska.
    Åvall-Lundqvist, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Karolinska.
    Stock, Solveig
    Karolinska.
    Steineck, Gunnar
    Karolinska.
    Peterson, Curt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Effect of chemotherapy on circulating gastrointestinal hormone levels in ovarian cancer patients: Relationship to nausea and vomiting2005In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 40, no 6, p. 654-661Article in journal (Refereed)
    Abstract [en]

    Objective. The introduction of 5-HT3 receptor antagonists greatly reduced the problems associated with nausea and vomiting immediately after cancer chemotherapy. However, delayed nausea and vomiting is still a major problem and the underlying mechanism is obscure. Material and methods. We studied the effect of cisplatin-containing combination chemotherapy in 14 ovarian cancer patients on the levels of gastrin and a panel of other hormones as well as glucose and prostaglandin F2α. Blood samples were obtained once daily in the morning before chemotherapy and for 4 days after chemotherapy. Results. Concentrations of many hormones including gastrin were generally high. A pronounced increase in plasma insulin levels occurred on the day after chemotherapy accompanied by a modest increase in plasma glucose concentrations. Minor increases were observed for gastrin, oxytocin and prostaglandin F2α. In contrast, a transient decrease after chemotherapy was observed for motilin. Plasma cortisol decreased markedly after chemotherapy as expected since betamethasone was given as an antiemetic prophylaxis. Certain trends concerning the relationship between some hormones and nausea and vomiting were noted. A high plasma gastrin concentration before chemotherapy was related to delayed vomiting. Relative day-to-day variability of cholecystokinin tended to correlate positively with delayed nausea, whereas an inverse relationship was observed for gastrin variability. Conclusions. Changes in hormone plasma levels were found but only few could be distinguished as possible mediators of delayed nausea and vomiting. © 2005 Taylor & Francis.

  • 40.
    Ingeström, Emma
    Linköping University, Department of Physics, Chemistry and Biology, Biology.
    Phenotypic plasticity of the heart and skeletal muscles in cold acclimated Red Junglefowls (Gallus gallus)2015Independent thesis Basic level (degree of Bachelor), 10,5 credits / 16 HE creditsStudent thesis
    Abstract [en]

    The ability of the heart and skeletal muscles to remodel to environmental demands, their plasticity, is of interest when studying animals’ adaptation to environment changes. Temperature variation due to seasonal change seems to lead to the development of a cold acclimated phenotype in small birds. To endure cold conditions a higher metabolism is required for shivering thermogenesis in aerobic skeletal muscles. This in turn leads to several physiological changes, including a heart and muscle hypertrophy as well as an increased oxygen carrying capacity of the blood. In this study were Red Junglefowls (Gallus gallus) bred indoors and outdoors and physiological aspects such as body size, growth rate, relative size of heart and skeletal muscles (pectoralis major and gastrocnemius maximus) as well as hematocrit and hemoglobin concentrations of the blood were compared between the groups. Observed significant differences included a slower growth rate in fowls bred outdoors, 2.5 (0.7) g/day than indoors, 3.8 (0.4) g/day, as well as a larger relative size of the heart and gastrocnemius muscle. The average relative size of the heart was more than twice as big in fowls bred outdoors, 0.97 (0.08) %, than indoors, 0.40-42 (0.05) %. The average relative size of the gastrocnemius muscle for the fowl bred outdoor was significantly larger than for fowl bred indoors (0.95 (0.11) %, vs. 0.58-0,63 (0.09) %). In addition, fowl bred outdoors showed an increased capacity for oxygen transportation, with blood hematocrit values of 43 (3) % higher than 35-37 (3) % for the indoor animals. Fowls bred outdoors also showed higher hemoglobin concentrations in the blood, 127 (7) g/l, than fowls bred indoors, 113 (7) g/l. Findings indicate a cold acclimated phenotype among the outdoor bred fowls.

  • 41.
    Iredahl, Fredrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Högstedt, Alexandra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Henricson, Joakim
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Dermatology and Venerology. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences.
    Sjöberg, Folke
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Tesselaar, Erik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Farnebo, Simon
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Skin glucose metabolism and microvascular blood flow during local insulin delivery and after an oral glucose load2016In: Microcirculation, ISSN 1073-9688, E-ISSN 1549-8719, Vol. 23, no 7, p. 597-605Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Insulin causes capillary recruitment in muscle and adipose tissue, but the metabolic and microvascular effects of insulin in the skin have not been studied in detail. The aim of this study was to measure glucose metabolism and microvascular blood flow in the skin during local insulin delivery and after an oral glucose load.

