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  • 1.
    Berglund, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Separation of Water and Fat Signal in Magnetic Resonance Imaging: Advances in Methods Based on Chemical Shift2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Magnetic resonance imaging (MRI) is one of the most important diagnostic tools of modern healthcare. The signal in medical MRI predominantly originates from water and fat molecules. Separation of the two components into water-only and fat-only images can improve diagnosis, and is the premier non-invasive method for measuring the amount and distribution of fatty tissue.

    Fat-water imaging (FWI) enables fast fat/water separation by model-based estimation from chemical shift encoded data, such as multi-echo acquisitions. Qualitative FWI is sufficient for visual separation of the components, while quantitative FWI also offers reliable estimates of the fat percentage in each pixel. The major problems of current FWI methods are long acquisition times, long reconstruction times, and reconstruction errors that degrade image quality.

    In this thesis, existing FWI methods were reviewed, and novel fully automatic methods were developed and evaluated, with a focus on fast 3D image reconstruction. All MRI data was acquired on standard clinical scanners.

    A triple-echo qualitative FWI method was developed for the specific application of 3D whole-body imaging. The method was compared with two reference methods, and demonstrated superior image quality when evaluated in 39 volunteers.

    The problem of qualitative FWI by dual-echo data with unconstrained echo times was solved, allowing faster and more flexible image acquisition than conventional FWI. Feasibility of the method was demonstrated in three volunteers and the noise performance was evaluated.

    Further, a quantitative multi-echo FWI method was developed. The signal separation was based on discrete whole-image optimization. Fast 3D image reconstruction with few reconstruction errors was demonstrated by abdominal imaging of ten volunteers.

    Lastly, a method was proposed for quantitative mapping of average fatty acid chain length and degree of saturation. The method was validated by imaging different oils, using gas-liquid chromatography (GLC) as the reference. The degree of saturation agreed well with GLC, and feasibility of the method was demonstrated in the thigh of a volunteer.

    The developed methods have applications in clinical settings, and are already being used in several research projects, including studies of obesity, dietary intervention, and the metabolic syndrome.

    List of papers
    1. Three-point Dixon method enables whole-body water and fat imaging of obese subjects
    Open this publication in new window or tab >>Three-point Dixon method enables whole-body water and fat imaging of obese subjects
    2010 (English)In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 63, no 6, p. 1659-1668Article in journal (Refereed) Published
    Abstract [en]

    Dixon imaging techniques derive chemical shift-separated water and fat images, enabling the quantification of fat content and forming an alternative to fat suppression. Whole-body Dixon imaging is of interest in studies of obesity and the metabolic syndrome, and possibly in oncology. A three-point Dixon method is proposed where two solutions are found analytically in each voxel. The true solution is identified by a multiseed three-dimensional region-growing scheme with a dynamic path, allowing confident regions to be solved before unconfident regions, such as background noise. 2 pi-Phase unwrapping is not required. Whole-body datasets (256 x 184 x 252 voxels) were collected from 39 subjects (body mass index 19.8-45.4 kg/m(2)), in a mean scan time of 5 min 15 sec. Water and fat images were reconstructed offline, using the proposed method and two reference methods. The resulting images were subjectively graded on a four-grade scale by two radiologists, blinded to the method used. The proposed method was found superior to the reference methods. It exclusively received the two highest grades, implying that only mild reconstruction failures were found. The computation time for a whole-body dataset was 1 min 51.5 sec +/- 3.0 sec. It was concluded that whole-body water and fat imaging is feasible even for obese subjects, using the proposed method.

    Keywords
    three-point Dixon, whole-body MRI, water and fat separation, chemical shift imaging, fat suppression
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-129498 (URN)10.1002/mrm.22385 (DOI)000278164400026 ()20512869 (PubMedID)
    Available from: 2010-08-17 Created: 2010-08-17 Last updated: 2017-12-12Bibliographically approved
    2. Two-point dixon method with flexible echo times
    Open this publication in new window or tab >>Two-point dixon method with flexible echo times
    2011 (English)In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 65, no 4, p. 994-1004Article in journal (Refereed) Published
    Abstract [en]

    The two-point Dixon method is a proton chemical shift imaging technique that produces separated water-only and fat-only images from a dual-echo acquisition. It is shown how this can be achieved without the usual constraints on the echo times. A signal model considering spectral broadening of the fat peak is proposed for improved water/fat separation. Phase errors, mostly due to static field inhomogeneity, must be removed prior to least-squares estimation of water and fat. To resolve ambiguity of the phase errors, a corresponding global optimization problem is formulated and solved using a message-passing algorithm. It is shown that the noise in the water and fat estimates matches the Cramér-Rao bounds, and feasibility is demonstrated for in vivo abdominal breath-hold imaging. The water-only images were found to offer superior fat suppression compared with conventional spectrally fat suppressed images.

    Keywords
    chemical shift imaging, fat suppression, two-point Dixon, water and fat separation
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-150936 (URN)10.1002/mrm.22679 (DOI)000288612000011 ()21413063 (PubMedID)
    Available from: 2011-04-08 Created: 2011-04-08 Last updated: 2017-12-11Bibliographically approved
    3. Three-dimensional water/fat separation and T2* estimation based on whole-image optimization: application in breathhold liver imaging at 1.5 T
    Open this publication in new window or tab >>Three-dimensional water/fat separation and T2* estimation based on whole-image optimization: application in breathhold liver imaging at 1.5 T
    2012 (English)In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 67, no 6, p. 1684-1693Article in journal (Refereed) Published
    Abstract [en]

    The chemical shift of water and fat resonances in proton MRI allows separation of water and fat signal from chemical shift encoded data. This work describes an automatic method that produces separate water and fat images as well as quantitative maps of fat signal fraction and T2* from complex multi-echo gradient recalled datasets. Accurate water and fat separation is challenging due to signal ambiguity at the voxel level. Whole-image optimization can resolve this ambiguity, but might be computationally demanding, especially for three-dimensional (3D) data. In this work, periodicity of the model fit residual as a function of the off-resonance was utilized to modify a previously proposed formulation of the problem. This gives a smaller solution space and allows rapid optimization. Feasibility and accurate separation of water and fat signal was demonstrated in breathhold 3D liver imaging of ten volunteer subjects, with both acquisition and reconstruction times below 20 seconds.

    Keywords
    water and fat separation, chemical shift imaging, quantitative MRI, liver fat, T2* mapping, QPBO
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-158097 (URN)10.1002/mrm.23185 (DOI)000304086000020 ()22189760 (PubMedID)
    Available from: 2011-08-31 Created: 2011-08-31 Last updated: 2017-12-08Bibliographically approved
    4. Model-based mapping of fat unsaturation and chain length by chemical shift imaging: phantom validation and in vivo feasibility
    Open this publication in new window or tab >>Model-based mapping of fat unsaturation and chain length by chemical shift imaging: phantom validation and in vivo feasibility
    2012 (English)In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 68, no 6, p. 1815-1827Article in journal (Refereed) Published
    Abstract [en]

    Knowledge about the triglyceride (fat) 1H spectrum enables quantitative determination of several triglyceride characteristics. This work describes a model-based chemical shift imaging method that separates water and fat signal and provides maps of three triglyceride quantities: fatty acid carbon chain length (CL), number of double bond pairs (ndb), and number of methylene-interrupted double bonds (nmidb). The method was validated by imaging a phantom containing ten different oils using 1.5 T and 3.0 T clinical scanners, with gas-liquid chromatography (GLC) as reference. Repeated acquisitions demonstrated high reproducibility of the method. Statistical tests of correlation and linear regression were performed to examine the accuracy of the method. Significant correlation was found at both field strengths for all three quantities, and high correlation (r2 > 0.96) was found for measuring ndb and nmidb. Feasibility of the method for in vivo imaging of the thigh was demonstrated at both field strengths. The estimates of ndb and nmidb in subcutaneous adipose tisse were in agreement with literature values, while CL appears overestimated. The method has potential use in large-scale cross-sectional and longitudinal studies of triglyceride composition, and its relation to diet and various diseases.

    Keywords
    water/fat separation, chemical shift imaging, quantitative MRI, fat unsaturation, triglyceride mapping, fatty acid composition
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-158098 (URN)10.1002/mrm.24196 (DOI)000311398600015 ()22334300 (PubMedID)
    Available from: 2011-08-31 Created: 2011-08-31 Last updated: 2017-12-08Bibliographically approved
  • 2.
    Bergman, Daniel
    et al.
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hansson-Hamlin, Helene
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Ström Holst, Bodil
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Investigation of interference from canine anti-mouse antibodies in hormone immunoassays.2019In: Veterinary clinical pathology, ISSN 0275-6382, E-ISSN 1939-165XArticle in journal (Refereed)
    Abstract [en]

    BACKGROUND: Canine anti-mouse antibodies are a potential source of immunoassay interference, but erroneous immunoassay results are not always easily identifiable. Anti-Müllerian hormone (AMH) is a marker for the presence of gonads in dogs, but elevated AMH concentrations in neutered dogs could also be caused by antibody interference. For other assays, a discrepant result obtained after antibody precipitation might indicate antibody interference.

    OBJECTIVES: We aimed to evaluate if canine anti-mouse antibodies are a source of erroneous results in the AMH assay and if antibody precipitation with polyethylene glycol (PEG) is a useful tool for detecting antibody interference in a variety of immunoassays used in the veterinary clinical laboratory.

    METHODS: Twenty-nine positive and 25 negative samples for anti-mouse antibodies were analyzed for AMH, canine total thyroxine (TT4 ), canine thyroid-stimulating hormone (TSH) and progesterone before and after treatment with PEG. Results that differed by more than four SDs from the intra-assay coefficients of variation were considered discrepant. Elevated AMH concentrations in neutered dogs with anti-mouse antibodies and no visible gonads present were considered evidence of interference.

    RESULTS: Evidence of antibody interference was found in two samples analyzed for AMH. The presence of anti-mouse antibodies did not lead to a higher proportion of discrepant results after PEG treatment for any of the immunoassays. The overall incidence of discrepant results for healthy controls was very high (73%).

    CONCLUSIONS: Canine anti-mouse antibodies are a source of erroneous AMH results. Antibody precipitation with PEG is not a useful tool for detecting interference caused by such antibodies.

  • 3.
    Bergman, Daniel
    et al.
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hansson-Hamlin, Helene
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden..
    Svensson, Anna
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden..
    Holst, Bodil Ström
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden..
    Prevalence of interfering antibodies in dogs and cats evaluated using a species-independent assay.2018In: Veterinary clinical pathology, ISSN 0275-6382, E-ISSN 1939-165X, Vol. 47, no 2, p. 205-212Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Interfering antibodies in human serum and plasma are known to react with mammalian antibodies in immunoassays and cause false-positive test results. Although this phenomenon was recently shown in companion animals, knowledge regarding immunoassay interference in veterinary medicine is very limited.

    OBJECTIVES: The aims of this study were to set up a species-independent immunoassay procedure to detect interference in serum samples, to screen for interference in a cross-section of canine and feline patient samples from an animal hospital, and to determine if the detected interference could be neutralized using an immunoassay based on nonmammalian reagents.

    METHODS: A 2-site sandwich-type interference assay was set up using commercially available mouse reagents. A total of 369 serum samples from 320 dogs and 263 samples from 218 cats were analyzed using the interference assay. Multiple samples were submitted from 36 dogs and 39 cats. Nineteen samples identified as interference-positive were analyzed in an assay using chicken antibodies.

    RESULTS: Interference was detected in samples from 28 dogs (9%) and 10 cats (5%) screened with the interference assay. Except for 1 cat, consistent results were obtained for all 75 dogs and cats that submitted more than 1 sample. The interference was eliminated when analyzed in the chicken-based assay (P < .001).

    CONCLUSIONS: Substances with reactivity toward mouse IgG can be detected in serum samples from dog and cat patients using a 2-site interference assay. The detected substances are most likely interfering antibodies, possibly originating from immunization with other mammalian species.

  • 4.
    Börjesson, Andreas
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Investigations of Strategies to Counteract Proinflammatory Cytokines in Experimental Type 1 Diabetes2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Type 1 diabetes (T1D) is a chronic autoimmune disease targeted against the pancreatic β-cells. Proinflammatory cytokines are considered to play a major role in the destruction of the insulin-producing β-cells. This thesis studied strategies to counteract proinflammatory cytokines in experimental T1D. Both animal models for T1D as well as β-cell preparations exposed in vitro to putative noxious conditions were examined.

    In the first study we observed that cytokine treatment of mouse pancreatic islets lacking inducible nitric oxide synthase (iNOS) induced a prolongation of the early stimulatory phase of glucose stimulated insulin secretion. Various experiments led to the conclusion that this prolonged stimulatory effect may involve the DAG/PLD/PKC pathway.

    Next, we transplanted mouse islets deficient in iNOS to spontaneously diabetic NOD mice. We observed a normalization of hyperglycemia but not a delayed allograft rejection compared to transplanted wild type islets. Thus, absence of iNOS in the graft was not sufficient to prolong allograft survival.

