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  • 201.
    Punga, Tanel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bartoccioni, Emanuela
    Catholic Univ, Dept Lab Med, Rome, Italy.
    Lewandowska, Marta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Damato, Valentina
    Catholic Univ, Dept Neurol, Rome, Italy.
    Evoli, Amelia
    Catholic Univ, Dept Neurol, Rome, Italy.
    Punga, Anna Rostedt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Disease specific enrichment of circulating let-7 family microRNA in MuSK+ myasthenia gravis.2016In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 292, p. 21-26Article in journal (Refereed)
    Abstract [en]

    Myasthenia gravis (MG) patients with antibodies against the muscle specific tyrosine kinase (MuSK+) have predominantly involvement of cranio-bulbar muscles and do not display thymus pathology, as do acetylcholine receptor antibody seropositive (AChR+) MG patients. In search of novel biomarkers for MuSK+ MG, we evaluated circulating serum microRNAs. Four analyzed microRNAs were specifically elevated in MuSK+ MG patient serum samples: let-7a-5p, let-7f-5p, miR-151a-3p and miR-423-5p. The circulating microRNA profile in MuSK+ MG differs from the profile previously observed in the serum of AChR+ MG, thus indicating the etiological difference between these two entities. We propose that the identified microRNAs could serve as potential serum biomarkers for MuSK+ MG.

  • 202.
    Punga, Tanel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Le Panse, Rozen
    Andersson, Mats
    Truffault, Frédérique
    Berrih-Aknin, Sonia
    Punga, Anna Rostedt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Circulating miRNAs in myasthenia gravis: miR-150-5p as a new potential biomarker2014In: Annals of clinical and translational neurology, ISSN 2328-9503, Vol. 1, no 1, p. 49-58Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Myasthenia gravis (MG) is a chronic autoimmune disorder where autoantibodies target the nicotinic acetylcholine receptors (AChR+) in about 85% of cases, in which the thymus is considered to play a pathogenic role. As there are no reliable biomarkers to monitor disease status in MG, we analyzed circulating miRNAs in sera of MG patients to find disease-specific miRNAs.

    METHODS: Overall, 168 miRNAs were analyzed in serum samples from four AChR+ MG patients and four healthy controls using Exiqon Focus miRNA polymerase chain reaction (PCR) Panel I + II. Specific accumulation pattern of 13 miRNAs from the discovery set was subsequently investigated in the sera of 16 AChR+ MG patients and 16 healthy controls. All patients were without immunosuppressive treatment. Selected specific miRNAs were further analyzed in the serum of nine MG patients before and after thymectomy to assess the effect of thymus removal on the accumulation of the candidate miRNAs in patient sera.

    RESULTS: Three miRNAs were specifically dysregulated in AChR+ MG patient sera samples. Hsa-miR150-5p, which induces T-cell differentiation, as well as hsa-miR21-5p, a regulator of Th1 versus Th2 cell responses, were specifically elevated in MG sera. Additionally, hsa-miR27a-3p, involved in natural killer (NK) cell cytotoxicity, was decreased in MG. Hsa-miR150-5p levels had the highest association with MG and were significantly reduced after thymus removal in correlation with disease improvement.

    INTERPRETATION: WE PROPOSE THAT THE VALIDATED MIRNAS: hsa-miR150-5p, hsa-miR21-5p, and hsa-miR27a-3p can serve as novel serum biomarkers in AChR+ MG. Hsa-miR-150-5p could be a helpful marker to monitor disease severity.

  • 203.
    Qaisar, Rizwan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Myonuclear Organization and Regulation of Muscle Contraction in Single Muscle Fibres: Effects of Ageing, Gender, Species, Endocrine Factors and Muscle Size2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The skeletal muscle fibre is a syncitium where each myonucleus regulates the gene products in a finite volume of cytoplasm i.e., the myonuclear domain (MND). A novel image analysis algorithm applied to confocal images, analyzing MND size and myonuclear spatial distribution in 3-dimensions in single skeletal muscle fibres has been used in this project. The goal was to explore the modulation of myonuclei count and MND size in response to muscle adaptation processes. The effects of ageing, gender, hormones, muscle hypertrophy and body size were investigated on MND size.

    A strong linear relationship was found between MND size and body size in the muscle fibres from mammals representing a 100,000-fold difference in body size. Independent of species, MND size was highly dependent on MyHC isoform type and mitochondrial contents of skeletal muscle fibres. In hypertrophic mice, a significant effect of MND size on specific force and myosin content was observed. This effect was muscle fibre type-specific and shows that the bigger MNDs in fast-twitch EDL muscle fibres are optimally tuned for force production while smaller MNDs in slow-twitch soleus muscle fibres have a much more dynamic range of hypertrophy without functional compromise. This indicates a critical volume individual myonuclei can support efficiently for a proportional gain in muscle fibre force and size. In human muscle fibres, spatial organization of myonuclei was affected by both ageing and MyHC isoform expression. In fibres expressing type I MyHC isoform, an increased MND size variability and myonuclear aggregates were observed in old age although average MND size was unchanged. In contrast, in type IIa fibres, the average MND size was smaller reflecting smaller size of muscle fibres. Those changes may influence the transcriptional activity per myonucleus and/or local cooperatively of myonuclei in a gender and muscle fibre-type specific manner. Finally, hormone replacement therapy was shown to negate menopause-related functional impairment in skeletal muscle fibres. The positive effect on force was due to quantitative effect in fibres expressing fast myosin isoform while the effect was both quantitative and qualitative in fibres expressing slow myosin isoform. The effect on MND size was fibre type dependent and was achieved by significantly reducing domain size in slow- but not the fast-twitch muscle fibres.

    Together, our data suggest that modulation of myonuclei count and MND size is a mechanism contributing to remodelling of skeletal muscle in muscle adaptation process. These findings should be considered when developing therapeutic approaches towards restoring muscle mass and strength in muscle wasting conditions.

    List of papers
    1. Myonuclear domain size and myosin isoform expression in muscle fibres from mammals representing a 100 000-fold difference in body size
    Open this publication in new window or tab >>Myonuclear domain size and myosin isoform expression in muscle fibres from mammals representing a 100 000-fold difference in body size
    Show others...
    2009 (English)In: Experimental Physiology, ISSN 0958-0670, E-ISSN 1469-445X, Vol. 94, no 1, p. 117-129Article in journal (Refereed) Published
    Abstract [en]

    This comparative study of myonuclear domain (MND) size in mammalian species representing a 100 000-fold difference in body mass, ranging from 25 g to 2500 kg, was undertaken to improve our understanding of myonuclear organization in skeletal muscle fibres. Myonuclear domain size was calculated from three-dimensional reconstructions in a total of 235 single muscle fibre segments at a fixed sarcomere length. Irrespective of species, the largest MND size was observed in muscle fibres expressing fast myosin heavy chain (MyHC) isoforms, but in the two smallest mammalian species studied (mouse and rat), MND size was not larger in the fast-twitch fibres expressing the IIA MyHC isofom than in the slow-twitch type I fibres. In the larger mammals, the type I fibres always had the smallest average MND size, but contrary to mouse and rat muscles, type IIA fibres had lower mitochondrial enzyme activities than type I fibres. Myonuclear domain size was highly dependent on body mass in the two muscle fibre types expressed in all species, i.e. types I and IIA. Myonuclear domain size increased in muscle fibres expressing both the β/slow (type I; r= 0.84, P < 0.001) and the fast IIA MyHC isoform (r= 0.90; P < 0.001). Thus, MND size scales with body size and is highly dependent on muscle fibre type, independent of species. However, myosin isoform expression is not the sole protein determining MND size, and other protein systems, such as mitochondrial proteins, may be equally or more important determinants of MND size.