    METHODS: Microdialysis catheters were inserted intracutanously in human subjects. In eight subjects two microdialysis catheters were inserted, one perfused with insulin and one with control solution. First the local effects of insulin was studied, followed by a systemic provocation by an oral glucose load. Additionally, as control experiment, six subjects did not recieve local delivery of insulin or the oral glucose load. During microdialysis the local blood flow was measured by urea clearance and by laser speckle contrast imaging (LSCI).

    RESULTS: Within 15 minutes of local insulin delivery, microvascular blood flow in the skin increased (urea clearance: P=.047, LSCI: P=.002) paralleled by increases in pyruvate (P=.01) and lactate (P=.04), indicating an increase in glucose uptake. An oral glucose load increased urea clearance from the catheters, indicating an increase in skin perfusion, although no perfusion changes were detected with LSCI. The concentration of glucose, pyruvate and lactate increased in the skin after the oral glucose load.

    CONCLUSION: Insulin has metabolic and vasodilatory effects in the skin both when given locally and after systemic delivery through an oral glucose load.

  • 42.
    Iredahl, Fredrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Löfberg, Andreas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Sjöberg, Folke
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Farnebo, Simon
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Linköping University, Faculty of Medicine and Health Sciences.
    Tesselaar, Erik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Non-Invasive Measurement of Skin Microvascular Response during Pharmacological and Physiological Provocations2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 8, p. 1-15, article id e0133760Article in journal (Refereed)
    Abstract [en]

    Introduction Microvascular changes in the skin due to pharmacological and physiological provocations can be used as a marker for vascular function. While laser Doppler flowmetry (LDF) has been used extensively for measurement of skin microvascular responses, Laser Speckle Contrast Imaging (LSCI) and Tissue Viability Imaging (TiVi) are novel imaging techniques. TiVi measures red blood cell concentration, while LDF and LSCI measure perfusion. Therefore, the aim of this study was to compare responses to provocations in the skin using these different techniques. Method Changes in skin microcirculation were measured in healthy subjects during (1) iontophoresis of sodium nitroprusside (SNP) and noradrenaline (NA), (2) local heating and (3) post-occlusive reactive hyperemia (PORH) using LDF, LSCI and TiVi. Results Iontophoresis of SNP increased perfusion (LSCI: baseline 40.9 +/- 6.2 PU; 10-min 100 +/- 25 PU; pless than0.001) and RBC concentration (TiVi: baseline 119 +/- 18; 10-min 150 +/- 41 AU; p = 0.011). No change in perfusion (LSCI) was observed after iontophoresis of NA (baseline 38.0 +/- 4.4 PU; 10-min 38.9 +/- 5.0 PU; p = 0.64), while RBC concentration decreased (TiVi: baseline 59.6 +/- 11.8 AU; 10-min 54.4 +/- 13.3 AU; p = 0.021). Local heating increased perfusion (LDF: baseline 8.8 +/- 3.6 PU; max 112 +/- 55 PU; pless than0.001, LSCI: baseline 50.8 +/- 8.0 PU; max 151 +/- 22 PU; pless than0.001) and RBC concentration (TiVi: baseline 49.2 +/- 32.9 AU; max 99.3 +/- 28.3 AU; pless than0.001). After 5 minutes of forearm occlusion with prior exsanguination, a decrease was seen in perfusion (LDF: p = 0.027; LSCI: pless than0.001) and in RBC concentration (p = 0.045). Only LSCI showed a significant decrease in perfusion after 5 minutes of occlusion without prior exsanguination (pless than0.001). Coefficients of variation were lower for LSCI and TiVi compared to LDF for most responses. Conclusion LSCI is more sensitive than TiVi for measuring microvascular changes during SNP-induced vasodilatation and forearm occlusion. TiVi is more sensitive to noradrenaline-induced vasoconstriction. LSCI and TiVi show lower inter-subject variability than LDF. These findings are important to consider when choosing measurement techniques for studying skin microvascular responses.