    In paper III we found that sustained glucose stimulation of rat pancreatic islets was coupled to a decreased conversion of proinsulin to insulin. Islet treatment with IL-1β was also coupled to a decreased proinsulin conversion. Islet proconvertase activity may be a target in islet damage.

    In paper IV prolactin (PRL) was administered to mice in the multiple low dose streptozotocin model and we observed that PRL enhanced a Th2 response. This may contribute to the protective action by PRL in this model of autoimmune T1D.

    Finally, by examining β-cells overexpressing Suppressor of cytokine signalling 3 (SOCS-3) it was found that this could inhibit IL-1β induced signalling through the NF-κB and MAPK pathways. SOCS-3 overexpression also inhibited apoptosis induced by cytokines in primary β-cells. Lastly, we demonstrated that SOCS-3 transgenic islets were protected in an allogeneic transplantation model.

    List of papers
    1.
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    5. Suppressor of cytokine signalling-3 expression inhibits cytokine-mediated destruction of primary mouse and rat pancreatic islets and delays allograft rejection
    Open this publication in new window or tab >>Suppressor of cytokine signalling-3 expression inhibits cytokine-mediated destruction of primary mouse and rat pancreatic islets and delays allograft rejection
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    2008 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 51, no 10, p. 1873-1882Article in journal (Refereed) Published
    Abstract [en]

    Aims/hypothesis The pro-inflammatory cytokines IL-1 and IFN gamma are critical molecules in immune-mediated beta cell destruction leading to type 1 diabetes mellitus. Suppressor of cytokine signalling (SOCS)-3 inhibits the cytokine-mediated destruction of insulinoma-1 cells. Here we investigate the effect of SOCS3 in primary rodent beta cells and diabetic animal models. Methods Using mice with beta cell-specific Socs3 expression and a Socs3-encoding adenovirus construct, we characterised the protective effect of SOCS3 in mouse and rat islets subjected to cytokine stimulation. In transplantation studies of NOD mice and alloxan-treated mice the survival of Socs3 transgenic islets was investigated. Results Socs3 transgenic islets showed significant resistance to cytokine-induced apoptosis and impaired insulin release. Neither glucose-stimulated insulin release, insulin content or glucose oxidation were affected by SOCS3. Rat islet cultures transduced with Socs3-adenovirus displayed reduced cytokine-induced nitric oxide and apoptosis associated with inhibition of the IL-1-induced nuclear factor-kappa B and mitogen-activated protein kinase (MAPK) pathways. Transplanted Socs3 transgenic islets were not protected in diabetic NOD mice, but showed a prolonged graft survival when transplanted into diabetic allogenic BALB/c mice. Conclusions/interpretation SOCS3 inhibits IL-1-induced signalling through the nuclear factor-kappa B and MAPK pathways and apoptosis induced by cytokines in primary beta cells. Moreover, Socs3 transgenic islets are protected in an allogenic transplantation model. SOCS3 may represent a target for pharmacological or genetic engineering in islet transplantation for treatment of type 1 diabetes mellitus.

    Keywords
    apoptosis, autoimmunity, diabetes, IFN gamma, IL-1, inflammation; signalling, SOCS, suppressor of cytokine signalling
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97610 (URN)10.1007/s00125-008-1090-0 (DOI)000258958400017 ()
    Available from: 2008-10-10 Created: 2008-10-10 Last updated: 2017-12-14Bibliographically approved
  • 5.
    Cristea, Alexander
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Effects of Ageing and Physical Activity on Regulation of Muscle Contraction2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aims of this study were to investigate the mechanisms underlying (1) the ageing-related motor handicap at the whole muscle, cellular, contractile protein and myonuclear levels; and (2) ageing-related differences in muscle adaptability.

    In vivo muscles function was studied in the knee extensors. Decreases were observed in isokinetic and isometric torque outputs in old age in the sedentary men and women and elite master sprinters. A 20-week long specific sprint and resistance training successfully improved the maximal isometric force and rate of force development in a subgroup of master sprinters.

    In vitro measurements were performed in muscle biopsies from the vastus lateralis muscle. Immunocytochemical and contractile measurements in single membrane permeabilized muscle fibres demonstrated ageing- and gender-related changes at the myofibrillar level. In sedentary subjects, data showed a preferential decrease in the size of muscle fibres expressing type IIa MyHC in men, lower force generating capacity in muscle fibres expressing the type I MyHC isoform in both men and women and lower maximum velocity of unloaded shortening (V0) in fibres expressing types I and IIa MyHC isoforms in both men and women. The master sprinters also experienced the typical ageing-related reduction in the size of fast-twitch fibres, a shift toward a slower MyHC isoform profile and a lower V0 of type I MyHC fibres, which played a role in the decline in explosive force production capacity. The fast-twitch fibre area increased after the resistance training period. A model combining single muscle fibre confocal microscopy with a novel algorithm for 3D imaging of myonuclei in single muscle fibre segments was introduced to study the spatial organisation of myonuclei and the size of individual myonuclear domains (MNDs). Significant changes in the MND size variability and myonuclear organization were observed in old age, irrespective gender and fibre type. Those changes may influence the local quantity of specific proteins per muscle fibre volume by decreased and/or local cooperativity of myonuclei in a gender and muscle fibre specific manner.

    In conclusion, the ageing-related impairments in in vivo muscle function were related to significant changes in morphology, contractile protein expression and regulation at the muscle fibre level. It is suggested that the altered myonuclear organisation observed in old age impacts on muscle fibre protein synthesis and degradation with consequences for the ageing-related changes in skeletal muscle structure and function. However, the improved muscle function in response to a 20-week intense physical training regime in highly motivated physically active old subjects demonstrates that all ageing-related in muscle function are not immutable.

    List of papers
    1. Effects of ageing and gender on contractile properties in human skeletal muscle and single fibres
    Open this publication in new window or tab >>Effects of ageing and gender on contractile properties in human skeletal muscle and single fibres
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    2007 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 190, no 3, p. 229-241Article in journal (Refereed) Published
    Abstract [en]

    Aim: The objective of this study is to improve our understanding of the mechanisms underlying the ageing- and gender-related muscle weakness.

    Methods: Ageing- and gender-related differences in regulation of muscle contraction have been studied in knee-extensor muscles at the whole muscle and single muscle fibre levels in young and old sedentary men and women. In vivo knee-extensor muscle function was measured at slow (30° s−1) and faster (180 ° s−1) speeds of movement. Maximum velocity of unloaded shortening (V0) and maximum force normalized to cross-sectional area (CSA) [specific tension (ST)] were measured in single 'skinned' skeletal muscle fibre segments.

    Results: Significant ageing- and gender-related differences were observed in muscle torque. A 33–55% ageing-related decline (P < 0.001) in maximum torque was observed irrespective of gender. At the single muscle fibre level, the ageing-related decline in knee-extensor muscle function was accompanied by a 20–28% decline in ST in muscle fibres expressing the type I MyHC isoform in both men and women, and a 29% decline in type IIa muscle fibre CSA, but the decreased fast-twitch fibre size was restricted to the men. Furthermore, in both men and women, V0 decreased in muscle cells expressing the type I and IIa MyHC isoforms.

    Conclusion: The present results provide evidence of specific ageing- and gender-related differences in regulation of muscle contraction at the cellular level. It is suggested that these cellular changes have a significant impact on muscle function and the ageing-related motor handicap.

    Keywords
    maximum velocity of unloaded shortening, muscle mass, skinned fibres, slack test, specific tension, torque-velocity
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97417 (URN)10.1111/j.1748-1716.2007.01699.x (DOI)000247318600006 ()
    Available from: 2008-08-29 Created: 2008-08-29 Last updated: 2017-12-14Bibliographically approved
    2. Aging, muscle fiber type, and contractile function in sprint-trained athletes
    Open this publication in new window or tab >>Aging, muscle fiber type, and contractile function in sprint-trained athletes
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    2006 (English)In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 101, no 3, p. 906-917Article in journal (Refereed) Published
    Abstract [en]

    Biopsy samples were taken from the vastus lateralis of 18- to 84-yr-old male sprinters (n = 91). Fiber-type distribution, cross-sectional area, and myosin heavy chain (MHC) isoform content were identified using ATPase histochemistry and SDS-PAGE. Specific tension and maximum shortening velocity (V-o) were determined in 144 single skinned fibers from younger (18-33 yr, n = 8) and older (53-77 yr, n = 9) runners. Force-time characteristics of the knee extensors were determined by using isometric contraction. The cross-sectional area of type I fibers was unchanged with age, whereas that of type II fibers was reduced (P < 0.001). With age there was an increased MHC I (P < 0.01) and reduced MHC IIx isoform content (P < 0.05) but no differences in MHC IIa. Specific tension of type I and IIa MHC fibers did not differ between younger and older subjects. V-o of fibers expressing type I MHC was lower (P < 0.05) in older than in younger subjects, but there was no difference in V-o of type IIa MHC fibers. An aging-related decline of maximal isometric force (P < 0.001) and normalized rate of force development (P < 0.05) of knee extensors was observed. Normalized rate of force development was positively associated with MHC II (P < 0.05). The sprint-trained athletes experienced the typical aging-related reduction in the size of fast fibers, a shift toward a slower MHC isoform profile, and a lower V-o of type I MHC fibers, which played a role in the decline in explosive force production. However, the muscle characteristics were preserved at a high level in the oldest runners, underlining the favorable impact of sprint exercise on aging muscle.

    Keywords
    exercise, myosin heavy chain, single-fiber contractile properties, muscle strength
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97418 (URN)10.1152/japplphysiol.00299.2006 (DOI)000240124100031 ()16690791 (PubMedID)
    Available from: 2008-08-29 Created: 2008-08-29 Last updated: 2017-12-14Bibliographically approved
    3. Effects of combined strength and sprint training on regulation of muscle contraction at the whole-muscle and single fibre levels in elite master sprinters
    Open this publication in new window or tab >>Effects of combined strength and sprint training on regulation of muscle contraction at the whole-muscle and single fibre levels in elite master sprinters
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    2008 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 193, no 3, p. 275-289Article in journal (Refereed) Published
    Abstract [en]

    AIM: This study aims at examining the effects of progressive strength and sprint training on regulation of muscle contraction at the whole-muscle and single-fibre levels in older sprint-trained athletes. METHODS: Eleven men (52-78 years) were randomized to a training (EX, n = 7) or control (CTRL, n = 4) group. EX participated in a 20-week programme that combined sprint training with heavy and explosive strength exercises, while CTRL maintained their usual run-based training schedules. RESULTS: EX improved maximal isometric and dynamic leg strength, explosive jump performance and force production in running. Specific tension and maximum shortening velocity of single fibres from the vastus lateralis were not altered in EX or CTRL. Fibre type and myosin heavy chain isoform distributions remained unchanged in the two groups. There was a general increase in fibre areas in EX, but this was significant only in IIa fibres. The 10% increase in squat jump in EX was accompanied by a 9% increase in the integrated EMG (iEMG) of the leg extensors but the 21-40% increases in isometric and dynamic strength were not paralleled by changes in iEMG. CONCLUSION: Adding strength training stimulus to the training programme improved maximal, explosive and sport-specific force production in elite master sprinters. These improvements were primarily related to hypertrophic muscular adaptations.

    Keywords
    ageing, fibre types, hypertrophy, master athletes, neural activity, skinned fibres
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97419 (URN)10.1111/j.1748-1716.2008.01843.x (DOI)000256442100010 ()18284658 (PubMedID)
    Available from: 2008-08-29 Created: 2008-08-29 Last updated: 2017-12-14Bibliographically approved
    4. Effects of ageing and gender on the spatial organisation of nuclei in single human skeletal muscle cells
    Open this publication in new window or tab >>Effects of ageing and gender on the spatial organisation of nuclei in single human skeletal muscle cells
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    2009 (English)In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 19, no 8, p. 605-606Article in journal (Refereed) Published
    National Category
    Medical Image Processing
    Research subject
    Computerized Image Processing
    Identifiers
    urn:nbn:se:uu:diva-97420 (URN)10.1016/j.nmd.2009.06.196 (DOI)
    Available from: 2008-08-29 Created: 2008-08-29 Last updated: 2018-12-18
  • 6.
    Ekstrand, Carl
    et al.
    Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Biomed Sci & Vet Publ Hlth, Box 7058, S-75007 Uppsala, Sweden.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, S-75189 Uppsala, Sweden.
    Giving, Ellen
    Romerike Hesteklin, Riisveien 75, N-2007 Kjeller, Norway.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, S-75189 Uppsala, Sweden.
    Ingvast-Larsson, Carina
    Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Biomed Sci & Vet Publ Hlth, Box 7058, S-75007 Uppsala, Sweden.
    Jacobsen, Stine
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Vet Clin Sci, Dyrlaevej 16, DK-1870 Frederiksberg C, Denmark.
    Löfgren, Maria
    Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Biomed Sci & Vet Publ Hlth, Box 7058, S-75007 Uppsala, Sweden.
    Moen, Lars
    Romerike Hesteklin, Riisveien 75, N-2007 Kjeller, Norway.
    Rhodin, Marie
    Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Anat Physiol & Biochem, Box 7011, S-75007 Uppsala, Sweden.
    Saetra, Tonje
    Rikstotoklinikken Bjerke, Postboks 194, N-0510 Oslo, Norway.
    Ranheim, Birgit
    Norwegian Univ Life Sci, Fac Vet Med, Prod Anim Clin Sci, Box 369 Sentrum, N-0102 Oslo, Norway.
    Disposition and effect of intra-articularly administered dexamethasone on lipopolysaccharide induced equine synovitis2019In: Acta Veterinaria Scandinavica, ISSN 1751-0147, E-ISSN 1751-0147, Vol. 61, article id 28Article in journal (Refereed)
    Abstract [en]

    Background: Dexamethasone is used for the intra-articular route of administration in management of aseptic arthritis in horses. Despite its widespread use there is very little quantitative data of the disposition and response to dexamethasone. The aim of this study was to investigate and describe the synovial fluid and plasma dexamethasone concentration over time and to explore the relation between synovial fluid concentration and response using clinical endpoints as response biomarkers after IA injection of dexamethasone disodium salt solution in an equine model of synovitis.