    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-87940 (URN)10.1113/expphysiol.2008.043877 (DOI)000261961800014 ()18820003 (PubMedID)
    Available from: 2009-01-15 Created: 2009-01-15 Last updated: 2018-12-02Bibliographically approved
    2. Is functional hypertrophy and specific force coupled with the addition of myonuclei at the single muscle fiber level?
    Open this publication in new window or tab >>Is functional hypertrophy and specific force coupled with the addition of myonuclei at the single muscle fiber level?
    Show others...
    2012 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 3, p. 1077-1085Article in journal (Refereed) Published
    Abstract [en]

    Muscle force is typically proportional to muscle size, resulting in constant force normalized to muscle fiber cross-sectional area (specific force). Mice overexpressing insulin-like growth factor-1 (IGF-1) exhibit a proportional gain in muscle force and size, but not the myostatin-deficient mice. In an attempt to explore the role of the cytoplasmic volume supported by individual myonuclei [myonuclear domain (MND) size] on functional capacity of skeletal muscle, we have investigated specific force in relation to MND and the content of the molecular motor protein, myosin, at the single muscle fiber level from myostatin-knockout (Mstn(-/-)) and IGF-1-overexpressing (mIgf1(+/+)) mice. We hypothesize that the addition of extra myonuclei is a prerequisite for maintenance of specific force during muscle hypertrophy. A novel algorithm was used to measure individual MNDs in 3 dimensions along the length of single muscle fibers from the fast-twitch extensor digitorum longus and the slow-twitch soleus muscle. A significant effect of the size of individual MNDs in hypertrophic muscle fibers on both specific force and myosin content was observed. This effect was muscle cell type specific and suggested there is a critical volume individual myonuclei can support efficiently. The large MNDs found in fast muscles of Mstn(-/-) mice were correlated with the decrement in specific force and myosin content in Mstn(-/-) muscles. Thus, myostatin inhibition may not be able to maintain the appropriate MND for optimal function.-Qaisar, R., Renaud, G., Morine, K., Barton, E. R., Sweeney, H. L., Larsson, L. Is functional hypertrophy and specific force coupled with the addition of myonuclei at the single muscle fiber level?

    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-166951 (URN)10.1096/fj.11-192195 (DOI)000300949300012 ()22125316 (PubMedID)
    Available from: 2012-01-17 Created: 2012-01-17 Last updated: 2018-01-12Bibliographically approved
    3. Effects of aging and gender on the spatial organization of nuclei in single human skeletal muscle cells
    Open this publication in new window or tab >>Effects of aging and gender on the spatial organization of nuclei in single human skeletal muscle cells
    Show others...
    2010 (English)In: Aging Cell, ISSN 1474-9718, E-ISSN 1474-9726, Vol. 9, no 5, p. 685-697Article in journal (Refereed) Published
    Abstract [en]

    The skeletal muscle fibre is a syncitium where each myonucleus regulates the gene products in a finite volume of the cytoplasm, i.e., the myonuclear domain (MND). We analysed aging- and gender-related effects on myonuclei organization and the MND size in single muscle fibres from six young (21–31 years) and nine old men (72–96 years), and from six young (24–32 years) and nine old women (65–96 years), using a novel image analysis algorithm applied to confocal images. Muscle fibres were classified according to myosin heavy chain (MyHC) isoform expression. Our image analysis algorithm was effective in determining the spatial organization of myonuclei and the distribution of individual MNDs along the single fibre segments. Significant linear relations were observed between MND size and fibre size, irrespective age, gender and MyHC isoform expression. The spatial organization of individual myonuclei, calculated as the distribution of nearest neighbour distances in 3D, and MND size were affected in old age, but changes were dependent on MyHC isoform expression. In type I muscle fibres, average NN-values were lower and showed an increased variability in old age, reflecting an aggregation of myonuclei in old age. Average MND size did not change in old age, but there was an increased MND size variability. In type IIa fibres, average NN-values and MND sizes were lower in old age, reflecting the smaller size of these muscle fibres in old age. It is suggested that these changes have a significant impact on protein synthesis and degradation during the aging process.

    Keywords
    aging, human skeletal muscle, myonuclear domain, 3D imaging
    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-139870 (URN)10.1111/j.1474-9726.2010.00594.x (DOI)000281897400003 ()20633000 (PubMedID)
    Available from: 2010-12-30 Created: 2010-12-30 Last updated: 2018-12-02Bibliographically approved
    4. Contractile function and myonuclear organization in single fibers from monozygotic female twins discordant for hormone replacement therapy
    Open this publication in new window or tab >>Contractile function and myonuclear organization in single fibers from monozygotic female twins discordant for hormone replacement therapy
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-166952 (URN)
    Available from: 2012-01-17 Created: 2012-01-17 Last updated: 2018-01-12
  • 204.
    Qaisar, Rizwan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Hedström, Yvette
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Kovanen, Vuokko
    Sipila, Sarianna
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Contractile function and myonuclear organization in single fibers from monozygotic female twins discordant for hormone replacement therapyManuscript (preprint) (Other academic)
    Abstract [en]

    Ageing is associated with a decline in muscle mass and strength leading to increased physical dependency in old age. Post-menopausal women experience a greater decline than men of similar age due to a dramatic decrease in sex hormones production. We recruited six monozygous female twin pairs (55 – 59 years old) discordant for postmenopausal hormone replacement therapy (HRT use = 7.8 ± 4.3 years) to investigate the association of HRT with the cytoplasmic domain supported by individual myonuclei (myonuclear domain size, MND) together with specific force at the single fiber level. MyHC isoform content of the fibers was determined using silver-stained SDS-PAGE. HRT use was associated with a significantly smaller (~27%; p < 0.05) mean MND size in muscle fibers expressing the type I but not the IIa MyHC isoform. An increase in specific force was recorded in the HRT user group both in muscle fibers expressing type I (~27%; p < 0.05) and type IIa (~23%; p < 0.05) MyHC isoforms. These positive effects on specific force were fiber-type dependent, i.e., in fast-twitch muscle fibers the increased specific force was primarily caused by an increased force per cross-bridge while slow-twitch fibers relied on both an increase in both number and force per cross-bridge. HRT use had no effect on fiber cross-sectional area (CSA), velocity of unloaded shortening (V0) and relative proportion of MyHC isoforms. In conclusion, HRT has significant positive effects on both regulation of muscle contraction and myonuclei organization in menopausal women, but the response is fiber-type specific.

  • 205.
    Qaisar, Rizwan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Renaud, Guillaume
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Hedström, Yvette
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Pollanen, Eija
    Ronkainen, Paula
    Kaprio, Jaakko
    Alen, Markku
    Sipila, Sarianna
    Artemenko, Konstantin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Kovanen, Vuokko
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Hormone replacement therapy improves contractile function and myonuclear organization of single muscle fibres from postmenopausal monozygotic female twin pairs2013In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 591, no 9, p. 2333-2344Article in journal (Refereed)
    Abstract [en]

    Ageing is associated with a decline in muscle mass and strength leading to increased physical dependency in old age. Postmenopausal women experience a greater decline than men of similar age in parallel with the decrease in female sex steroid hormone production. We recruited six monozygous female twin pairs (5559 years old) where only one twin pair was on hormone replacement therapy (HRT use = 7.8 +/- 4.3 years) to investigate the association of HRT with the cytoplasmic volume supported by individual myonuclei (myonuclear domain (MND) size,) together with specific force at the single fibre level. HRT use was associated with a significantly smaller (approximate to 27%; P < 0.05) mean MND size in muscle fibres expressing the type I but not the IIa myosin heavy chain (MyHC) isoform. In comparison to non-users, higher specific force was recorded in HRT users both in muscle fibres expressing type I (approximate to 27%; P < 0.05) and type IIa (approximate to 23%; P < 0.05) MyHC isoforms. These differences were fibre-type dependent, i.e. the higher specific force in fast-twitch muscle fibres was primarily caused by higher force per cross-bridge while slow-twitch fibres relied on both a higher number and force per cross-bridge. HRT use had no effect on fibre cross-sectional area (CSA), velocity of unloaded shortening (V0) and relative proportion of MyHC isoforms. In conclusion, HRT appears to have significant positive effects on both regulation of muscle contraction and myonuclei organization in postmenopausal women.