  • 43.
    Joyce, William
    et al.
    Department of Zoophysiology, Aarhus University, Aarhus, Denmark.
    Axelsson, Michael
    Department of Biological and Environmental Sciences, University of Gothenburg, Gothenburg, Sweden..
    Altimiras, Jordi
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Wang, Tobias
    Department of Zoophysiology, Aarhus University, Aarhus, Denmark..
    In situ cardiac perfusion reveals interspecific variation of intraventricular flow separation in reptiles2016In: Journal of Experimental Biology, ISSN 0022-0949, E-ISSN 1477-9145, Vol. 219, no pt 14, p. 2220-2227Article in journal (Refereed)
    Abstract [en]

    The ventricles of non-crocodilian reptiles are incompletely dividedand provide an opportunity for mixing of oxygen-poor blood andoxygen-rich blood (intracardiac shunting). However, both cardiacmorphology and in vivo shunting patterns exhibit considerableinterspecific variation within reptiles. In the present study, wedevelop an in situ double-perfused heart approach to characterisethe propensity and capacity for shunting in five reptile species: theturtle Trachemys scripta, the rock python Python sebae, the yellowanaconda Eunectes notaeus, the varanid lizard Varanusexanthematicus and the bearded dragon Pogona vitticeps. Tosimulate changes in vascular bed resistance, pulmonary andsystemic afterloads were independently manipulated and changesin blood flow distribution amongst the central outflow tracts weremonitored. As previously demonstrated in Burmese pythons, rockpythons and varanid lizards exhibited pronounced intraventricularflow separation. As pulmonary or systemic afterload was raised, flowin the respective circulation decreased. However, flow in the othercirculation, where afterload was constant, remained stable. Thiscorrelates with the convergent evolution of intraventricular pressureseparation and the large intraventricular muscular ridge, whichcompartmentalises the ventricle, in these species. Conversely, inthe three other species, the pulmonary and systemic flows werestrongly mutually dependent, such that the decrease in pulmonaryflow in response to elevated pulmonary afterload resulted inredistribution of perfusate to the systemic circuit (and vice versa).Thus, in these species, the muscular ridge appeared labile and bloodcould readily transverse the intraventricular cava. We conclude thatrelatively minor structural differences between non-crocodilianreptiles result in the fundamental changes in cardiac function.Further, our study emphasises that functionally similar intracardiacflow separation evolved independently in lizards (varanids) andsnakes (pythons) from an ancestor endowed with the capacity forlarge intracardiac shunts.

  • 44.
    Karlsson, Linn
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Gerdle, Björn
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Ghafouri, Bijar
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Bäckryd, Emmanuel
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Olausson, Patrik
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Ghafouri, Nazdar
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Larsson, Britt
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Intramuscular pain modulatory substances before and after exercise in women with chronic neck pain2015In: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 19, no 8, p. 1075-1085Article in journal (Refereed)
    Abstract [en]

    BackgroundIn peripheral tissue, several substances influence pain and pain modulation. Exercise has been found to decrease pain and improve function for chronic pain conditions, but how and why exercise produces beneficial effects remains unclear. This study investigates whether aspects of pain and concentrations of substances with algesic, analgesic and metabolic functions differ between women with chronic neck shoulder pain (CNSP) and healthy women (CON) and whether changes are found after an exercise intervention for CNSP. MethodsForty-one women with CNSP and 24 CON subjects were included. The participants attended two microdialysis sessions with 4-6 months between the experiments. During this period, the CNSP subjects underwent an exercise intervention. Expression levels of substance P, beta-endorphin, cortisol, glutamate, lactate and pyruvate as well as pain intensity and pressure pain thresholds were analysed. ResultsAt baseline, higher concentrations of glutamate and beta-endorphin and lower concentrations of cortisol in CNSP than CON were found. After exercise, decreased levels of substance P and possibly of glutamate, increased levels of beta-endorphin and cortisol as well as decreased pain intensity and increased pain pressure thresholds were found for CNSP. ConclusionsThe findings at baseline indicated algesic and analgesic alterations in the painful trapezius muscles. The findings for CNSP after the exercise intervention, with changes in peripheral substances and decreased pain intensity and sensitivity, could reflect a long-term physiological effect of the exercise.