    Results: Inflammation was induced in the radiocarpal joint of six horses by injection of 2ng lipopolysaccharide (LPS). Two hours later either saline or dexamethasone was injected in the same joint in a two treatment cross over design. Each horse was treated once with one of the six doses dexamethasone used (0.01, 0.03, 0.1, 0.3, 1 or 3mg) and once with saline. Dexamethasone was quantified by means of UHPLC-MS/MS. Dexamethasone disposition was characterised by means of a non-linear mixed effects model. Lameness was evaluated both objectively with an inertial sensor based system and subjectively scored using a numerical scale (0-5). Joint circumference, skin temperature over the joint and rectal temperature were also recorded. The LPS-challenge induced lameness in all horses with high inter-individual variability. Dexamethasone significantly decreased lameness compared with saline. Other variables were not statistically significant different between treatments. Objective lameness scoring was the most sensitive method used in this study to evaluate the lameness response. A pharmacokinetic/pharmacodynamic model was successfully fitted to experimental dexamethasone and lameness data. The model allowed characterization of the dexamethasone synovial fluid concentration-time course, the systemic exposure to dexamethasone after intra-articular administration and the concentration-response relation in an experimental model of synovitis.

    Conclusions: The quantitative data improve the understanding of the pharmacology of dexamethasone and might serve as input for future experiments and possibly contribute to maintain integrity of equine sports.

  • 7.
    Fuchs, Dieter
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Novel Treatment Modalities for High-Risk Neuroblastoma: Studies in Animal Models2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Neuroblastoma, the most common extracranial solid tumor of childhood, is a heterogeneous tumor. In some patients, the tumor can go into spontaneous regression and disappear whereas other patients have rapidly growing tumors with a poor prognosis. The overall long-term survival rate in patients with high-risk neuroblastoma is less than 30%, indicating the need for new treatment strategies.

    Angiogenesis inhibition hampers the formation of new blood vessels, thereby limiting the tumors’ metabolic exchange. Neuroblastoma is rapidly growing and high tumor angiogenesis has been associated with poor outcome. Therefore, the aim of this thesis was to investigate the effect of novel treatment modalities for angiogenesis inhibition on high-risk neuroblastoma xenografts. For that purpose, we used subcutaneous mouse models and characterized orthotopic mouse models for high-risk neuroblastoma.

    We found that xenotransplantation of neuroblastoma cells into the adrenal gland of SCID and SCID beige mice resulted in orthotopic tumors resembling clinical neuroblastoma in respect to tumor site, growth and spread. Using contrast-enhanced ultrasound, we observed that the receptor tyrosine kinase inhibitor SU11248 reduced orthotopic neuroblastoma growth and spread by reducing tumor angiogenesis.

    In subcutaneous xenografts for high-risk neuroblastoma, valuable for studies requiring continuous assessment of tumor volume, we demonstrated that immune-neutralizing VEGF with the anti-VEGF antibody bevacizumab significantly reduced neuroblastoma growth.

    Finally, we found that formulations of the chemotherapeutic drug GMX1778 inhibited angiogenesis and induced tumor regression in a dose dependent manner without host toxicity. We showed that relapsing tumors remained responsive to GMX-therapy without accelerated growth or induced drug resistance.

    In conclusion, SU11248, bevacizumab, and formulations of the active compound GMX1778 may become useful for treating high-risk neuroblastoma.

    List of papers
    1. The Anti-VEGF Antibody Bevacizumab Potently Reduces the Growth Rate of High-Risk Neuroblastoma Xenografts
    Open this publication in new window or tab >>The Anti-VEGF Antibody Bevacizumab Potently Reduces the Growth Rate of High-Risk Neuroblastoma Xenografts
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    2006 (English)In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 60, no 5, p. 576-581Article in journal (Refereed) Published
    Abstract [en]

    Neuroblastoma (NB) is a rapidly growing, well-vascularized childhood cancer that often presents with metastases. The overall five-year survival in NB is approximately 45% despite multimodality treatment, and therefore there is a clinical need for new therapeutic strategies. NB frequently overexpresses the angiogenic factor VEGF (vascular endothelial growth factor). The aim of this study was to investigate the effect of bevacizumab (Avastin, Genentech/Roche), a humanized anti-VEGF-A antibody, on NB growth in three different xenograft models, chosen to resemble high-risk NB. The human NB cell lines SK-N-AS, IMR-32 and SH-SY5Y, which are poorly differentiated and overexpress VEGF-A, were injected s.c. in immunodeficient mice. Bevacizumab was given intraperitoneally twice weekly at 5 mg/kg body weight, starting at a tumor volume of 0.3 mL. Bevacizumab significantly (p < 0.01-0.05) reduced NB growth in vivo without toxicity by causing a 30-63% reduction of angiogenesis, but had no effect on NB cell survival in vitro. Serum concentrations of VEGF-A increased two- to six-fold during bevacizumab therapy which did not result in faster tumor growth compared with control animals. Based on our experimental data we suggest consideration of bevacizumab in treatment of high-risk NB that does not respond to conventional therapy and that overexpresses VEGF.

    Keywords
    angiogenesis, bevacizumab, neuroblastoma, VEGF-A, human
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-98023 (URN)10.1203/01.pdr.0000242494.94000.52 (DOI)000241570300013 ()16988184 (PubMedID)
    Available from: 2009-02-06 Created: 2009-02-06 Last updated: 2017-12-14Bibliographically approved
    2. Regression of orthotopic neuroblastoma in mice by targeting the endothelial and tumor cell compartments
    Open this publication in new window or tab >>Regression of orthotopic neuroblastoma in mice by targeting the endothelial and tumor cell compartments
    Show others...
    2009 (English)In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 7, p. 16-Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: High-risk neuroblastoma has an overall five-year survival of less than 40%, indicating a need for new treatment strategies such as angiogenesis inhibition. Recent studies have shown that chemotherapeutic drugs can inhibit angiogenesis if administered in a continuous schedule. The aim of this study was primarily to characterize tumor spread in an orthotopic, metastatic model for aggressive, MYCN-amplified neuroblastoma and secondarily to study the effects of daily administration of the chemotherapeutic agent CHS 828 on tumor angiogenesis, tumor growth, and spread. METHODS: MYCN-amplified human neuroblastoma cells (IMR-32, 2 x 10(6)) were injected into the left adrenal gland in SCID mice through a flank incision. Nine weeks later, a new laparotomy was performed to confirm tumor establishment and to estimate tumor volume. Animals were randomized to either treatment with CHS 828 (20 mg/kg/day; p.o.) or vehicle control. Differences between groups in tumor volume were analyzed by Mann-Whitney U test and in metastatic spread using Fisher's exact test. Differences with p < 0.05 were considered statistically significant. RESULTS: The orthotopic model resembled clinical neuroblastoma in respect to tumor site, growth and spread. Treatment with CHS 828 resulted in tumor regression (p < 0.001) and reduction in viable tumor fraction (p < 0.001) and metastatic spread (p < 0.05) in correlation with reduced plasma levels of the putative tumor marker chromogranin A (p < 0.001). These effects were due to increased tumor cell death and reduced angiogenesis. No treatment-related toxicities were observed. CONCLUSION: The metastatic animal model in this study resembled clinical neuroblastoma and is therefore clinically relevant for examining new treatment strategies for this malignancy. Our results indicate that daily scheduling of CHS 828 may be beneficial in treating patients with high-risk neuroblastoma.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-98024 (URN)10.1186/1479-5876-7-16 (DOI)000265143500001 ()19284605 (PubMedID)
    Available from: 2009-02-06 Created: 2009-02-06 Last updated: 2017-12-14Bibliographically approved
    3. SU11248-mediated angiogenesis inhibition reduces tumor growth and spread in orthotopic neuroblastoma in mice monitored with contrast-enhanced ultrasound
    Open this publication in new window or tab >>SU11248-mediated angiogenesis inhibition reduces tumor growth and spread in orthotopic neuroblastoma in mice monitored with contrast-enhanced ultrasound
    (English)Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-98025 (URN)
    Available from: 2009-02-06 Created: 2009-02-06 Last updated: 2011-01-11Bibliographically approved
    4. Metronomic GMX1777 results in tumor regression and vessel maturation in subcutaneous neuroblastoma in mice without inducing drug resistance
    Open this publication in new window or tab >>Metronomic GMX1777 results in tumor regression and vessel maturation in subcutaneous neuroblastoma in mice without inducing drug resistance
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    (English)Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-98026 (URN)
    Available from: 2009-02-06 Created: 2009-02-06 Last updated: 2011-06-28Bibliographically approved
  • 8.
    Heiene, Reidun
    et al.
    University of Utrecht.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Neusüß, Christian
    Aalen University.
    Hedeland, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Carbamylated hemoglobin project AKI vs CKD- or the magnitude of the chronic component2016Conference paper (Refereed)
  • 9.
    Hjelmblink, Finn
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Understanding Life After Stroke2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Stroke is an acute, neurological dysfunction of vascular origin with sudden occurrence and it influences physical, cognitive and psychological functions. Initial treatment aims at eliminating or reducing the brain damage. Soon, however, the influence of the stroke on the entire life of stroke survivors has to be considered.

    This thesis explores the meaning of life after stroke to 19 elderly stroke survivors during the first year post stroke. Survivors were interviewed twice and the interviews were analysed through qualitative methods.

    Study I was about four survivors who delayed hospital arrival far beyond time limits for trombolytic treatment. The survivors had a strong need for control of body, autonomy and integrity and they demanded to be encountered in consultations as a person by a person. To make them search for emergency evaluation in time might demand an emergency care treating them according to these needs.

    In Study II the voice of an aphasic survivor was heard. Because of the damaged language his rehabilitation unilaterally focussed on language training and his need for comprehensive support and planning for the future was not observed. Implementation of a qualitative research method for text analysis adapted to practical use in dialogues with aphasic persons might ensure these survivors an adequate rehabilitation.

    Study III showed how time models in narratives helped stroke survivors to overcome uncertainty and recreate narrative coherence in their lives. Professionals can support survivors through revealing and reinforcing the meaning of these models.

    Study IV found that the meaning of rehabilitation to stroke survivors was social reintegration. Many probably did not socially reintegrate because their own strategies and subjectively experienced disabilities were unacknowledged in their rehabilitation. Through integrating illness-as-lived perspectives with biomedical perspectives, subjective dysfunctions and rehabilitation strategies of survivors could be acknowledged in stroke rehabilitation.

    List of papers
    1. Stroke patients' delay of emergency treatment
    Open this publication in new window or tab >>Stroke patients' delay of emergency treatment
    2010 (English)In: Scandinavian Journal of Caring Sciences, ISSN 0283-9318, E-ISSN 1471-6712, Vol. 24, no 2, p. 307-311Article in journal (Refereed) Published
    Abstract [en]

    Treatment of stroke victims with fibrinolysis should take place within a time limit of 3 hours. In spite of comprehensive endeavours to reduce hospital arrival time, too many patients still delay arrival beyond this time limit. This qualitative case study explored the meaning of acute stroke and treatment to four patients with more than 24-hour delayed arrival. The setting of the study was the catchment area of a university hospital. Semi-structured interviews were analysed through the empirical psychological, phenomenological method. An essence was found which was constituted by four themes. The essence of stroke symptoms and treatment was: 'Threatened control of bodily function, autonomy and integrity'. When the patients fell ill they acted as if nothing had happened. They treated their body like a defective device. In encounters with physicians they demanded to be met as a person by a person; otherwise they rejected both the physician and her or his prescriptions. They did not involve their near ones in decision-making. The conclusions were the following: Health care information about how to act in cases of early stroke symptoms may need to imbue people with an understanding of how early treatment of neurological symptoms and preserved control of life are intimately connected. Furthermore emergency care of acute stroke patients might need to take place in an organisation where patients are sure to be met by physicians as a person by a person.