  • 206.
    Qaisar, Rizwan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Renaud, Guillaume
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Morine, Kevin
    Barton, Elisabeth
    Sweeney, Lee
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Is functional hypertrophy and specific force coupled with the addition of myonuclei at the single muscle fiber level?2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 3, p. 1077-1085Article in journal (Refereed)
    Abstract [en]

    Muscle force is typically proportional to muscle size, resulting in constant force normalized to muscle fiber cross-sectional area (specific force). Mice overexpressing insulin-like growth factor-1 (IGF-1) exhibit a proportional gain in muscle force and size, but not the myostatin-deficient mice. In an attempt to explore the role of the cytoplasmic volume supported by individual myonuclei [myonuclear domain (MND) size] on functional capacity of skeletal muscle, we have investigated specific force in relation to MND and the content of the molecular motor protein, myosin, at the single muscle fiber level from myostatin-knockout (Mstn(-/-)) and IGF-1-overexpressing (mIgf1(+/+)) mice. We hypothesize that the addition of extra myonuclei is a prerequisite for maintenance of specific force during muscle hypertrophy. A novel algorithm was used to measure individual MNDs in 3 dimensions along the length of single muscle fibers from the fast-twitch extensor digitorum longus and the slow-twitch soleus muscle. A significant effect of the size of individual MNDs in hypertrophic muscle fibers on both specific force and myosin content was observed. This effect was muscle cell type specific and suggested there is a critical volume individual myonuclei can support efficiently. The large MNDs found in fast muscles of Mstn(-/-) mice were correlated with the decrement in specific force and myosin content in Mstn(-/-) muscles. Thus, myostatin inhibition may not be able to maintain the appropriate MND for optimal function.-Qaisar, R., Renaud, G., Morine, K., Barton, E. R., Sweeney, H. L., Larsson, L. Is functional hypertrophy and specific force coupled with the addition of myonuclei at the single muscle fiber level?

  • 207.
    Qaisar, Rizwan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Yvette, Hedstrom
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Vuokko, Kovanen
    Sipilä, Sarianna
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Contractile function and myonuclear organization in single fibers from monozygotic female twins discordant for hormone replacement therapyManuscript (preprint) (Other academic)
  • 208.
    Ramamurthy, B.
    et al.
    The Pennsylvania State University.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Detection of an aging-related increase in advanced glycation end products in fast- and slow-twitch skeletal muscles in the rat2013In: Biogerontology (Dordrecht), ISSN 1389-5729, E-ISSN 1573-6768, Vol. 14, no 3, p. 293-301Article in journal (Refereed)
    Abstract [en]

    Glycation, a non-enzymatic addition of reducing sugars to ε-amino groups of proteins, is a post-translational modification that results in the formation of irreversible advanced glycation end products (AGEs). Ageing related decline in myofibrillar protein function is effected by a number of structural and functional modifications including glycation. Functional properties of skeletal muscles, such as maximum velocity of unloaded shortening, are known to be profoundly affected by ageing at the motor unit, cellular and tissue levels. However, the contribution of protein modifications to a decline in muscle function is not well understood. In this study we measured AGEs of intracellular and sarcolemmal proteins, using an anti-AGE antibody in soleus (SOL) and extensor digiotorum longus (EDL) muscles of male and female rats of five different age groups. Using a fluorescent secondary antibody to visualize AGEs in the confocal microscope, we found that myosin is glycated in both fiber types in all age groups; an ageing related increase in AGEs was observed in both intracellular and sarcolemmal regions in all age groups, with the exception of sarcolemma of SOL (unchanged) and EDL (reduced) in female rats; the greatest concentration of AGEs was found intracellularly in the SOL of the oldest age group (27–30) of females. While an ageing related decline in motor properties can be partially attributed to the observed increase in myofibrillar protein glycation, our results also indicate that intracellular and the less well studied sarcolemmal protein modification likely contribute to an aging-related decline in muscle function. Further studies are required to establish a link between the observed ageing related increase in glycation and muscle function at the motor unit, cellular and tissue levels.

  • 209. Reinholdson, J.
    et al.
    Lundgren, J.
    Edelvik, A.
    Flink, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Hallbook, T.
    Olsson, I
    Rydenhag, B.
    Malmgren, K.
    Seizure Outcome after Resective Epilepsy Surgery in Infancy and Early Childhood2014In: Epilepsia, ISSN 0013-9580, E-ISSN 1528-1167, Vol. 55, p. 25-25Article in journal (Other academic)
  • 210.
    Renaud, Guillaume
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Intensive care Muscle Wasting and Weakness: Underlying Mechanisms, Muscle Specific Differences and a Specific Intervention Strategy2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The intensive care unit (ICU) condition, i.e., immobilisation, sedation and mechanical ventilation, often results in severe muscle wasting and weakness as well as a specific acquired myopathy, i.e., Acute Quadriplegic Myopathy (AQM). The exact mechanisms underlying AQM remain incomplete, but this myopathy is characterised a preferential myosin loss and a decreased muscle membrane leading to a delayed recovery from the primary disease, increased mortality and morbidity and altered quality of life of survivors. This project aims at improving our understanding of the mechanisms underlying the muscle wasting and weakness associated with AQM and explore the effects of a specific intervention strategy. Time-resolved analyses have been undertaken using a unique experimental rodent ICU model and specifically studying the muscle wasting and weakness in limb and diaphragm muscles over a two week period. Further, we used passive mechanical loading in an attempt to alleviate the impaired muscle function and wasting associated with the ICU condition. Subsequently, the knowledge gained from the animal model was translated into a clinical study. Mechanical silencing (absence of external and internal strain) due to immobilisation, pharmacological neuromuscular blockade and sedation, was identified as a key factor triggering the muscle wasting and weakness associated with AQM in limb muscles. In addition, MuRF1, a member of the ubiquitin proteasome degradation pathway is playing a major role in the contractile protein degradation observed in both the diaphragm and limb muscles offering a potential candidate for future therapeutic approaches. Moreover, passive mechanical loading resulted in significant positive effects on muscle structure and function in the rodent ICU model, decreasing muscle atrophy and the loss of force generating capacity. In ICU patients passive mechanical loading improved the muscle fibre force generating capacity but did not affect muscle wasting. Nevertheless, this work strongly supports the importance of early physical therapy and mobilization in deeply sedated and mechanically ventilated ICU patients.

    Furthermore, we observed significant differences in the phenotype and mechanism underlying the loss of force generating capacity between the diaphragm and limb muscles in response to controlled mechanical ventilation (CMV) and immobilisation. This knowledge will have to be taken into account when designing intervention strategies to alleviate the muscle wasting and weakness that occurs in mechanically ventilated and immobilized ICU patients.