  • 45.
    Karlsson, Matts
    et al.
    Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, The Institute of Technology. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ingels, Neil B.
    Stanford University, USA.
    Dynamic Relationship between the Mitral Annulus and the Basal Left Ventricular Myocardium in the Beating Ovine Heart2014Conference paper (Other academic)
  • 46.
    Karlsson, Matts
    et al.
    Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, The Institute of Technology. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ingels, Neil B.
    Stanford University, USA.
    Stability of anterior mitral leaflet shape and position throughout ejection in the beating ovine heart2014Conference paper (Other academic)
  • 47.
    Kato, Naoko P.
    et al.
    University of Tokyo, Japan.
    Okada, Ikuko
    University of Tokyo, Japan.
    Imamura, Teruhiko
    University of Tokyo, Japan.
    Kagami, Yukie
    University of Tokyo, Japan.
    Endo, Miyoko
    University of Tokyo, Japan.
    Nitta, Daisuke
    University of Tokyo, Japan.
    Fujino, Takeo
    University of Tokyo, Japan.
    Muraoka, Hironori
    University of Tokyo, Japan.
    Minatsuki, Shun
    University of Tokyo, Japan.
    Maki, Hisataka
    University of Tokyo, Japan.
    Inaba, Toshiro
    University of Tokyo, Japan.
    Kinoshita, Osamu
    University of Tokyo, Japan.
    Nawata, Kan
    University of Tokyo, Japan.
    Hatano, Masaru
    University of Tokyo, Japan.
    Yao, Atsushi
    University of Tokyo, Japan.
    Kyo, Shunei
    University of Tokyo, Japan.
    Ono, Minoru
    University of Tokyo, Japan.
    Jaarsma, Tiny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Social and Welfare Studies, Division of Health, Activity and Care.
    Kinugawa, Koichiro
    University of Tokyo, Japan.
    Quality of Life and Influential Factors in Patients Implanted With a Left Ventricular Assist Device2015In: Circulation Journal, ISSN 1346-9843, E-ISSN 1347-4820, Vol. 79, no 10, p. 2186-2192Article in journal (Refereed)
    Abstract [en]

    Background: Improving quality of life (QOL) has become an important goal in left ventricular assist device (LVAD) therapy. We aimed (1) to assess the effect of an implantable LVAD on patients QOL, (2) to compare LVAD patients QOL to that of patients in different stages of heart failure (HF), and (3) to identify factors associated with patients QOL. Methods and Results: The QOL of 33 Japanese implantable LVAD patients was assessed using the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and Short-form 8 (SF-8), before and at 3 and 6 months afterwards. After LVAD implantation, QOL significantly improved [MLHFQ, SF-8 physical component score (PCS), SF-8 mental component score (MCS), all Pless than0.05]. Implanted LVAD patients had a better QOL than extracorporeal LVAD patients (n=33, 32.1 +/- 21.9 vs. n=17, 47.6 +/- 18.2), and Stage D HF patients (n=32, 51.1 +/- 17.3), but the score was comparable to that of patients who had undergone a heart transplant (n=13). In multiple regression analyses, postoperative lower albumin concentration and right ventricular failure were independently associated with poorer PCS. Female sex and postoperative anxiety were 2 of the independent factors for poorer MCS (all Pless than0.05). Conclusions: Having an implantable LVAD improves patients QOL, which is better than that of patients with an extracorporeal LVAD. Both clinical and psychological factors are influence QOL after LVAD implantation.

  • 48.
    Klubb, Sofia
    Linköping University, Department of Physics, Chemistry and Biology.
    Cold-induced vasodilation in the brood patch of Zebra finches (Taeniopygia guttata)2010Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    The development of the avian embryo is dependent of heat provisioning from the parents. To increase the heat transfer to a cooled egg the Zebra finch females develop a brood patch. Mild cooling generally constricts the blood vessels but the Arterio-venous anastomoses (AVA) in the brood patch in birds dilate. This is called cold-induced vasodilation CIVD. The Zebra finches were anesthetized with isoflurane and the brood patch was stimulated with a cooling probe set at 20-21 °C. Differences in the vascular changes to cooling in broody and non- broody birds were studied by comparing males and broody females. The brood patch skin was cooled, but no cold-induced vasodilation (CIVD) was documented for the males or the broody females. Isoflurane anesthesia depresses the sympathetic nervous system activity and the results support that the mechanism for CIVD in the brood patch of Zebra finches depends on a neural pathway, but does not exclude a local non-neural mechanism.