    Keywords
    cerebrovascular accident, stroke, emergency treatment, delay of treatment, patient centredness
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97531 (URN)10.1111/j.1471-6712.2009.00721.x (DOI)000277713500014 ()20233357 (PubMedID)
    Available from: 2008-09-18 Created: 2008-09-18 Last updated: 2017-12-14Bibliographically approved
    2. Understanding the meaning of rehabilitation to an aphasic patient through phenomenological analysis - a case study 
    Open this publication in new window or tab >>Understanding the meaning of rehabilitation to an aphasic patient through phenomenological analysis - a case study 
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    2007 (English)In: International Journal of Qualitative Studies on Health and Well-Being, ISSN 1748-2623, Vol. 2, no 2, p. 93-100Article in journal (Refereed) Published
    Abstract [en]

    Stroke patients with aphasia commonly suffer from distress related to their language deficit. They are often unable to express what they experience during their rehabilitation. Hence, the aim of this study was to reveal the meaning of rehabilitation to an aphasic person. With an approach based on the philosophy of Husserl and Merleau-Ponty, two open-ended interviews were analysed through the Empirical Phenomenological Psychological (EPP) method. The essential structure of the meaning of rehabilitation to the informant was that he lived as being responsible in a dichotomised situation. The informant had to adapt his behaviour, thereby destroying his chances of normal interactions; he was supposed to train in a goal-oriented way and believe in recuperation, but at the same time, he had to prepare himself and his next of kin for a failure. The defined impairment of aphasia misled both the informant and health care professionals to focus only language therapy, hence leaving the informant unsupported in other important aspects of the rehabilitation.

    Keywords
    Stroke, aphasia, case study, phenomenology, rehabilitation
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97532 (URN)10.1080/17482620701296358 (DOI)
    Available from: 2008-09-18 Created: 2008-09-18 Last updated: 2010-06-02Bibliographically approved
    3. To cope with uncertainty: stroke patients' use of temporal models in narratives
    Open this publication in new window or tab >>To cope with uncertainty: stroke patients' use of temporal models in narratives
    2006 (English)In: Scandinavian Journal of Caring Sciences, ISSN 0283-9318, E-ISSN 1471-6712, Vol. 20, no 4, p. 367-374Article in journal (Refereed) Published
    Abstract [en]

    Stroke victims have to cope with a disrupted autobiography and anxiety because of an uncertain future. Professionals share this uncertainty. The patients reveal their experiences in narratives, and when they try to regain coherence and confidence in life, they use narratives in the reconstructions. Because they have a temporal problem, time might be an important issue in these narratives. The aim of this study was to elucidate the use of time models in stroke patients' narratives. Nineteen stroke patients, who had recently been discharged to their homes after the stroke, accepted to participate in the study. Their age span was between 56 and 89 years. They had lived active urban lives before the stroke, and poststroke only three had more serious physical impairment, and none was demented. They were asked to talk about their present life and their conceptions of future life. The interviews were audio-taped and transcribed verbatim and narratives that referred to temporal aspects were thematically analysed with reference to narrative time models. The stroke accident had caused an autobiographical disruption and a temporal split because of a new awareness of human temporality and an uncertainty of the future. Confronted with these problems of time, the stroke victims constructed narratives based on the time models: time cycles and dissolution of time limits, exchange of time and exclusion from time. Hence, the time models worked as tools when the stroke victims re-established coherence in their present and future life. Stroke patients handled an uncertain future by using temporal models in their narratives. Professionals can support stroke patients by reinforcing these models.

    Keywords
    Anxiety, Discourse of medicine, Narrative, Stroke, Temporality, Time models
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97533 (URN)10.1111/j.1471-6712.2006.00415.x (DOI)000243152000002 ()17116145 (PubMedID)
    Available from: 2008-09-18 Created: 2008-09-18 Last updated: 2017-12-14Bibliographically approved
    4. The meaning of rehabilitation for older people who have survived stroke
    Open this publication in new window or tab >>The meaning of rehabilitation for older people who have survived stroke
    2009 (English)In: Journal of Nursing and Healthcare of Chronic Illness, ISSN 1752-9816, E-ISSN 1752-9824, Vol. 1, no 2, p. 186-195Article in journal (Refereed) Published
    Abstract [en]

    Aim. To explore the meaning of rehabilitation to older, Swedish stroke survivors, from the time of the acute stroke to the end of the rehabilitation.

    Background. Many people who are stroke survivors do not resume social activities even though they have regained physical functions. However, the contents of stroke rehabilitation seems to depend on whether rehabilitation is understood from the disease perspective or the illness perspective contained in the International Classification of Functioning, Disability and Health. This in turn may determine the kind of rehabilitation offered to survivors.

    Design. Inductive, qualitative interview study undertaken during 2003.

    Method. Nineteen Swedish stroke survivors were interviewed twice, and the interviews were analysed using a Grounded Theory approach.

    Findings. To the older survivors, the meaning of rehabilitation was social reintegration. To achieve this they tried to regain lost physical and cognitive functions, relations (including play activities, everyday narratives and self-esteem) and lost certainty. The survivors needed to regain their ability to be not only to perform social activities. However, their rehabilitation ended when its focus turned to impairments found in the illness experiences of the survivors. The survivors developed their own cognitive and behavioural strategies for overcoming these kinds of obstacles to their social reintegration.

    Conclusion. Older, Swedish stroke survivors strive for a socially integrated life. Unacknowledged impairments experienced from the illness perspective of the survivors and the survivors’ own rehabilitation strategies should therefore be considered in their rehabilitation.

    Relevance to clinical practice. Stroke survivors need support from professionals who can understand and acknowledge the illness perspective of rehabilitation. Professionals should be able to understand how to facilitate the cognitive and behavioural strategies found in survivors’ illness narratives. In order to socially reintegrate, survivors’ rehabilitation should be transferred to the places where they have previously performed play activities together with family and friends.

    Keywords
    cerebrovascular, geriatrics, qualitative research, rehabilitation, stroke
    National Category
    Medical and Health Sciences
    Research subject
    Health Care Research
    Identifiers
    urn:nbn:se:uu:diva-97534 (URN)10.1111/j.1752-9824.2009.01020.x (DOI)
    Available from: 2008-09-18 Created: 2008-09-18 Last updated: 2017-12-14Bibliographically approved
  • 10.
    Holdstock, Camilla
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Gastric Bypass in Morbid Obesity: Postoperative Changes in Metabolic, Inflammatory and Gut Regulatory Peptides2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis examines the effect of surgical weight loss on gut and adipose tissue peptides involved in appetite regulation and energy homeostasis in morbidly obese humans. Roux-en-Y gastric bypass (RYGBP) is the gold standard operation used for effective long-term weight loss and improved health. The exact mechanisms for this outcome are under investigation.

    We measured ghrelin, a recently discovered hunger hormone, insulin, adiponectin and leptin along with anthropometry measures in 66 morbidly obese patients prior to and 6 and 12 months after RYGBP. Impressive weight loss occurred postoperatively as did alterations in the peptides. Consistent correlations were found between weight, leptin, ghrelin and insulin. The main findings were low ghrelin concentrations in obesity and an increase after RYGBP.

    We explored inflammatory proteins C-reactive protein (CRP), serum amyloid A and interleukin-6 before and during massive weight loss 6 and 12 months after RYGBP in morbidly obese subjects. The studied proteins declined after surgery and a correlation between CRP and homeostatic model of assessment for insulin resistance, independent of BMI, strongly linked insulin resistance and inflammation. CRP declined most in insulin-sensitive subjects.

    We examined the excluded stomach mucosa and vagus nerve by measuring gastrin, pepsinogen I (PGI), pancreatic polypeptide (PP) and ghrelin levels during week 1 and year after RYGBP. Ghrelin levels rose with weight loss but declined 24-hours after surgery, like PP, indicating transient vagal nerve damage. Low levels of gastrin and PGI suggest a resting mucosa.

    We evaluated gut peptides: peptide YY (PYY), glucaogon like peptide-1 (GLP-1), pro-neurotensin (pro-NT) and PP, in lean (young and middle-aged), obese and postoperative RYGBP subjects pre- and postprandially. RYGBP subjects had exaggerated levels of PYY and GLP-1 postprandially and higher basal proNT levels, implying a ‘satiety peptide tone’ that may contribute to the maintenance of weight loss.

    In summary, RYGBP results in marked weight loss and alterations in gut and adipose tissue peptides involved in appetite regulation and energy homeostasis. These postoperative peptide changes may contribute to impressive weight loss observed after RYGBP.

    List of papers
    1. Ghrelin and Adipose Tissue Regulatory Peptides: Effect of Gastric Bypass Surgery in Obese Humans
    Open this publication in new window or tab >>Ghrelin and Adipose Tissue Regulatory Peptides: Effect of Gastric Bypass Surgery in Obese Humans
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    2003 In: The Journal of Clinical Endocrinology & Metabolism, ISSN 0021-972X, Vol. 88, no 7, p. 3177-3183Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-97580 (URN)
    Available from: 2008-10-02 Created: 2008-10-02Bibliographically approved
    2. CRP reduction following gastric bypass surgery is most
    Open this publication in new window or tab >>CRP reduction following gastric bypass surgery is most
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    2005 In: International Journal of Obesity, ISSN 0307-0565, Vol. 29, no 10, p. 1275-Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-97581 (URN)
    Available from: 2008-10-02 Created: 2008-10-02Bibliographically approved
    3. Early Changes in Ghrelin following Roux-en-Y Gastric Bypass: Influence of Vagal Nerve Functionality?
    Open this publication in new window or tab >>Early Changes in Ghrelin following Roux-en-Y Gastric Bypass: Influence of Vagal Nerve Functionality?
    2007 (English)In: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 17, no 3, p. 304-310Article in journal (Refereed) Published
    Abstract [en]

    Background  Roux-en-Y gastric bypass (RYGBP) effectively produces massive weight reduction, improving health in morbidly obese patients. The mechanisms for the weight loss, and the fate of the excluded gastric mucosa, are not fully clarified. To what extent the appetite-stimulating gastric peptide ghrelin is affected remains controversial. Methods  Circulating concentrations of ghrelin, pancreatic polypeptide (PP), pepsinogen I (PGI) and gastrin were examined in 15 morbidly obese patients (median BMI 45 kg/m2) preoperatively, and on days 1, 2, 4, 6 and at months 1, 6 and 12 after RYGBP. Results  Ghrelin levels fell on postoperative day 1 and increased after 1 month to preoperative levels, and rose further at 6 and 12 months. PP concentrations decreased on day 1 and subsequently returned to preoperative levels. PGI levels peaked transiently the first days after surgery and subsequently declined to lower than preoperative levels. Gastrin levels were gradually reduced postoperatively. Conclusion  Ghrelin and PP fall transiently after surgery, possibly due to vagal dysfunction, and ultimately, as weight loss ensues, ghrelin secretion increases to higher than preoperative levels. The RYBGP procedure affects the gastric mucosa, as reflected by a transient increase in circulating PGI, and subsequently, the mucosa in the excluded stomach is at rest, as shown by low levels of PGI and gastrin.

    Keywords
    gastric bypass, ghrelin, pepsinogen, gastrin, pancreatic polypeptide, morbid obesity, vagus nerve
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97582 (URN)10.1007/s11695-007-9056-8 (DOI)000245043900004 ()17546836 (PubMedID)
    Available from: 2008-10-02 Created: 2008-10-02 Last updated: 2017-12-14Bibliographically approved
    4. Postprandial changes in gut regulatory peptides in gastric bypass patients
    Open this publication in new window or tab >>Postprandial changes in gut regulatory peptides in gastric bypass patients
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    2008 (English)In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 32, p. 1640-6Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE: The marked weight loss induced by Roux-en-Y gastric bypass (RYGBP) for morbid obesity is still incompletely understood. It has been suggested that, besides the restriction imposed by the surgical procedure, alterations in gut regulatory peptides signaling the brain might contribute. The aim of this study was to measure the putative satiety peptides peptide YY (PYY), glucagon-like peptide-1 (GLP-1), pancreatic polypeptide (PP) and pro-neurotensin (pro-NT) in response to fasting and feeding. DESIGN: The study is a cross-sectional study. After a prolonged overnight 14 h fast, a standardized mixed meal (574 kcal) was provided. Blood samples for peptide measurements were obtained before and after the meal. SUBJECTS: Forty subjects (20 males and females) were included; 10 morbidly obese; (mean age 41+/-7 years; mean BMI 44+/-3 kg/m(2)), 10 operated with RYGBP (age 45+/-5 years; BMI 35+/-6 kg/m(2)), 10 aged-matched lean (age 44+/-5 years; BMI 24+/-3 kg/m(2)) and 10 young lean subjects (age 26+/-2 years; BMI 23+/-2 kg/m(2)). MEASUREMENTS: Plasma concentrations of PYY, GLP-1, PP and pro-NT were obtained. RESULTS: PYY levels increased more in the RYGBP group than in the other groups after the test meal. GLP-1 levels rose in the RYGBP patients, with a small increase seen in the age-matched lean group. PP concentrations increased similarly in all groups postprandially. Pro-NT levels were highest in surgical patients, with no meal effect. CONCLUSION: RYGBP subjects displayed exaggerated PYY and GLP-1 responses to a standardized meal and demonstrated higher pro-NT levels both pre- and postprandially. The findings indicate that possibly the alterations in gut peptide secretion may promote weight loss after gastric bypass surgery.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97583 (URN)10.1038/ijo.2008.157 (DOI)000260925300006 ()18794895 (PubMedID)
    Available from: 2008-10-02 Created: 2008-10-02 Last updated: 2017-12-14Bibliographically approved
  • 11.
    Jemtå, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Rehabilitation Medicine.
    Children and Adolescents Living with Mobility Impairment2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Aim: This thesis aims to describe perceived overall well-being, coping strategies, experiences of intimacy and sexuality, and global and dimension-specific self-esteem among children and adolescents with mobility impairment.