    List of papers
    1. Preferential skeletal muscle myosin loss in response to mechanical silencing in a novel rat intensive care unit model: underlying mechanisms
    Open this publication in new window or tab >>Preferential skeletal muscle myosin loss in response to mechanical silencing in a novel rat intensive care unit model: underlying mechanisms
    Show others...
    2011 (English)In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 589, no 8, p. 2007-2026Article in journal (Refereed) Published
    Abstract [en]

    Non-technical summary Wasting and severely impaired function of skeletal muscle is frequently observed in critically ill intensive care unit (ICU) patients, with negative consequences for recovery and quality of life. An experimental rat ICU model has been used to study the mechanisms underlying this unique wasting condition in neuromuscularly blocked and mechanically ventilated animals at durations varying between 6 h and 2 weeks. The complete 'mechanical silencing' of skeletal muscle (removal of both weight bearing and activation) resulted in a specific myopathy frequently observed in ICU patients and characterized by a preferential loss of the motor protein myosin. A highly complex and coordinated protein synthesis and degradation system was observed in the time-resolved analyses. It is suggested the 'mechanical silencing' of skeletal muscle is a dominating factor triggering the specific myopathy associated with the ICU intervention, and strongly supporting the importance of interventions counteracting the complete unloading in ICU patients.The muscle wasting and impaired muscle function in critically ill intensive care unit (ICU) patients delay recovery from the primary disease, and have debilitating consequences that can persist for years after hospital discharge. It is likely that, in addition to pernicious effects of the primary disease, the basic life support procedures of long-term ICU treatment contribute directly to the progressive impairment of muscle function. This study aims at improving our understanding of the mechanisms underlying muscle wasting in ICU patients by using a unique experimental rat ICU model where animals are mechanically ventilated, sedated and pharmacologically paralysed for duration varying between 6 h and 14 days. Results show that the ICU intervention induces a phenotype resembling the severe muscle wasting and paralysis associated with the acute quadriplegic myopathy (AQM) observed in ICU patients, i.e. a preferential loss of myosin, transcriptional down-regulation of myosin synthesis, muscle atrophy and a dramatic decrease in muscle fibre force generation capacity. Detailed analyses of protein degradation pathways show that the ubiquitin proteasome pathway is highly involved in this process. A sequential change in localisation of muscle-specific RING finger proteins 1/2 (MuRF1/2) observed during the experimental period is suggested to play an instrumental role in both transcriptional regulation and protein degradation. We propose that, for those critically ill patients who develop AQM, complete mechanical silencing, due to pharmacological paralysis or sedation, is a critical factor underlying the preferential loss of the molecular motor protein myosin that leads to impaired muscle function or persisting paralysis.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-152844 (URN)10.1113/jphysiol.2010.202044 (DOI)000289527200018 ()
    Available from: 2011-05-03 Created: 2011-05-02 Last updated: 2017-12-11Bibliographically approved
    2. Sparing of muscle mass and function by passive loading in an experimental intensive care unit model
    Open this publication in new window or tab >>Sparing of muscle mass and function by passive loading in an experimental intensive care unit model
    Show others...
    2013 (English)In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 591, no 5, p. 1385-1402Article in journal (Refereed) Published
    Abstract [en]

    The response to mechanical stimuli, i.e., tensegrity, plays an important role in regulating cell physiological and pathophysiological function and the mechanical silencing observed in intensive care unit (ICU) patients leads to a severe and specific muscle wasting condition. This study aims at unravelling the underlying mechanisms and the effects of passive mechanical loading on skeletal muscle mass and function at the gene, protein and cellular levels. A unique experimental rat ICU model has been used allowing long-term (weeks) time-resolved analyses of the effects of standardized unilateral passive mechanical loading on skeletal muscle size and function and underlying mechanisms. Results show that passive mechanical loading alleviated the muscle wasting and the loss of force-generation associated with the ICU intervention, resulting in a doubling of the functional capacity of the loaded vs. the unloaded muscles after a 2-week ICU intervention. We demonstrated that the improved maintenance of muscle mass and function is likely a consequence of a reduced oxidative stress revealed by lower levels of carbonylated proteins, and a reduced loss of the molecular motor protein myosin. A complex temporal gene expression pattern, delineated by microarray analysis, was observed with loading-induced changes in transcript levels of sarcomeric proteins, muscle developmental processes, stress response, ECM/cell adhesion proteins and metabolism. Thus, the results from this study show that passive mechanical loading alleviates the severe negative consequences on muscle size and function associated with the mechanical silencing in ICU patients, strongly supporting early and intense physical therapy in immobilized ICU patients.

    National Category
    Clinical Laboratory Medicine
    Research subject
    Clinical Neurophysiology
    Identifiers
    urn:nbn:se:uu:diva-189247 (URN)10.1113/jphysiol.2012.248724 (DOI)000315514300018 ()23266938 (PubMedID)
    Available from: 2012-12-28 Created: 2012-12-28 Last updated: 2017-12-06Bibliographically approved
    3. Mechanisms underlying intensive care unit muscle wasting and effects of passive mechanical loading
    Open this publication in new window or tab >>Mechanisms underlying intensive care unit muscle wasting and effects of passive mechanical loading
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    2012 (English)In: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 16, no 5, p. R209-Article in journal (Refereed) Published
    Abstract [en]

    ABSTRACT: INTRODUCTION: Critical ill intensive care unit (ICU) patients commonly develop severe muscle wasting and impaired muscle function, leading to delayed recovery, with subsequent increased morbidity and financial costs, and decreased quality of life of survivors. Critical illness myopathy (CIM) is a frequently observed neuromuscular disorder in ICU patients. Sepsis, systemic corticosteroid hormone treatment and post-synaptic neuromuscular blockade have been forwarded as the dominating triggering factors. Recent experimental results from our group using a unique experimental rat ICU model have shown that the "mechanical silencing" associated with the ICU condition is the primary triggering factor. This study aims at (1) unraveling the mechanisms underlying CIM, and (2) evaluating the effects of a specific intervention aiming at reducing the mechanical silencing in sedated and mechanically ventilated ICU patients. METHODS: Muscle gene/protein expression, post-translational modifications (PTMs), muscle membrane excitability, muscle mass measurements, and contractile properties at the single muscle fiber level were explored in seven deeply sedated and mechanically ventilated ICU patients (not exposed to systemic corticosteroid hormone treatment, post-synaptic neuromuscular blockade or sepsis) subjected to unilateral passive mechanical loading 10 hours per day (2.5 hours, 4 times) for 9 +/- 1 days. RESULTS: These patients developed a phenotype considered pathognomonic of CIM, i.e., severe muscle wasting and a preferential myosin loss (P<0.001). In addition, myosin PTMs specific to the ICU condition were observed in parallel with an increased sarcolemmal expression and cytoplasmic translocation of nNOS. Passive mechanical loading for 9 +/- 1 resulted in a 35% higher specific force (P<0.001) compared with the unloaded leg, although it was not sufficient to prevent the loss of muscle mass. CONCLUSIONS: Mechanical silencing is suggested to be a primary mechanism underlying CIM, i.e., triggering the myosin loss, muscle wasting and myosin PTMs. The higher nNOS expression found in the ICU patients and its cytoplasmic translocation are forwarded as a probable mechanism underlying these modifications. The positive effect of passive loading on muscle fiber function strongly supports the importance of early physical therapy and mobilization in deeply sedated and mechanically ventilated ICU patients.

    National Category
    Clinical Laboratory Medicine
    Research subject
    Clinical Neurophysiology
    Identifiers
    urn:nbn:se:uu:diva-183734 (URN)10.1186/cc11841 (DOI)000317499900046 ()23098317 (PubMedID)
    Note

    De två (2) första författarna delar förstaförfattarskapet.