  • 49.
    Källman, Ulrika
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Södra Älvsborgs Sjukhus, Sweden.
    Bergstrand, Sara
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering.
    Ek, Anna-Christina
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine.
    Engström, Maria
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Lindgren, Margareta
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Nursing Science.
    Blood flow responses over sacrum in nursing home residents during one hour bed rest2016In: Microcirculation, ISSN 1073-9688, E-ISSN 1549-8719, Vol. 23, no 7, p. 530-539Article in journal (Refereed)
    Abstract [en]

    ObjectivesTo describe individual BF responses in a nursing home resident population for one-hour periods of bed rest. MethodsBF was measured for one hour over the sacrum in 0 degrees supine position and 30 degrees supine tilt position in 25 individuals aged 65 y or older while lying on a pressure-redistributing mattress. Measurements were made at three tissue depths (1, 2, and 10 mm) using the noninvasive optical techniques, LDF and PPG. ResultsEleven participants had a PIV response at 1mm depth in both positions and seven participants had a lack of this response at this depth and positions. The BF response at 1mm depth appeared immediately and remained over, or below, baseline for the entire 60min of loading in both positions. These BF patterns were also seen in deeper tissue layers. ConclusionsThe cutaneous BF response among the nursing home residents was distinct, appeared early, and remained during the one hour of loading.

  • 50.
    Laustsen, Christoffer
    et al.
    Aarhus University, Denmark.
    Mose Nielsen, Per
    Aarhus University, Denmark.
    Stokholm Norlinger, Thomas
    Aarhus University, Denmark.
    Qi, Haiyun
    Aarhus University, Denmark.
    Kjaergaard Pedersen, Uffe
    Aarhus University, Denmark.
    Bonde Bertelsen, Lotte
    Aarhus University, Denmark.
    Appel Ostergaard, Jakob
    Aarhus University, Denmark; Danish Diabet Acad, Denmark.
    Flyvbjerg, Allan
    Aarhus University, Denmark.
    Henrik Ardenkjaer-Larsen, Jan
    GE Healthcare, Denmark; Technical University of Denmark, Denmark.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Uppsala University, Sweden.
    Stodkilde-Jorgensen, Hans
    Aarhus University, Denmark.
    Antioxidant treatment attenuates lactate production in diabetic nephropathy2017In: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, ISSN 1931-857X, Vol. 312, no 1, p. F192-F199Article in journal (Refereed)
    Abstract [en]

    The early progression of diabetic nephropathy is notoriously difficult to detect and quantify before the occurrence of substantial histological damage. Recently, hyperpolarized [1-C-13] pyruvate has demonstrated increased lactate production in the kidney early after the onset of diabetes, implying increased lactate dehydrogenase activity as a consequence of increased nicotinamide adenine dinucleotide substrate availability due to upregulation of the polyol pathway, i.e., pseudohypoxia. In this study, we investigated the role of oxidative stress in mediating these metabolic alterations using state-of-the-art hyperpolarized magnetic resonance (MR) imaging. Ten-week-old female Wistar rats were randomly divided into three groups: healthy controls, untreated diabetic (streptozotocin treatment to induce insulinopenic diabetes), and diabetic, receiving chronic antioxidant treatment with TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) via the drinking water. Examinations were performed 2, 3, and 4 wk after the induction of diabetes by using a 3T Clinical MR system equipped with a dual tuned C-13/H-1-volume rat coil. The rats received intravenous hyperpolarized [1-C-13] pyruvate and were imaged using a slice-selective C-13-IDEAL spiral sequence. Untreated diabetic rats showed increased renal lactate production compared with that shown by the controls. However, chronic TEMPOL treatment significantly attenuated diabetes-induced lactate production. No significant effects of diabetes or TEMPOL were observed on [C-13] alanine levels, indicating an intact glucose-alanine cycle, or [C-13] bicarbonate, indicating normal flux through the Krebs cycle. In conclusion, this study demonstrates that diabetes-induced pseudohypoxia, as indicated by an increased lactate-to-pyruvate ratio, is significantly attenuated by antioxidant treatment. This demonstrates a pivotal role of oxidative stress in renal metabolic alterations occurring in early diabetes.

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