    Methods: The study included 141 children and adolescents aged 7–18 years with mobility impairment. Data was gathered by comprehensive semi-structured interviews and the self-report inventories “Children’s Coping Strategies Checklist” (CCSC) and “I Think I am”. Perceived overall well-being was measured by the nine-grade visual “Snoopy scale”. Motor function and pain were measured by the BL motor assessment, and independence or dependence by Katz Index of Independence in Activities of Daily Living.

    Results: The majority reported a favourable level of perceived overall well-being and positive global and dimension-specific self-esteem. Lower global self-esteem was significantly related to: greater age, being a first-generation immigrant, having an acquired disease or injury and experience of pain, while lower level of perceived overall well-being was significantly related to all of these in addition to not living with both parents. Generally, children and adolescents identified themselves as sexual beings and most expressed future aspirations as living together with partner having children. However, many had limited or no experience of partner-related intimacy and sexual activities, and socio-demographic and disability characteristics had a marginal influence. A history of sexual abuse was reported by 7% in the age cohort 13–18 years. A four-dimensional model of coping strategies including “active coping”, “distraction”, “avoidance” and “support seeking” strategies provided an adequate fit to the CCSC data. Three of the four strategies, all except “avoidance”, were significantly related to several demographic and disability features. Well-being was not significantly related to coping strategies, although the higher the trust in the strategies, the higher the estimation of well-being.

    Conclusion: The understanding of vulnerability factors as well as identification of coping strategies among children and adolescents with mobility impairment is essential for providing proper care, treatment and support during childhood and adolescence.

    List of papers
    1. Well-being among children and adolescents with mobility impairment in relation to demographic data and disability characteristics
    Open this publication in new window or tab >>Well-being among children and adolescents with mobility impairment in relation to demographic data and disability characteristics
    2005 In: Acta Paediatrica, ISSN 0803-5253, Vol. 94, p. 616-623Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-97551 (URN)
    Available from: 2008-10-03 Created: 2008-10-03Bibliographically approved
    2. Coping strategies among Swedish children and adolescents with mobility impairment in relation to demographic data, disability characteristics and well-being
    Open this publication in new window or tab >>Coping strategies among Swedish children and adolescents with mobility impairment in relation to demographic data, disability characteristics and well-being
    2007 (English)In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 96, no 8, p. 1184-1189Article in journal (Refereed) Published
    Abstract [en]

    Aim: The first aim of the present study was to evaluate the applicability of a four-dimensional model of coping strategies, which includes 'active coping', 'distraction', 'avoidance' and 'support seeking' strategies, on children and adolescents with mobility impairment. The second aim was to identify coping strategies in this group. Finally, we analysed the relation between coping strategies and demographic data, disability characteristics and well-being.

    Methods: Children and adolescents aged 7–18 years with mobility impairment (n = 133) were interviewed, and demographic and disability characteristics were recorded. The Children's Coping Strategies Checklist, a 52-item self-report inventory, was used to characterise dispositional style in coping.

    Results: The four-factor model of coping strategies provides an adequate fit to the data of the sample studied. Three of the four coping strategies, all except 'avoidance', were significantly related to several demographic and disability features. Well-being was not significantly related to any of the four coping strategies, although the higher the trust in the strategies, the higher the estimation of one's own well-being.

    Conclusion: Identification of coping strategies among children and adolescents with mobility impairment should form the basis of our understanding of how they face the complexity of challenges while growing up.

    Keywords
    Adolescent, Children, Coping strategy, Disability, Well-being
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97552 (URN)10.1111/j.1651-2227.2007.00387.x (DOI)000248282500018 ()17590192 (PubMedID)
    Available from: 2008-10-03 Created: 2008-10-03 Last updated: 2018-01-17Bibliographically approved
    3. On intimacy, sexual activities and exposure to sexual abuse among children and adolescents with mobility impairment
    Open this publication in new window or tab >>On intimacy, sexual activities and exposure to sexual abuse among children and adolescents with mobility impairment
    2008 (English)In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 97, no 5, p. 641-646Article in journal (Refereed) Published
    Abstract [en]

    Aim: The aim was to describe experiences of intimacy and sexual activity and exposure to sexual abuse among children and adolescents with mobility impairment, and to relate these experiences to socio-demographic data, disability characteristics and well-being. Methods: This study included semi-structured interviews with 141 children and adolescents aged 7-18 years with mobility impairment. Interpersonal experiences of intimacy and sexuality, socio-demographic data, disability characteristics and well-being were registered. Results: About half of the children and adolescents in the study had been in a boy- or a girlfriend relationship, and about a fifth had an ongoing relationship. Of the adolescents, 15% had at least one experience of a sexual relationship. Whereas no particular sexual dysfunction was reported, 15% had concerns about their future sexual activities, presumably related to mobility impairment. A history of sexual abuse was reported by 7% in the age cohort of 13-18 years. The socio-demographic and disability-related features had a marginal influence on the experiences of intimacy and sexual activities. Conclusion: Several aspects of sexual health are not fully realized for children and adolescents with impaired mobility, and there is a need for specialized sexual health care services to protect the sexual rights of this group.

    Keywords
    Adolescent, Children, Disability, Sexual abuse, Sexuality
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97553 (URN)10.1111/j.1651-2227.2008.00757.x (DOI)000254988600025 ()18394110 (PubMedID)
    Available from: 2008-10-03 Created: 2008-10-03 Last updated: 2017-12-14Bibliographically approved
    4. Self-esteem in children and adolescents with mobility impairment: impact on well-being and coping strategies
    Open this publication in new window or tab >>Self-esteem in children and adolescents with mobility impairment: impact on well-being and coping strategies
    2009 (English)In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 98, no 3, p. 567-572Article in journal (Refereed) Published
    Abstract [en]

    AIM: The first aim was to investigate dimension-specific and global self-esteem in children and adolescents with mobility impairment and to analyse the relation between self-esteem and demographic data and disability characteristics. The second aim was to identify the impact of five self-esteem dimensions on well-being and coping strategies. METHODS: A total of 138 children and adolescents aged 7-18 years with mobility impairment took part in a semi-structured interview. Demographic and disability characteristics were recorded and motor function was assessed. Self-esteem was measured by the 'I think I am' inventory. Perceived overall well-being was measured by a nine-grade visual scale, the Snoopy scale, and coping strategies by the Children's Coping Strategies Checklist. RESULTS: Although a majority estimated a relatively high level of dimension-specific and global self-esteem, several demographic and disability factors for lower self-esteem were identified. Those who estimated their 'physical characteristics' lower used the coping strategy 'distraction' more often. Three out of five dimensions of self-esteem were positively associated with perceived overall well-being: 'physical characteristics', 'psychological well-being' and 'relationships with others'. CONCLUSION: Awareness of vulnerability factors for lower self-esteem in children and adolescents with mobility impairment offer health care professionals specific opportunities to enhance self-esteem in this group.

    Keywords
    Adolescents, Children, Coping, Disability, Self-esteem, Well-being
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97554 (URN)10.1111/j.1651-2227.2008.01081.x (DOI)000262878200028 ()18976365 (PubMedID)
    Available from: 2008-10-03 Created: 2008-10-03 Last updated: 2017-12-14Bibliographically approved
  • 12. Jitpean, Supranee
    et al.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Pettersson, Ann
    Höglund, Odd V
    Ström, Bodil Holst
    Hagman, Ragnvi
    Decreased plasma Chromogranin A361-372 (Catestatin) but not Chromogranin A17-38 (Vasostatin) in female dogs with bacterial uterine infection (pyometra).2015In: BMC veterinary research, ISSN 1746-6148, Vol. 11, no 1, p. 14-Article in journal (Refereed)
    Abstract [en]

    BackgroundPyometra often induces systemic inflammatory response syndrome (SIRS) and early diagnosis is crucial for survival. Chromogranin A (CgA) is a neuroendocrine secretory protein that is co-released with catecholamines from the adrenal medulla and sympathetic nerve endings. A prognostic value of CgA has been found in humans that are critically ill or that have SIRS associated with infection. CgA has not yet been studied in dogs with bacterial infection. The aim of the study was to investigate CgA, measured by Chromogranin A361-372 (Catestatin; Cst) and Chromogranin A17-38 (Vasostatin; VS) in healthy dogs and in dogs with pyometra.ResultsFifty dogs with pyometra, sampled prior to surgery and 64 healthy female dogs were included. In 19 pyometra cases, blood samples were also collected postoperatively. Concentrations of Cst and VS were measured in heparinised plasma and Cst also measured in EDTA plasma, by in-house radioimmunoassays. Student¿s t-test and Wilcoxon two-sample test was used to test for differences between dog groups. Pre- and postoperative samples in dogs with pyometra were analysed by paired t-test. Pearson correlation was used to investigate associations of laboratory variables and hospitalization. P < 0.05 was considered significant.Concentrations of Cst were decreased in pyometra dogs (mean ± SE, 1.01 ± 0.05 nmol/L) compared to healthy dogs (mean ± SE, 1.70 ± 0.03 nmol/L) (p ¿ 0.0001). VS concentrations did not differ significantly between dogs with pyometra (0.40 ± 0.04 nmol/L) and healthy dogs (0.42 ± 0.03 nmol/L). Mean ± SE pre- and postoperative concentration of Cst (1.0 ± 0.04 nmol/L and 0.9 ± 0.2 nmol/L) and VS (0.36 ± 0.04 nmol/L and 0.36 ± 0.04 nmol/L) in dogs with pyometra did not differ significantly. Neither Cst nor VS concentrations were associated with duration of hospitalization and were not significantly different in the four dogs with pyometra that had prolonged (¿3 d) postoperative hospitalization.ConclusionConcentrations of Cst, but not VS, were decreased in pyometra. Cst and VS concentrations before and after ovariohysterectomy did not differ significantly and were not associated with duration of hospitalization. Further studies are warranted to evaluate a possible diagnostic or prognostic value for Cst and VS.

  • 13.
    Kask, Kristiina
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Women's and Children's Health.
    Hormones, Mood and Cognition2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ovarian steroid hormones are neuroactive steroids with widespread actions in the brain, and are thus able to influence mood, behavior and cognition.

    In this thesis the effects of progesterone withdrawal and the direct effects of the progesterone metabolite allopregnanolone are evaluated.

    Allopregnanolone, through binding to the GABAA receptor complex, enhances inhibitory neurotransmission, thus exerting anxiolytic, sedative and antiepileptic effects.

    The acoustic startle response (ASR) is a withdrawal reflex evoked by sudden or noxious auditory stimuli, and can be measured in humans as an eye blink. ASR is significantly increased in several anxiety disorders, and notably also during progesterone withdrawal.

    Sensorimotor gating can be assessed by measuring prepulse inhibition of the startle response (PPI). The CNS circuits regulating PPI are sensitive to hormone fluctuations. GABAergic drugs are involved in cognitive impairment and animal studies have indicated that allopregnanolone may inhibit learning.

    The main purpose of this research was to evaluate the behavioral effects of progesterone withdrawal on the startle response and sensorimotor gating in PMDD patients and healthy controls, in healthy third trimester pregnant women and healthy postpartum women. A second aim was to evaluate allopregnanolone effects on memory and cognition in healthy women and also on the startle response and PPI.

    We found that PMDD patients have an increased startle response across the menstrual cycle and a deficiency in sensorimotor gating during the late luteal phase.

    Ovarian steroids affect sensorimotor gating; pregnant women have lower levels of PPI than late postpartum women. Acutely administered allopregnanolone did not affect the ASR or PPI. Allopregnanolone impairs episodic memory in healthy women.

    In conclusion, our studies suggest that ovarian steroids, including allopregnanolone, do not influence the startle response. Ovarian steroids affect sensorimotor gating; pregnancy, a condition with high levels of ovarian steroids, suppresses PPI. Theoretically, the variability in PPI across reproductive events is due to effects mediated by the progesterone or estradiol receptors but is not mediated by allopregnanolone. PMDD patients display decreased PPI during the late luteal phase, suggesting underlying pathophysiology in common with other anxiety disorders. The most vulnerable memory system, the episodic memory, is impaired by the allopregnanolone in healthy women.