    Available from: 2012-11-01 Created: 2012-11-01 Last updated: 2017-12-07Bibliographically approved
    4. Time-course analysis of mechanical ventilation-induced diaphragm contractile muscle dysfunction in the rat
    Open this publication in new window or tab >>Time-course analysis of mechanical ventilation-induced diaphragm contractile muscle dysfunction in the rat
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    2014 (English)In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 592, no 17, p. 3859-3880Article in journal (Refereed) Published
    Abstract [en]

    Controlled mechanical ventilation (CMV) plays a key role in triggering the impaired diaphragm muscle function and the concomitant delayed weaning from the respirator in critically ill intensive care unit (ICU) patients. To date, experimental and clinical studies have primarily focused on early effects on the diaphragm by CMV, or at specific time points. To improve our understanding of the mechanisms underlying the impaired diaphragm muscle function in response to mechanical ventilation, we have performed time‐resolved analyses between 6 h and 14 days using an experimental rat ICU model allowing detailed studies of the diaphragm in response to long‐term CMV. A rapid and early decline in maximum muscle fibre force and preceding muscle fibre atrophy was observed in the diaphragm in response to CMV, resulting in an 85% reduction in residual diaphragm fibre function after 9–14 days of CMV. A modest loss of contractile proteins was observed and linked to an early activation of the ubiquitin proteasome pathway, myosin:actin ratios were not affected and the transcriptional regulation of myosin isoforms did not show any dramatic changes during the observation period. Furthermore, small angle X‐ray diffraction analyses demonstrate that myosin can bind to actin in an ATP‐dependent manner even after 9–14 days of exposure to CMV. Thus, quantitative changes in muscle fibre size and contractile proteins are not the dominating factors underlying the dramatic decline in diaphragm muscle function in response to CMV, in contrast to earlier observations in limb muscles. The observed early loss of subsarcolemmal neuronal nitric oxide synthase activity, onset of oxidative stress, intracellular lipid accumulation and post‐translational protein modifications strongly argue for significant qualitative changes in contractile proteins causing the severely impaired residual function in diaphragm fibres after long‐term mechanical ventilation. For the first time, the present study demonstrates novel changes in the diaphragm structure/function and underlying mechanisms at the gene, protein and cellular levels in response to CMV at a high temporal resolution ranging from 6 h to 14 days.

    National Category
    Physiology Neurology
    Identifiers
    urn:nbn:se:uu:diva-192529 (URN)10.1113/jphysiol.2014.277962 (DOI)000341771400013 ()
    Funder
    Swedish Research Council, 8651, 4423
    Available from: 2013-01-22 Created: 2013-01-22 Last updated: 2018-01-11Bibliographically approved
  • 211.
    Renaud, Guillaume
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Llano-Diez, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Ravar, Barbara
    Gorza, Luisa
    Feng, Han-Zhong
    Jin, Jian-Ping
    Cacciani, Nicola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Gustafson, Ann-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Ochala, Julien
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Corpeno, Rebeca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Li, Meishan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Hedström, Yvette
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Ford, G Charles
    Nair, K Sreekumaran
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Sparing of muscle mass and function by passive loading in an experimental intensive care unit model2013In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 591, no 5, p. 1385-1402Article in journal (Refereed)
    Abstract [en]

    The response to mechanical stimuli, i.e., tensegrity, plays an important role in regulating cell physiological and pathophysiological function and the mechanical silencing observed in intensive care unit (ICU) patients leads to a severe and specific muscle wasting condition. This study aims at unravelling the underlying mechanisms and the effects of passive mechanical loading on skeletal muscle mass and function at the gene, protein and cellular levels. A unique experimental rat ICU model has been used allowing long-term (weeks) time-resolved analyses of the effects of standardized unilateral passive mechanical loading on skeletal muscle size and function and underlying mechanisms. Results show that passive mechanical loading alleviated the muscle wasting and the loss of force-generation associated with the ICU intervention, resulting in a doubling of the functional capacity of the loaded vs. the unloaded muscles after a 2-week ICU intervention. We demonstrated that the improved maintenance of muscle mass and function is likely a consequence of a reduced oxidative stress revealed by lower levels of carbonylated proteins, and a reduced loss of the molecular motor protein myosin. A complex temporal gene expression pattern, delineated by microarray analysis, was observed with loading-induced changes in transcript levels of sarcomeric proteins, muscle developmental processes, stress response, ECM/cell adhesion proteins and metabolism. Thus, the results from this study show that passive mechanical loading alleviates the severe negative consequences on muscle size and function associated with the mechanical silencing in ICU patients, strongly supporting early and intense physical therapy in immobilized ICU patients.

  • 212.
    Rostedt Punga, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Flink, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Cholinergic neuromuscular hyperactivity in patients with myasthenia gravis seropositive for MuSK antibody2006In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 34, no 1, p. 111-115Article in journal (Refereed)
    Abstract [en]

    A 75-year-old man with severe oculobulbar myasthenia gravis (MG) treated with acetylcholine esterase inhibitors (AChEIs) was found to have muscle-specific tyrosine kinase (MuSK) antibodies. Neurophysiological examination displayed extra repetitive discharges after the compound motor action potential (CMAP) at low-frequency stimulation, possibly triggered by AChEI. This indicates an abnormal sensitivity to acetylcholine in patients with MuSK antibodies and may be a useful indicator of the adverse effect of AChEI treatment in these patients. Muscle Nerve, 2006

  • 213.
    Rostedt Punga, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Kaminski, Henry J
    Richman, David P
    Benatar, Michael
    How clinical trials of myasthenia gravis can inform pre-clinical drug development2015In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 270, no SI, p. 78-81Article in journal (Refereed)
    Abstract [en]

    Pre-clinical evaluations often provide the rationale for therapeutic assessments in humans; however, in many diseases an agent found successful in animal models does not show efficacy in human subjects. Our contention is that the approach of rigorous, clinical trials can be used to inform how preclinical assessments should be performed. Clinical trials in humans are carefully designed investigations executed with consideration of critical methodological issues, such as pre-specified entrance criteria and validated, outcome measures coupled with power analysis to identify sample size. Blinding of evaluators of subjective measures and randomization of subjects are also critical aspects of trial performance. Investigative agents are also tested in subjects with active disease, rather than prior to disease induction as in some pre-clinical assessments. Application of standard procedures, including uniform reporting standards, would likely assist in reproducibility of pre-clinical experiments. Adapting methods of clinical trial performance will likely improve the success rate of therapeutics to ultimately achieve human use.

  • 214.
    Rostedt Punga, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Liik, Maarika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Reply to "high abnormal rate in the repetitive nerve stimulation test in acute onset myasthenia gravis"2018In: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 129, no 6, p. 1339-1339Article in journal (Other academic)
  • 215.
    Rostedt Punga, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Lin, Shuo
    Oliveri, Filippo
    Meinen, Sarina
    Rüeegg, Markus A.
    Muscle-selective synaptic disassembly and reorganization in MuSK antibody positive MG mice2011In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 230, no 2, p. 207-217Article in journal (Refereed)
    Abstract [en]

    MuSK antibody seropositive (MuSK+) Myasthenia Gravis (MG) patients present a distinct selective fatigue, and sometimes atrophy, of bulbar, facial and neck muscles. Here, we study the mechanism underlying the focal muscle involvement in mice with MuSK+ experimental autoimmune MG (EAMG). 8 week-old female wildtype C57BL6 mice and transgenic mice, which express yellow fluorescence protein (YFP) in their motor neurons, were immunized with the extracellular domain of rat MuSK and compared with control mice. The soleus, EDL, sternomastoid, omohyoid, thoracic paraspinal and masseter muscles were examined for pre- and postsynaptic changes with whole mount immunostaining and confocal microscopy. Neuromuscular junction derangement was quantified and compared between muscles and correlated with transcript levels of MuSK and other postsynaptic genes. Correlating with the EAMG disease grade, the postsynaptic acetylcholine receptor (AChR) clusters were severely fragmented with a subsequent reduction also of the presynaptic nerve terminal area. Among the muscles analyzed, the thoracic paraspinal, sternomastoid and masseter muscles were more affected than the leg muscles. The masseter muscle was the most affected, leading to denervation and atrophy and this severity correlated with the lowest levels of MuSK mRNA. On the contrary, the soleus with high MuSK mRNA levels had less postsynaptic perturbation and more terminal nerve sprouting. We propose that low muscle-intrinsic MuSK levels render some muscles, such as the masseter, more vulnerable to the postsynaptic perturbation of MuSK antibodies with subsequent denervation and atrophy. These findings augment our understanding of the sometimes severe, facio-bulbar phenotype of MuSK+ MG.