    List of papers
    1. Patients with premenstrual dysphoric disorder have increased startle response across both cycle phases and lower levels of prepulse inhibition during the late luteal phase of the menstrual cycle
    Open this publication in new window or tab >>Patients with premenstrual dysphoric disorder have increased startle response across both cycle phases and lower levels of prepulse inhibition during the late luteal phase of the menstrual cycle
    Show others...
    2008 (English)In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 33, no 9, p. 2283-2290Article in journal (Refereed) Published
    Abstract [en]

    Patients with premenstrual dysphoric disorder (PMDD) experience their most intense symptoms during the late luteal phase. The aim of the current study was to compare acoustic startle response and prepulse inhibition in PMDD patients and controls during the follicular and late luteal phases of the menstrual cycle. Following two months of prospective daily ratings on the Cyclicity Diagnoser scale, 30 PMDD patients and 30 asymptomatic controls, between the ages of 20 and 46, were included in the study. The eyeblink component of the acoustic startle reflex was assessed using electromyographic measurements of m. orbicularis oculi. Twenty pulse-alone trials (115 dB 40 ms broad-band white noise) and 40 prepulse-pulse trials were presented. The prepulse stimuli consisted of a 115 dB 40 ms noise burst preceded at a 100 ms interval by 20 ms prepulses that were 72, 74, 78, or 86 dB. PMDD patients had a significantly higher startle response than controls during both phases of the menstrual cycle (p<0.05). PMDD patients exhibited lower levels of prepulse inhibition with 78 dB and 86 dB prepulses compared to control subjects in the luteal (p<0.01) but not in the follicular phase. Whereas control subjects displayed increased PPI during the late luteal phase compared to the follicular phase (p<0.01), PPI magnitude remained unchanged in PMDD patients between cycle phases. Relative to controls, PMDD patients displayed increased startle reactivity across both menstrual cycle phases and deficits in prepulse inhibition of acoustic startle during the late luteal phase. These findings are consistent with an altered response to ovarian steroids among PMDD patients.

    Keywords
    startle response, prepulse inhibition, premenstrual dysphoric disorder, menstrual cycle, estradiol, progesterone
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97753 (URN)10.1038/sj.npp.1301599 (DOI)000257622200023 ()17940552 (PubMedID)
    Available from: 2008-11-14 Created: 2008-11-14 Last updated: 2017-12-14Bibliographically approved
    2. Lower levels of prepulse inhibition of startle response in pregnant women compared to postpartum women
    Open this publication in new window or tab >>Lower levels of prepulse inhibition of startle response in pregnant women compared to postpartum women
    2008 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 33, no 1, p. 100-107Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE: During the postpartum period, estradiol and progesterone levels decline from very high levels during late pregnancy to low levels within 48h of parturition. This period is associated with dysphoric states such as the postpartum blues. Animal studies have suggested an enhanced acoustic startle response and deficient prepulse inhibition (PPI) of startle response following progesterone withdrawal and during the postpartum period. The aim of the current study was to compare acoustic startle response and PPI in healthy third trimester pregnant women and healthy postpartum women. METHODS: Twenty-eight healthy pregnant and 21 healthy postpartum women (examined between 48h and 1 week after delivery) were recruited for the study. In addition, to evaluate the time-course of postpartum changes 11 early postpartum women (examined within 48h following delivery) were included in the study. The eyeblink component of the acoustic startle reflex was assessed using electromyographic measurements of m. Orbicularis Oculi. Twenty pulse-alone trials (115dB 40ms broad-band white noise) and 40 prepulse-pulse trials were presented. The prepulse stimuli consisted of a 115dB 40ms noise burst preceded at a 100ms interval by 20ms prepulses that were 72, 74, 78 or 86dB. RESULTS: Pregnant women exhibited lower levels of PPI compared to late postpartum women, p<0.05. There was no difference between pregnant women and postpartum women examined within 48h of delivery. There was no difference in startle response or habituation to startle response between pregnant women and either of the two groups of postpartum women. CONCLUSION: Healthy women display lower levels of PPI during late pregnancy when estradiol and progesterone levels are high compared to the late postpartum period when ovarian steroid levels have declined.

    Keywords
    Prepulse inhibition, Startle response, Pregnancy, Postpartum, Estradiol, Progesterone
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97754 (URN)10.1016/j.psyneuen.2007.10.005 (DOI)000253027800011 ()18037247 (PubMedID)
    Available from: 2008-11-14 Created: 2008-11-14 Last updated: 2017-12-14Bibliographically approved
    3. Allopregnanolone has no effect on startle response and prepulse inhibition of startle response in patients with premenstrual dysphoric disorder or healthy controls
    Open this publication in new window or tab >>Allopregnanolone has no effect on startle response and prepulse inhibition of startle response in patients with premenstrual dysphoric disorder or healthy controls
    2009 (English)In: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 92, no 4, p. 608-613Article in journal (Refereed) Published
    Abstract [en]

    Background: Allopregnanolone is an endogenous neuroactive steroid  which, through the binding to the GABA(A) receptor. enhances inhibitory   neurotransmission and exerts anxiolytic, sedative and antiepileptic  effects. Following acute administration, allopregnanolone reliably acts as an anxiolytic compound. The primary aim of this study was to investigate if allopregnanolone, administered to healthy women and   women with premenstrual dysphoric disorder (PMDD), would have an anxiolytic effect, expressed as a decreased startle response.   Materials and methods: Sixteen PMDD patients and twelve healthy   controls completed the study. The participants were scheduled for the   startle tests twice in the luteal phase. During the test sessions an intravenous allopregnanolone and placebo bolus injection was administered in double-blinded, randomized order at intervals of 48 h. Following the allopregnanolone/placebo injections startle response and   prepulse inhibition of startle response (PPI) were assessed by   electromyography.   Results: Following the intravenous allopregnanolone administration the   serum concentrations of allopregnanolone increased to 50-70 nmol/l.   corresponding to levels that are seen during pregnancy. The obtained   serum concentrations of allopregnanolone were significantly lower in   PMDD patients than among the healthy controls, p<0.05. The   allopregnanolone injection resulted in significant increases of   self-rated sedation in both groups, p<0.01. Allopregnanolone did not induce any changes in startle response or prepulse inhibition of   startle response in comparison to placebo. No differences in allopregnanolone-induced changes in startle response or PPI could be detected between PMDD patients and controls subjects. Conclusion: Startle response and PPI were unaffected by acute   intravenous administration of allopregnanolone in PMDD patients and healthy controls.

    Keywords
    Allopregnanolone, Premenstrual dysphoric disorder, Startle response, Prepulse inhibition
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97755 (URN)10.1016/j.pbb.2009.02.014 (DOI)000266538800008 ()19268499 (PubMedID)
    Available from: 2008-11-14 Created: 2008-11-14 Last updated: 2017-12-14Bibliographically approved
    4. Allopregnanolone impairs episodic memory in healthy women
    Open this publication in new window or tab >>Allopregnanolone impairs episodic memory in healthy women
    2008 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 199, no 2, p. 161-168Article in journal (Refereed) Published
    Abstract [en]

    Allopregnanolone is an endogenous neuroactive steroid that, through its binding to the γ-aminobutyric acid (GABA) A receptor, has GABA-active properties. Animal studies indicate that allopregnanolone administration results in diminished learning and memory impairment. The aim of the current study was to investigate the effect of intravenously administered allopregnanolone on episodic memory, semantic memory, and working memory in healthy women.

    Twenty-eight healthy women were included in the study. The participants were scheduled for the memory tests twice in the follicular phase. During the test sessions, an intravenous allopregnanolone and placebo infusion were administered in a double-blinded, randomized order at intervals of 48 h. Before and 10 min after the allopregnanolone/placebo injections, memory tasks were performed.The study demonstrated that allopregnanolone impaired episodic memory in healthy women. There was a significant difference between pre- and postallopregnanolone injection episodic memory scores (p < 0.05), whereas there was no change in episodic memory performance following the placebo injections. There was also a significant difference between allopregnanolone and placebo postinjection episodic memory scores (p < 0.05). There were no effects of allopregnanolone on the semantic memory task or working memory task.Intravenous allopregnanolone impairs episodic memory in healthy women, but there is a high degree of individual variability.

    Keywords
    Allopregnanolone, Healthy women, Follicular phase of menstrual cycle, Episodic memory, Semantic memory, Working memory, Estradiol, Progesterone
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97756 (URN)10.1007/s00213-008-1150-7 (DOI)000257383100003 ()
    Available from: 2008-11-14 Created: 2008-11-14 Last updated: 2017-12-14Bibliographically approved
  • 14.
    Mustafa, Mudassir Imran
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Informatics and Media.
    Design Principles for Data Export: Action Design Research in U-CARE2012Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    In this thesis, we report the findings of designing data export functionality in Uppsala University Psychosocial Care Program (U-CARE) at Uppsala University. The aim of this thesis was to explore the design space for generic data export functionality in data centric clinical research applications for data analysis. This was attained by the construction and evaluation of a prototype for a data-centric clinical research application. For this purpose Action Design Research (ADR) was conducted, situated in the domain of clinical research. The results consist of a set of design principles expressing key aspects needed to address when designing data export functionality. The artifacts derived from the development and evaluation process each one constitutes an example of how to design for data export functionality of this kind.

  • 15.
    Pelander, Lena
    et al.
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden..
    Häggström, Jens
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Syme, Harriet
    Department of Clinical Science and Services, The Royal Veterinary College, Hertfordshire, United Kingdom.
    Elliott, Jonathan
    Department of Comparative Biomedical Sciences, The Royal Veterinary College, London, United Kingdom..
    Heiene, Reidun
    ABC Dyreklinikk Lillehammer AS, Hamarvegen 68A, 26 13 Lillehammer, Norway..
    Ljungvall, Ingrid
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden..
    Comparison of the diagnostic value of symmetric dimethylarginine, cystatin C, and creatinine for detection of decreased glomerular filtration rate in dogs2019In: Journal of Veterinary Internal Medicine, ISSN 0891-6640, E-ISSN 1939-1676, Vol. 33, no 2, p. 630-639Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Early detection of decreased glomerular filtration rate (GFR) in dogs is challenging. Current methods are insensitive and new biomarkers are required.

    OBJECTIVE: To compare overall diagnostic performance of serum symmetric dimethylarginine (SDMA) and serum cystatin C to serum creatinine, for detection of decreased GFR in clinically stable dogs, with or without chronic kidney disease (CKD).

    ANIMALS: Ninety-seven client-owned dogs: 67 dogs with a diagnosis or suspicion of CKD and 30 healthy dogs were prospectively included.

    METHODS: Prospective diagnostic accuracy study. All dogs underwent physical examination, systemic arterial blood pressure measurement, urinalysis, hematology and blood biochemistry analysis, cardiac and urinary ultrasound examinations, and scintigraphy for estimation of glomerular filtration rate (mGFR). Frozen serum was used for batch analysis of SDMA and cystatin C.

    RESULTS: The area under the curve of creatinine, SDMA, and cystatin C for detection of an mGFR <30.8 mL/min/L was 0.98 (95% confidence interval [CI], 0.93-1.0), 0.96 (95% CI, 0.91-0.99), and 0.87 (95% CI, 0.79-0.93), respectively. The sensitivity of both creatinine and SDMA at their prespecified cutoffs (115 μmol/L [1.3 mg/dL] and 14 μg/dL) for detection of an abnormal mGFR was 90%. The specificity was 90% for creatinine and 87% for SDMA. When adjusting the cutoff for cystatin C to correspond to a diagnostic sensitivity of 90% (0.49 mg/L), specificity was lower (72%) than that of creatinine and SDMA.

    CONCLUSIONS AND CLINICAL IMPORTANCE: Overall diagnostic performance of creatinine and SDMA for detection of decreased mGFR was similar. Overall diagnostic performance of cystatin C was inferior to both creatinine and SDMA.

  • 16. Srithunyarat, Thanikul
    et al.
    Hagman, Ragnvi
    Höglund, Odd V
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Olsson, Ulf
    Hanson, Jeanette
    Nonthakotr, Chalermkwan
    Lagerstedt, Anne-Sofie
    Pettersson, Ann
    Catestatin, vasostatin, cortisol, and pain assessments in dogs suffering from traumatic bone fractures.2017In: BMC Research Notes, ISSN 1756-0500, E-ISSN 1756-0500, Vol. 10, no 1, article id 129Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Traumatic bone fractures cause moderate to severe pain, which needs to be minimized for optimal recovery and animal welfare, illustrating the need for reliable objective pain biomarkers for use in a clinical setting. The objectives of this study were to investigate catestatin (CST) and vasostatin (VS) concentrations as two new potential biomarkers, and cortisol concentrations, scores of the short form of the Glasgow composite measure pain scale (CMPS-SF), and visual analog scale (VAS) in dogs suffering from traumatic bone fractures before and after morphine administration in comparison with healthy dogs.

    METHODS: Fourteen dogs with hind limb or pelvic fractures and thirty healthy dogs were included. Dogs with fractures were divided into four groups according to analgesia received before participation. Physical examination, CMPS-SF, pain and stress behavior VAS scores were recorded in all dogs. Saliva and blood were collected once in healthy dogs and in dogs with fractures before and 35-70 min after morphine administration. Blood samples were analyzed for CST, VS, and cortisol. Saliva volumes, however, were insufficient for analysis.

    RESULTS: Catestatin and cortisol concentrations, and CMPS-SF, and VAS scores differed significantly between dogs with fractures prior to morphine administration and healthy dogs. After morphine administration, dogs with fractures had significantly decreased CMPS-SF and VAS scores and, compared to healthy dogs, CST concentrations, CMPS-SF, and VAS scores still differed significantly. However, CST concentrations remained largely within the normal range. Absolute delta values for CST significantly correlated with delta values for CMPS-SF. Catestatin and cortisol did not differ significantly before and after morphine administration. Vasostatin concentrations did not differ significantly between groups.

    CONCLUSIONS: Catestatin and cortisol concentrations, CMPS-SF, and VAS scores differed significantly in the dogs with traumatic bone fractures compared to the healthy dogs. Morphine treatment partially relieved pain and stress according to the subjective but not according to the objective assessments performed. However, because of the large degree of overlap with normal values, our results suggest that plasma CST concentrations have a limited potential as a clinically useful biomarker for pain-induced stress.

  • 17. Srithunyarat, Thanikul
    et al.
    Höglund, Odd V
    Hagman, Ragnvi
    Olsson, Ulf
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Lagerstedt, Anne-Sofie
    Pettersson, Ann
    Catestatin, vasostatin, cortisol, temperature, heart rate, respiratory rate, scores of the short form of the Glasgow composite measure pain scale and visual analog scale for stress and pain behavior in dogs before and after ovariohysterectomy.2016In: BMC Research Notes, ISSN 1756-0500, E-ISSN 1756-0500, Vol. 9, article id 381Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The stress reaction induced by surgery and associated pain may be detrimental for patient recovery and should be minimized. The neuropeptide chromogranin A (CGA) has shown promise as a sensitive biomarker for stress in humans. Little is known about CGA and its derived peptides, catestatin (CST) and vasostatin (VS), in dogs undergoing surgery. The objectives of this study were to investigate and compare concentrations of CGA epitopes CST and VS, cortisol, body temperature, heart rate, respiratory rate, scores of the short form of the Glasgow composite measure pain scale (CMPS-SF) and visual analog scales (VAS) for stress and pain behavior in dogs before and after ovariohysterectomy.

    METHODS: Thirty healthy privately owned female dogs admitted for elective ovariohysterectomy were included. Physical examination, CMPS-SF, pain behavior VAS, and stress behavior VAS were recorded and saliva and blood samples were collected before surgery, 3 h after extubation, and once at recall 7-15 days after surgery. Dogs were premedicated with morphine and received carprofen as analgesia for 7 days during the postoperative period.

    RESULTS: At 3 h after extubation, CMPS-SF and pain behavior VAS scores had increased (p < 0.0001) and stress behavior VAS scores, temperature, respiratory rate (p < 0.0001), plasma CST concentrations (p = 0.002) had decreased significantly compared to before surgery. No significant differences were observed in the subjective and physiological parameters between before surgery and at recall, but plasma CST (p = 0.04) and serum cortisol (p = 0.009) were significantly lower at recall. Plasma VS, saliva CST, and heart rate did not differ significantly at any observed time.

    CONCLUSION: Study parameters for evaluating surgery-induced stress and pain changed in dogs subjected to ovariohysterectomy. To further evaluate CST and VS usefulness as pain biomarkers, studies on dogs in acute painful situations are warranted.

  • 18. Strage, Emma M
    et al.
    Sundberg, Mårten
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Holst, Bodil S
    Andersson Franko, Mikael
    Ramström, Margareta
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lewitt, Moira
    Effect of insulin treatment on circulating insulin-like growth factor I and IGF-binding proteins in cats with diabetes mellitus.2018In: Journal of Veterinary Internal Medicine, ISSN 0891-6640, E-ISSN 1939-1676, Vol. 32, no 5, p. 1579-1590Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Insulin-like growth factor-I (IGF-I) is used to screen for acromegaly in diabetic cats. In humans, most circulating IGF-I forms ternary complexes (TC) with IGF-binding protein (IGFBP-3) and an acid-labile subunit. Compared to humans, the amount of TC in cats is more variable. Insulin-like growth factor-I concentrations are reported to increase during insulin treatment, more rapidly in cats achieving remission.

    OBJECTIVES: To investigate (i) factors associated with circulating IGF-I concentrations, including IGFBP-profiles (ii) effect of insulin treatment on IGF-I concentrations and (iii) IGF-I as prognostic marker of diabetes mellitus remission.

    ANIMALS: Thirty-one privately owned diabetic cats of which 24 were followed 1 year, and 13 healthy cats.

    METHODS: Prospective study. Serum insulin, IGF-I, glucose, and fructosamine concentrations were measured. IGF-binding forms were determined by chromatography in 14 diabetic and 13 healthy cats; and IGF-I, IGF-II, IGFBP-3, and IGFBP-5 by mass spectrometry in 3 cats achieving remission.

    RESULTS: Insulin-like growth factor-I median (interquartile range) before start of insulin treatment was 300 (160-556) ng/mL. Insulin-like growth factor-I was positively associated with TC (P < .0001) and endogenous insulin (P = .005) and negatively associated with fructosamine (P < .0001). Median IGF-I was higher 2-4 weeks after start of insulin treatment compared with baseline (300 versus 670 ng/mL, P = .0001) and predicted future remission (P = .046). In cats that went into remission, the amount of TC and IGFBP-3 increased, suggesting increase in IGF-I is dependent on TC formation.

    CONCLUSIONS: Insulin treatment should be accounted for when interpreting IGF-I in diabetic cats. Insulin-like growth factor-I 2-4 weeks after initiation of insulin treatment shows promise as prognostic marker for remission in diabetic cats.

  • 19.
    Stridsberg, Mats
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Pettersson, Ann
    Hagman, Ragnvi
    Westin, Christoffer
    Höglund, Odd
    Chromogranins can be measured in samples from cats and dogs2014In: BMC Research Notes, ISSN 1756-0500, E-ISSN 1756-0500, Vol. 7, article id 336Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Methods for objective evaluation of stress in animals are important, but clinically difficult. An alternative method to study the sympathetic activity may be to investigate Chromogranin A (CGA), Chromogranin B (CGB) and Secretogranin II (SG2). The aim of this study was to investigate the cross-reactivity of CGA, CGB and SG2 between man, cat and dog and to explore possibilities to measure these proteins in samples from cats and dogs.

    RESULTS: Adrenal gland extracts from feline and canine species were measured by region-specific radioimmunoassays in different dilution steps to explore possible inter species cross reactivity. High cross reactivity was found for cats in the CGA17-38, CGA324-337, CGA361-372, CGB and SG2 assays. High cross reactivity was found for dogs in the CGA17-38, CGA361-372, CGB and SN assays. The method measuring the intact CGA was not useful for measurements in cats and dogs.

    CONCLUSIONS: Region-specific assays measuring defined parts of CGA, CGB and SG2 can be used for measurements in samples from cats and dogs. These results are promising and will allow for further studies of these proteins as possible clinical biomarkers in cats and dogs.

  • 20.
    Ström Holst, Bodil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Reproductive Biology in Uppsala (CRU). Swedish Univ Agr Sci, Dept Clin Sci, Box 7054, SE-75007 Uppsala, Sweden.
    Hagberg Gustavsson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Reproductive Biology in Uppsala (CRU).
    Johannisson, Anders
    Swedish Univ Agr Sci, Dept Clin Sci, Box 7054, SE-75007 Uppsala, Sweden.
    Hillström, Anna
    Swedish Univ Agr Sci, Univ Anim Hosp, Clin Pathol Lab, Box 7038, SE-75007 Uppsala, Sweden.
    Strage, Emma
    Swedish Univ Agr Sci, Univ Anim Hosp, Clin Pathol Lab, Box 7038, SE-75007 Uppsala, Sweden.
    Olsson, Ulf
    Swedish Univ Agr Sci, Unit Appl Stat & Math, Box 7032, SE-75007 Uppsala, Sweden.
    Axnér, Eva
    Swedish Univ Agr Sci, Dept Clin Sci, Box 7054, SE-75007 Uppsala, Sweden.
    Lilliehöök, Inger
    Swedish Univ Agr Sci, Dept Clin Sci, Box 7054, SE-75007 Uppsala, Sweden.
    Inflammatory changes during canine pregnancy2019In: Theriogenology, ISSN 0093-691X, E-ISSN 1879-3231, Vol. 125, p. 285-292Article in journal (Refereed)
    Abstract [en]

    Pregnancy is considered a pro-inflammatory state that requires physiologic adaptation of the immune system of the mother. The aim of the present study was to study inflammatory and hormonal changes during canine pregnancy. Studies included analyses of peripheral concentrations of the acute phase proteins fibrinogen and C-reactive protein (CRP), the hormones progesterone and insulin-like growth factor I (IGF-I), hemoglobin, and analyses of the total leukocyte numbers and expression of cell surface antigens. Twenty bitches were included in the present study; 12 pregnant bitches and eight nonpregnant control bitches that were followed during the corresponding phase of the oestrous cycle. Blood samples were collected at the day of optimal mating (day 0) and then on days 7, 14, 21, 28 and 42. Progesterone, IGF-I and CRP were analysed in serum and fibrinogen in EDTA plasma. Haematology and leukocyte expression of a panel of inflammation-associated adhesion molecules (CD 11a, CD 18 and CD 49d) were evaluated from EDTA blood. The data were analyzed as repeated-measures data, using a mixed model approach. Progesterone varied with time in both pregnant and control bitches, and IGF-I varied with time in pregnant bitches. Both fibrinogen and CRP increased significantly with time for the pregnant bitches, but no significant change was detected for the control bitches. Increases were seen from day 21. The hemoglobin concentration decreased significantly with time in both pregnant and non-pregnant bitches. The neutrophil and monocyte numbers increased significantly in pregnant but not in control bitches. Pregnancy induced increased granulocyte expression of cell surface marker CD 18, increased monocyte expression of CD 18 and CD 49d, and increased lymphocyte expression of CD 49d. In conclusion, we describe inflammatory changes during canine pregnancy that are manifested as increases in concentrations of CRP and fibrinogen, an increase in neutrophils and monocytes, and in activation of granulocytes, monocytes and lymphocytes. The changes should be taken into account when evaluating concentrations of APPS and WBC in bitches during pregnancy. A variation in IGF-I concentrations was detected during pregnancy.

  • 21.
    Suarez Sipmann, Fernando
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Titrating Open Lung PEEP in Acute Lung Injury: A clinical method based on changes in dynamic compliance2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The recognition that supportive mechanical ventilation can also damage the lung, the so called ventilation induced lung injury (VILI), has revived the more than 40 year long debate on the optimal level of PEEP to be used. It is established that the prevention of VILI improves patient outcome and that PEEP exerts protective effects by preventing unstable diseased alveoli from collapsing. Therefore, the term “open lung PEEP” (OL-PEEP) has been introduced as the end-expiratory pressure that keeps the lung open after its collapse has been eliminated by an active lung recruitment manoeuvre. The determination of such an optimal level of PEEP under clinical circumstances is difficult and remains to be investigated.

    The aim of this study was to investigate the usefulness of breath by breath monitoring of dynamic compliance (Cdyn) as a clinical means to identify OL-PEEP at the bedside and to demonstrate the improvement in lung function resulting from its application.

    In a porcine lung lavage model of acute lung injury PEEP at maximum Cdyn during a decremental PEEP trial after full lung recruitment was related to the onset of lung collapse and OL-PEEP could be found 2 cmH2O above this level Ventilation at OL-PEEP was associated with improved gas exchange, efficiency of ventilation, lung mechanics and less than 5% collapse on CT scans. In addition, dead space, especially its portion related to alveolar gas changed characteristically during recruitment, PEEP titration and collapse thereby helping to identify OL-PEEP.

    The beneficial effects of OL-PEEP on lung function and mechanics was demonstrated in a porcine model of VILI. OL-PEEP improved lung function and mechanics when compared to lower or higher levels prior to or after lung recruitment. By using electrical impedance tomography it could be shown that PEEPs within the range of 14 to 22 cmH2O resulted in a similar redistribution of both ventilation and perfusion to the dorsal regions of the lung. OL-PEEP resulted in the best regional and global matching of ventilation and perfusion explaining the drastic improvements in gas exchange. Also regional compliance was greatly improved in the lower half of the lung as compared to all other situations.

    In ARDS patients OL-PEEP could be identified applying the same protocol. The physiological changes described could now be reproduced and maintained during a four hours study ventilation period in real patients at four study centres.

    In conclusion, the usefulness of dynamic compliance for identifying open lung PEEP during a decremental PEEP trial was demonstrated under experimental and clinical conditions. This PEEP should then be used as an essential part of any lung protective ventilation strategy. The impact of ventilating ARDS patients according to the principles described in these studies on outcome are currently being evaluated in an international randomized controlled trial.