  • 216.
    Rostedt Punga, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Nygren, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Stålberg, Erik V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Monozygous twins with neuromuscular transmission defects at opposite sides of the motor endplate2009In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 119, no 3, p. 207-211Article in journal (Refereed)
    Abstract [en]

    Disorders affecting the postsynaptic side of the neuromuscular junction include autoimmune myasthenia gravis (MG) as well as some of the congenital myasthenic syndromes (CMS). Lambert-Eaton myasthenic syndrome (LEMS) is an acquired autoimmune neuromuscular disorder in which autoantibodies are directed against the presynaptic calcium channels. Here we describe two monozygous twin brothers: case 1 was diagnosed with an indeterminate form of acquired postsynaptic neuromuscular junction defect at age 32 and case 2 with LEMS at age 47. Case 1 presented clinically with mild generalized myasthenic weakness, neurophysiological examination revealed disturbed neuromuscular transmission along with probable myositis and serum analysis regarding antibodies against the acetylcholine receptor and muscle-specific tyrosine kinase was negative. Case 2 presented with proximal muscle fatigue accompanied by areflexia at rest and antibodies against the P/Q-type voltage-gated calcium channels were present. Neurophysiologically, case 2 had reduced baseline compound motor action potential amplitudes on neurography, decrement on low-frequency repetitive nerve stimulation (RNS) and pathological increment on high frequency RNS. To our knowledge this is the first case report of its kind and adds an intriguing contrast to the more common diagnosis of CMS in monozygous twins.

     

  • 217.
    Rostedt Punga, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Padua, Luca
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Validation of the Swedish version of the disease- specific myasthenia gravis questionnaire.2006In: Neurological Sciences, ISSN 1590-1874, E-ISSN 1590-3478, Vol. 27, no 2, p. 91-96Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to translate and validate the disease-specific patient-derived Myasthenia Gravis (MG) Questionnaire to enable use among Swedish MG patients. The original Italian version of the MG Questionnaire (MGQ) was translated into Swedish and transculturally adapted. The validity and reliability was tested on 48 Swedish MG patients. We correlated MGQ scores with disease severity and with the Swedish version of the Short-Form 36-item general health survey (SF-36). Reproducibility was assessed on 18 clinically stable MG patients. A significant correlation regarding the MGQ scores was seen when correlated with physical scores of the SF-36 and the overall clinical status. Internal consistency and reproducibility was excellent. We conclude that the evaluation capacities of the Swedish MGQ are equivalent to those of the original Italian version of the MGQ. The questionnaire was successfully validated as an outcome measure also for Swedish MG patients, which is important for international multicentre clinical trials.

  • 218.
    Rostedt Punga, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Punga, Tanel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Circulating microRNAs as potential biomarkers in myasthenia gravis patients.2018In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1412, no 1, p. 33-40Article, review/survey (Refereed)
    Abstract [en]

    MicroRNAs (miRNAs) are small noncoding RNA molecules that bind to specific mRNA targets and regulate a wide range of important biological processes within cells. Circulating miRNAs are released into the extracellular space and can be measured in most biofluids, including blood serum and plasma. Recently, circulating miRNAs have emerged as easily accessible markers in various body fluids with different profiles and quantities specific for different human disorders, including autoimmune diseases. In myasthenia gravis (MG), diagnostic tests such as titers of serum autoantibodies specific for either the acetylcholine receptor (AChR+) or muscle‐specific tyrosine kinase (MuSK+) do not necessarily reflect disease progression, and there is a great need for reliable objective biomarkers to monitor the disease course and therapeutic response. Recent studies in AChR+ MG revealed elevated levels of the immuno‐miRNAs miR‐150‐5p and miR‐21‐5p. Of particular importance, levels of miR‐150‐5p were lower in immunosuppressed patients and in patients with clinical improvement following thymectomy. In MuSK+ MG, another profile of circulating miRNAs was found, including upregulation of the let‐7 family of miRNAs. Here, we summarize the potential role of circulating miRNAs as biomarkers in general and in MG, and highlight important considerations for the analysis of circulating miRNA.

  • 219.
    Rostedt Punga, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Ruegg, Markus A.
    Signaling and aging at the neuromuscular synapse: lessons learnt from neuromuscular diseases2012In: Current opinion in pharmacology (Print), ISSN 1471-4892, E-ISSN 1471-4973, Vol. 12, no 3, p. 340-346Article in journal (Refereed)
    Abstract [en]

    The neuromuscular junction (NMJ) is a specialized synapse between motor neurons and skeletal muscle with a complex signaling network that assures highly reliable neuromuscular transmission. Diseases of the NMJ cause skeletal muscle fatigue and include inherited and acquired disorders that affect presynaptic, intrasynaptic or postsynaptic components. Moreover, fragmentation of the NMJ contributes to sarcopenia, the loss of muscle mass during aging. Studies from recent years indicate that the formation and stabilization of NMJs differs between various muscles and that this difference affects their response under pathological conditions. This review summarizes the most important mechanisms involved in the development, maintenance and dysfunction of the NMJ and it discusses their significance in myasthenic disorders and aging and as targets for possible future treatment of NMJ dysfunction.

  • 220.
    Rostedt Punga, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Acetylcholinesterase inhibitors in myasthenia gravis: to be or not to be?2009In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 39, no 6, p. 724-728Article, review/survey (Refereed)
    Abstract [en]

    Myasthenia gravis (MG) is an autoimmune disorder usually caused by antibodies against either the acetylcholine receptor (AChR) or muscle-specific tyrosine kinase (MuSK) at the neuromuscular junction. Neuromuscular transmission failure results in muscle fatigue and weakness that can be treated symptomatically with acetylcholinesterase inhibitors (AChEIs). Long-term treatment with nonselective AChEIs may have considerable drawbacks; thus, this medication is ideally tapered when strength improves. Patients with AChR antibodies respond beneficially to treatment, whereas patients with MuSK antibodies generally do not. Recently, the selective AChEI EN101, which specifically targets the isoform of "read-through" AChE (AChE-R), has been developed and may be of importance for symptomatic relief in AChR-antibody seropositive MG. This article is a review of the mechanisms, therapeutic effects, and drawbacks, with both old and new AChEIs in MG.

  • 221. Rydenhag, B.
    et al.
    Flink, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Malmgren, K.
    Resective Reoperations in Sweden 1990-2010 - a National Prospective Observational Study2014In: Epilepsia, ISSN 0013-9580, E-ISSN 1528-1167, Vol. 55, p. 26-26Article in journal (Other academic)
  • 222. Rydenhag, B.
    et al.
    Flink, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Malmgren, K.
    Seizure Outcome and Etiologies in Frontal Lobe Epilepsy Surgery in Sweden 1990-20092012In: Epilepsia, ISSN 0013-9580, E-ISSN 1528-1167, Vol. 53, p. 185-185Article in journal (Other academic)
  • 223. Rydenhag, B.
    et al.
    Stigsdotter-Broman, L.
    Ingrid, O.
    Flink, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Malmgren, K.
    Long term follow-up after callosotomy2013In: Epilepsia, ISSN 0013-9580, E-ISSN 1528-1167, Vol. 54, no S3, p. 180-180Article in journal (Other academic)
  • 224. Rydenhag, Bertil
    et al.
    Flink, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Malmgren, Kristina
    Surgical outcomes in patients with epileptogenic tumours and cavernomas in Sweden: good seizure control but late referrals.2013In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 84, no 1, p. 49-53Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Seizure outcome after epilepsy surgery is to an important extent related to underlying aetiology. In this study of patients who underwent epilepsy surgery with a lesional aetiology in Sweden 1990-2004, the aim was to investigate seizure outcome and prognostic factors. METHODS: All patients operated on during the time period with a histopathological diagnosis of an epileptogenic tumour (ganglioglioma (GGL), dysembryoblastic neuroepithelial tumour (DNET) and low grade astrocytoma (AST)) or a cavernous haemangioma (CAH) were identified in the population based Swedish National Epilepsy Surgery Register. Univariate and multivariate analyses were performed to determine the independent contribution of the following variables to seizure outcome: age at surgery; epilepsy duration; preoperative seizure frequency; localisation of the resection; and histopathology. RESULTS: Of the 156 identified patients who had a 2 year follow-up (103 adults and 53 children), 71% had temporal, 16% frontal and 13% parietal and occipital lobe resections. Mean presurgical epilepsy duration was 13 years in adults and 5 years in children. Main histopathological diagnosis was GGL or DNET in 67, CAH in 42 and AST in 47 patients. 77% of patients had sustained seizure freedom (with or without aura) 2 years after surgery. In the multivariate analysis, only diagnosis other than AST was independently associated with becoming seizure free. CONCLUSION: In this population based series, 120/156 patients (77%) with epileptogenic tumours and cavernomas were seizure free 2 years after surgery. Many had a very long epilepsy history. Seizure outcome can be improved if epilepsy surgery is considered earlier in patients with epileptogenic lesions.

  • 225.
    Sabre, Liis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Guptill, Jeffrey T.
    Duke Univ, Dept Neurol, Durham, NC USA.
    Russo, Melissa
    Duke Univ, Dept Neurol, Durham, NC USA.
    Juel, Vern C.
    Duke Univ, Dept Neurol, Durham, NC USA.
    Massey, Janice M.
    Duke Univ, Dept Neurol, Durham, NC USA.
    Howard, James F., Jr.
    Univ N Carolina, Dept Neurol, Chapel Hill, NC 27515 USA.
    Hobson-Webb, Lisa D.
    Duke Univ, Dept Neurol, Durham, NC USA.
    Rostedt Punga, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Circulating microRNA plasma profile in MuSK plus myasthenia gravis2018In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 325, p. 87-91Article in journal (Refereed)
    Abstract [en]

    Muscle-specific tyrosine kinase antibody positive myasthenia gravis (MuSK+ MG) is an immunological subtype with distinctive pathogenic mechanisms and clinical features. The aim of this study was to analyze the circulating plasma microRNA profile of patients with MuSK + MG. From the discovery cohort miR-210-3p, miR-3243p and miR-328-3p were further analyzed in the validation cohort. We found a distinct plasma profile of miR210-3p and miR-324-3p that were significantly decreased in MuSK+ MG patients compared to healthy controls (4.1 +/- 1.4 vs 5.1 +/- 1.4, p = .006 and 4.7 +/- 1.0 vs 5.4 +/- 1.3, p = .02). These findings reveal a distinct plasma miRNA profile in MuSK+ MG.

  • 226.
    Sabre, Liis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Maddison, Paul
    Univ Nottingham, Hosp NHS Trust, Queens Med Ctr, Dept Neurol, Nottingham, Notts, England.
    Sadalage, Girija
    Univ Nottingham, Hosp NHS Trust, Queens Med Ctr, Dept Neurol, Nottingham, Notts, England.
    Ambrose, Philip Alexander
    Univ Nottingham, Hosp NHS Trust, Queens Med Ctr, Dept Neurol, Nottingham, Notts, England.
    Rostedt Punga, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Circulating microRNA miR-21-5p, miR-150-5p and miR-30e-5p correlate with clinical status in late onset myasthenia gravis2018In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 321, p. 164-170Article in journal (Refereed)
    Abstract [en]

    There are no biomarkers for late onset myasthenia gravis (LOMG; onset > 50 years). We evaluated circulating microRNA in a discovery cohort of 4 LOMG patients and 4 healthy controls and in a prospective diagnostic validation cohort of 73 LOMG patients (48 male) with longitudinal follow-up samples. In immunosuppression naive patients, levels of miRNAs miR-150-5p, miR-21-5p and miR-30e-5p decreased in parallel with clinical improvement after initiation of immunosuppression and their levels positively correlated with the clinical MG composite score. Levels of miR-150-5p and miR-21-5p were lower in patients with ocular compared to generalized LOMG. Circulating miR-150-5p, miR-21-5p and miR-30e-5p correlate with the clinical course in LOMG.

  • 227.
    Sabre, Liis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Maddison, Paul
    Nottingham Univ Hosp NHS Trust, Dept Neurol, Queens Med Ctr, Nottingham, Notts, England.
    Wong, Sui H.
    Moorfields Eye Hosp NHS Fdn Trust, Dept Neuroophthalmol, London, England.
    Sadalage, Girija
    Nottingham Univ Hosp NHS Trust, Dept Neurol, Queens Med Ctr, Nottingham, Notts, England.
    Ambrose, Philip A.
    Nottingham Univ Hosp NHS Trust, Dept Neurol, Queens Med Ctr, Nottingham, Notts, England.
    Plant, Gordon T.
    Moorfields Eye Hosp NHS Fdn Trust, Dept Neuroophthalmol, London, England.
    Rostedt Punga, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    miR-30e-5p as predictor of generalization in ocular myasthenia gravis2019In: Annals of clinical and translational neurology, E-ISSN 2328-9503, Vol. 6, no 2, p. 243-251Article in journal (Refereed)
    Abstract [en]

    Objective: To determine a predictive factor for the risk of conversion from ocular myasthenia gravis (OMG) to generalized MG (GMG) in a prospective study.

    Methods: RNA was isolated from serum samples and detection of microRNA (miRNA) expression analyzed with qPCR. In the discovery set, 179 human miRNAs were assayed for profiling of five OMG patients and four age- and gender-matched healthy controls. Based on the specific accumulation pattern of 19 miRNAs from the discovery set, in addition to miRNAs previously found elevated in generalized MG (GMG; miR-150-5p and miR-30e-5p), 21 miRNAs were subsequently analyzed in a validation cohort of 83 OMG patients (82 immunosuppression treatment naive; 49 male) within 3 months of diagnosis and at a follow-up visit (median duration 28 months from first visit).

    Results: Thirteen patients generalized 14.8 +/- 12.0 months after the diagnosis and the majority (85%) belonged to the late onset MG group. Two miRNAs were significantly higher in secondary GMG (SGMG) patients compared to OMG patients with late onset MG: miR-30e-5p (9.1 +/- 0.5 vs. 6.3 +/- 0.9; P < 0.0001) and miR-150-5p (7.4 +/- 1.1 vs. 6.4 +/- 1.1; P = 0.01). The sensitivity for miR-30e-5p in differentiating OMG and SGMG was 96% in all OMG patients and 100% in late onset OMG patients.