    List of papers
    1. Use of dynamic compliance for open lung positive end-expiratory pressure titration in an experimental study
    Open this publication in new window or tab >>Use of dynamic compliance for open lung positive end-expiratory pressure titration in an experimental study
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    2007 (English)In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 35, no 1, p. 214-221Article in journal (Refereed) Published
    Abstract [en]

    Objective: We tested whether the continuous monitoring of dynamic compliance could become a useful bedside tool for detecting the beginning of collapse of a fully recruited lung. Design: Prospective laboratory animal investigation. Setting: Clinical physiology research laboratory, University of Uppsala, Sweden. Subjects: Eight pigs submitted to repeated lung lavages. Interventions: Lung recruitment maneuver, the effect of which was confirmed by predefined oxygenation, lung mechanics, and computed tomography scan criteria, was followed by a positive end-expiratory pressure (PEEP) reduction trial in a volume control mode with a tidal volume of 6 mL/kg. Every 10 mins, PEEP was reduced in steps of 2 cm H2O starting from 24 cm H2O. During PEEP reduction, lung collapse was defined by the maximum dynamic compliance value after which a first measurable decrease occurred. Open lung PEEP according to dynamic compliance was then defined as the level of PEEP before the point of collapse. This value was compared with oxygenation (PaO2) and CT scans. Measurements and Main Results: PaO2 and dynamic compliance were monitored continuously, whereas computed tomography scans were obtained at the end of each pressure step. Collapse defined by dynamic compliance occurred at a PEEP of 14 cm H2O. This level coincided with the oxygenation-based collapse point when also shunt started to increase and occurred one step before the percentage of nonaerated tissue on the computed tomography exceeded 5%. Open lung PEEP was thus at 16 cm H2O, the level at which oxygenation and computed tomography scan confirmed a fully open, not yet collapsed lung condition. Conclusions: In this experimental model, the continuous monitoring of dynamic compliance identified the beginning of collapse after lung recruitment. These findings were confirmed by oxygenation and computed tomography scans. This method might become a valuable bedside tool for identifying the level of PEEP that prevents end-expiratory collapse.

    Keywords
    Lung collapse, Lung compliance, Open lung, Positive end-expiratory pressure, Recruitment, Spiral computed, Tomography
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-96743 (URN)10.1097/01.CCM.0000251131.40301.E2 (DOI)000243046700030 ()17110872 (PubMedID)
    Available from: 2008-02-20 Created: 2008-02-20 Last updated: 2017-12-14Bibliographically approved
    2. Monitoring dead space during recruitment and PEEP titration in an experimental model
    Open this publication in new window or tab >>Monitoring dead space during recruitment and PEEP titration in an experimental model
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    2006 (English)In: Intensive Care Medicine, ISSN 0342-4642, E-ISSN 1432-1238, Vol. 32, no 11, p. 1863-1871Article in journal (Refereed) Published
    Abstract [en]

    Objective: To test the usefulness of dead space for determining open-lung PEEP, the lowest PEEP that prevents lung collapse after a lung recruitment maneuver. Design: Prospective animal study. Setting: Department of Clinical Physiology, University of Uppsala, Sweden. Subjects: Eight lung-lavaged pigs. Interventions: Animals were ventilated using constant flow mode with VT of 6 ml/kg, respiratory rate of 30 bpm, inspiratory-to-expiratory ratio of 1 : 2, and FiO(2) of 1. Baseline measurements were performed at 6 cmH(2)O of PEEP. PEEP was increased in steps of 6 cmH(2)O from 6 to 24 cmH(2)O. Recruitment maneuver was achieved within 2 min at pressure levels of 60/30 cmH(2)O for Peak/PEEP. PEEP was decreased from 24 to 6 cmH(2)O in steps of 2 cmH(2)O and then to 0 cmH(2)O. Each PEEP step was maintained for 10 min. Measurements and results: Alveolar dead space (VDalv), the ratio of alveolar dead space to alveolar tidal volume (VDalv/VTalv), and the arterial to end-tidal PCO2 difference (Pa-ETCO2) showed a good correlation with PaO2, normally aerated areas, and non-aerated CT areas in all animals (minimum-maximum r(2) = 0.83-0.99; p < 0.01). Lung collapse (non-aerated tissue > 5%) started at 12 cmH(2)O PEEP; hence, open-lung PEEP was established at 14 cmH(2)O. The receiver operating characteristics curve demonstrated a high specificity and sensitivity of VDalv (0.89 and 0.90), VDalv/VTalv (0.82 and 1.00), and Pa-ETCO2 (0.93 and 0.95) for detecting lung collapse. Conclusions: Monitoring of dead space was useful for detecting lung collapse and for establishing open-lung PEEP after a recruitment maneuver.

    Keywords
    dead space, lung recruitment, SBT-CO2, atelectasis, oxygenation, PEEP
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-96744 (URN)10.1007/s00134-006-0371-7 (DOI)000241453400030 ()17047925 (PubMedID)
    Available from: 2008-02-20 Created: 2008-02-20 Last updated: 2017-12-14Bibliographically approved
    3. Regional distribution of ventilation and perfusion at different lung conditions in pigs with ALI: An electrical impedance tomography study
    Open this publication in new window or tab >>Regional distribution of ventilation and perfusion at different lung conditions in pigs with ALI: An electrical impedance tomography study
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-96745 (URN)
    Available from: 2008-02-20 Created: 2008-02-20 Last updated: 2010-01-13Bibliographically approved
    4. Open Lung PEEP titration in ARDS: a bedside method based on alveolar physiology
    Open this publication in new window or tab >>Open Lung PEEP titration in ARDS: a bedside method based on alveolar physiology
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-96746 (URN)
    Available from: 2008-02-20 Created: 2008-02-20 Last updated: 2010-01-13Bibliographically approved
  • 22.
    Svensson, Gustaf
    et al.
    Bla Stjarnans Djursjukhus, Gothenburg, Sweden.
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Danielsson, Fredrik
    Vetaid, Helsingborg, Sweden.
    Schwarz, Tobias
    Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Roslin, Midlothian, UK.
    Residual Spinal Cord Compression Following Hemilaminectomy and Mini-Hemilaminectomy in Dogs: A Prospective Randomized Study2017In: Frontiers in veterinary science, ISSN 2297-1769, Vol. 4, article id 42Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to compare the reduction of spinal cord compression after surgical treatment of dogs with acute thoracolumbar intervertebral disc (IVD) extrusion achieved using hemilaminectomy versus mini-hemilaminectomy techniques. This was a prospective randomized study with client-owned dogs presented with acute IVD extrusion that were allocated to surgical treatment using hemilaminectomy (n = 15) or mini-hemilaminectomy (n = 15) techniques. Plain and intravenous-contrast computed tomography was performed pre- and postoperatively. The preoperative minimal cross-sectional dimension of the spinal cord (MDSCpre) and the postoperative minimal cross-sectional dimension of the spinal cord (MDSCpost) were measured at the level of greatest compression. The minimal diameter of the uncompressed spinal cord was measured in a similar way both pre- (MDUSCpre) and postoperatively (MDUSCpost). Dogs in the mini-hemilaminectomy group had significantly greater reduction of compression (RC) (p < 0.01) after surgery compared to dogs in the hemilaminectomy group. The mean RC in the hemilaminectomy group was 34.6% and in the mini-hemilaminectomy group 62.6%. Our results showed a significantly greater reduction of spinal cord compression for mini-hemilaminectomy compared to hemilaminectomy. Additionally, mini-hemilaminectomy could be a preferred method due to its minimal invasiveness and easier access to lateral fenestration.

  • 23.
    Tvedten, H. W.
    et al.
    Swedish Univ Agr Sci, Univ Anim Hosp, Box 7038, S-75007 Uppsala, Sweden..
    Andersson, V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Lilliehook, I. E.
    Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Clin Sci, Uppsala, Sweden..
    Feline Differential Leukocyte Count with ProCyte Dx: Frequency and Severity of a Neutrophil-Lymphocyte Error and How to Avoid It2017In: Journal of Veterinary Internal Medicine, ISSN 0891-6640, E-ISSN 1939-1676, Vol. 31, no 6, p. 1708-1716Article in journal (Refereed)
    Abstract [en]

    Background: Erroneous neutrophil and lymphocyte counts from analysis of feline blood samples were transferred directly into the hospital information system from the ProCyte Dx hematology instrument in our after-hours laboratory. Errors usually were not detected by the users.

    Hypothesis/Objectives: To quantify the frequency and severity of errors associated with the ProCyte Dx analyzer and to identify methods to avoid the errors.

    Animals: One-hundred six EDTA blood samples routinely submitted from feline hospital patients were analyzed.

    Methods: ProCyte differential leukocyte counts were compared to 2 reference methods: Advia 2120 hematology instrument and manual enumeration. Limits for unacceptable deviation from the reference methods were defined as 18 for % lymphocytes and 23 for % neutrophils.

    Results: Fourteen of 106 samples had unacceptable errors for both lymphocytes and neutrophils compared to both reference methods. Median % lymphocytes in those 14 samples were 11.2, 15.0, and 53.0% for Advia, manual, and ProCyte, respectively. Median % neutrophils were 85.4, 81.5, and 34.2% for Advia, manual, and ProCyte, respectively. All errors were avoided by rejecting automated ProCyte differential leukocyte results whenever the dot plot appeared clearly incorrect, but only 9 of these 14 samples had a ProCyte WBC distribution error flag.

    Conclusions and Clinical Importance: Results reported by ProCyte had markedly falsely increased lymphocyte and decreased neutrophil counts in 13% of feline patient samples. Users must reject automated differential leukocyte count results when the WBC dot plot appears overtly incorrect. Rejection based only on ProCyte WBC error flag was insufficient.

  • 24.
    Tvedten, Harold W.
    Swedish Univ Agr Sci, Univ Anim Hosp, Uppsala, Sweden.
    What is your diagnosis?: Unusual cells in feline blood2018In: Veterinary clinical pathology, ISSN 0275-6382, E-ISSN 1939-165X, Vol. 47, no 2, p. 313-314Article in journal (Other academic)
  • 25.
    Valdes, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Lewitt, Moira
    Univ West Scotland, Sch Hlth & Life Sci, Paisley PA1 2BE, Renfrew, Scotland.
    Wiss, Erica
    Albano Anim Hosp, S-18236 Stockholm, Sweden.
    Ramström, Margareta
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Strage, Emma M.
    Swedish Univ Agr Sci, Univ Anim Hosp, Dept Clin Sci, S-75007 Uppsala, Sweden;Swedish Univ Agr Sci, Univ Anim Hosp, Clin Pathol Lab, S-75007 Uppsala, Sweden.
    Development of a Parallel Reaction Monitoring-MS Method To Quantify IGF Proteins in Dogs and a Case of Nonislet Cell Tumor Hypoglycemia2019In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 18, no 1, p. 18-29Article in journal (Refereed)
    Abstract [en]

    Nonislet-cell tumor hypoglycemia (NICTH) is a rare paraneoplastic phenomenon well described in dogs and humans. Tumors associated with NICTH secrete incompletely processed forms of insulin-like growth factor-II (IGF-II), commonly named big IGF-II. These forms have increased bioavailability and interact with the insulin and IGF-I receptor causing hypoglycemia and growth-promoting effects. Immunoassays designed for human samples have been used to measure canine IGF-I and -II, but they possess some limitations. In addition, there are no validated methods for measurement of big IGF-II in dogs. In the present study, a targeted parallel reaction monitoring MS-based method previously developed for cats has been optimized and applied to simultaneously quantify the serum levels of IGF-I, IGF-II, and IGFBP-3, and for the first time, the levels of big IGF-II in dogs. This method allows the absolute quantification of IGF proteins using a mixture of QPrEST proteins previously designed for humans. The method possesses good linearity and repeatability and has been used to evaluate the IGF-system in a dog with NICTH syndrome. In this dog, the levels of big IGF-II decreased by 80% and the levels of IGF-I and IGFBP-3 increased approximately 20- and 4-times, respectively, after removal of the tumor.

  • 26.
    Weis, Jan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Ortiz-Nieto, Francisco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Assessment of lipids in skeletal muscle by LCModel and AMARES2009In: Journal of Magnetic Resonance Imaging, ISSN 1053-1807, E-ISSN 1522-2586, Vol. 30, no 5, p. 1124-1129Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To process single voxel spectra of the human skeletal muscle by using an advanced method for accurate, robust, and efficient spectral fitting (AMARES) and by linear combination of model spectra (LCModel). To determine absolute concentrations of extra- (EMCL) and intramyocellular lipids (IMCL). MATERIALS AND METHODS: Single-voxel proton magnetic resonance spectroscopy (PRESS) was used to obtain the spectra of the calf muscles. Unsuppressed water line was used as a concentration reference. A new prior knowledge for AMARES was proposed to estimate the concentrations of EMCL and IMCL. The prior knowledge was derived from the spectrum of vegetable oil. The results were compared with the values estimated by LCModel. Absolute concentrations of total lipid content in millimoles per kilogram wet weight were used for the comparisons. RESULTS: Absolute concentrations of total lipid content in skeletal muscle were estimated by AMARES and LCModel. Very good correlation of the total fat (EMCL + IMCL) and IMCL concentrations was achieved between both data processing approaches. CONCLUSION: Assessment the absolute concentrations of muscular lipids by AMARES and LCModel can be performed with comparable accuracy.

1 - 26 of 26
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