    Interpretation: This is the first study to describe a potential predictive factor associated with the risk of generalization for patients with OMG. Raised levels (>8) of miR-30e-5p at initial presentation in patients with ocular MG symptoms, give a predictive cut-off for subsequent generalization of 96-100%.

  • 228.
    Sabre, Liis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology. Tartu Univ Hosp, Dept Neurol, Tartu, Estonia..
    Westerberg, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Liik, Maarika
    Tartu Univ Hosp, Dept Neurol, Tartu, Estonia..
    Punga, Anna R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Diversity in mental fatigue and social profile of patients with myasthenia gravis in two different Northern European countries2017In: Brain and Behavior, ISSN 2162-3279, E-ISSN 2162-3279, Vol. 7, no 4, article id e00653Article in journal (Refereed)
    Abstract [en]

    Tntroduction: Self-estimated health can be used for comparison of different diseases between countries. It is important to elaborate on whether disparities in self-estimated health are due to disease-specific parameters or socioeconomic differences. In this study, we aimed at evaluating clinical and social similarities and differences in myasthenia gravis (MG) patients between comparable regions in two Baltic Sea countries, Estonia and Sweden. Methods: This cross-sectional study included southern counties in Sweden and Estonia of comparable size. All patients with a confirmed MG diagnosis were asked to answer two questionnaires including demographic and disease-specific data, lifestyle issues, and mental fatigue (Fatigue Severity Scale [FSS]). Clinical fatigue was assessed objectively through the Quantitative Myasthenia Gravis Score (QMG). Results: Thirty-six of 92 identified patients in Estonia and 40 of 70 identified MG patients in Sweden chose to participate in the study. The demographic characteristics and symptoms reported by the patients were similar. QMG score did not differ; however, the Estonian patients scored their current subjective disease severity significantly higher (5.6 +/- 2.8) compared to the Swedish patients (3.4 +/- 2.3, p=.0005). Estonian patients also had significantly higher FSS scores (5.0 +/- 1.7) than Swedish patients (3.5 +/- 1.6; p=.001). Swedish patients were more active and performed physical activity more regularly (29.1% in Estonia and 74.2% in Sweden, p=.004). Conclusions: Although, the patients had comparable clinical fatigue, Estonian patients evaluated their health state as being more severe and reported more mental fatigue than Swedish patients. These data indicate large regional differences in disease perception of MG, which is important to consider in international studies.

  • 229.
    Sagafos, Dagrun
    et al.
    Natl Hosp Norway, Oslo Univ Hosp, Clin Neurophysiol Sect, Dept Neurol, Pb 4950 Nydalen, N-0424 Oslo, Norway..
    Kleggetveit, Inge P.
    Natl Hosp Norway, Oslo Univ Hosp, Clin Neurophysiol Sect, Dept Neurol, Pb 4950 Nydalen, N-0424 Oslo, Norway..
    Helas, Tormod
    Natl Hosp Norway, Oslo Univ Hosp, Clin Neurophysiol Sect, Dept Neurol, Pb 4950 Nydalen, N-0424 Oslo, Norway..
    Schmidt, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Minde, Jan
    Umea Univ, Unit Orthoped, Dept Surg, Perioperat Sci, Umea, Sweden..
    Namer, Barbara
    Univ Erlangen Nurnberg, Dept Physiol & Expt Pathophysiol, Erlangen, Germany..
    Schmelz, Martin
    Heidelberg Univ, Dept Anaesthesiol & Operat Intens Care, Mannheim, Germany..
    Jorum, Ellen
    Natl Hosp Norway, Oslo Univ Hosp, Clin Neurophysiol Sect, Dept Neurol, Pb 4950 Nydalen, N-0424 Oslo, Norway..
    Single-Fiber Recordings of Nociceptive Fibers in Patients With HSAN Type V With Congenital Insensitivity to Pain2016In: The Clinical Journal of Pain, ISSN 0749-8047, E-ISSN 1536-5409, Vol. 32, no 7, p. 636-642Article in journal (Refereed)
    Abstract [en]

    Objectives: Nerve growth factor (NGF) is a protein important for growth and survival, but also for modulation of sensitivity of nociceptors and sympathetic neurons. The purpose of the present study was to investigate the effects of reduced NGF signaling in patients with hereditary sensory and autonomic neuropathies type V, congenital insensitivity to pain, caused by a mutation of the NGF beta gene, including a characterization of single nociceptive fibers using microneurography (MNG). Materials and Methods: One homozygote and 2 heterozygote patients with this mutation were examined with electromyography/neurography, thermal testing, quantitative sudomotor axon reflex test, and electrically induced axon reflex erythema in addition to MNG. Results: Low quantitative sudomotor axon reflex test measurements of 0.02 (left foot) and 0.03 (right foot) mL/cm(2) and elevated thermal thresholds for warmth and cold detection testing showed clear impairment of small nerve fibers, both sudomotor efferent and somatic afferent fibers, in the patient homozygote for the mutation. MNG from one of the heterozygote patients revealed changes in the small nociceptive fibers in skin, including abnormally low conduction velocity, spontaneous activity in A-delta fibers and C-nociceptors and abnormal or lacking response to heat. Discussion: The findings of grossly intact pain thresholds compared with anamnestic insensitivity of pain in deep somatic tissue such as bone suggest a gradient of impairment dependent on different NGF availability in various tissues. Even though these patients in some aspects report insensitivity to pain, they also report chronic spontaneous pain as their main symptom, strikingly highlighting differential mechanisms of insensitivity to evoked pain versus spontaneous pain.

  • 230.
    Salah, Heba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Muscle Wasting in a Rat ICU Model: Underlying Mechanisms and Specific Intervention Strategies2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Critical care has undergone several developments in the recent years leading to improved survival. However, acquired muscle weakness in the intensive care unit (ICU) is an important complication that affects severely ill patients and can prolong their ICU stay. Critical illness myopathy (CIM) is the progressive decline in the function and mass of the limb muscles in response to exposure to the ICU condition, while ventilator-induced diaphragm dysfunction (VIDD) is the time dependent decrease in the diaphragm function after the initiation of mechanical ventilation. Since the complete underlying mechanisms for CIM and VIDD are not completely understood, there is a compelling need for research on the mechanisms of CIM and VIDD to develop intervention strategies targeting these mechanisms. The aim of this thesis was to investigate the effects of several intervention strategies and rehabilitation programs on muscle wasting associated with ICU condition. Moreover, muscle specific differences in response to exposure to the ICU condition and different interventions was investigated. Hence, a rodent ICU model was used to address the mechanistic and therapeutic aspects of CIM and VIDD. The effects of heat shock protein 72 co-inducer (HSP72), BGP-15, on diaphragm and soleus for rats exposed to different durations of ICU condition was investigated. We showed that 5 and 10 days treatment with BGP-15 improved diaphragm fiber and myosin function, protected myosin from posttranslational modification, induced HSP72 and improved mitochondrial function. Moreover, BGP-15 treatment for 5 days improved soleus muscle fibers function, improved mitochondrial structure and reduced the levels of some ubiquitin ligases. In addition to BGP-15 treatment, passive mechanical loading of the limb muscles was investigated during exposure to the ICU condition. We showed that mitochondrial dynamics and mitophagy gene expression was affected by Mechanical silencing while mechanical loading counteracted these effects. Our investigation for other pathways that can be involved in muscle wasting associated with ICU condition showed that the Janus kinase 2/ Signal transducer and activator of transcription 3 (JAK2/STAT3) pathway is differentially activated in plantaris, intercostals and diaphragm. However, further studies are required with JAK2/STAT3 inhibitors to fully examine the role of this pathway in the pathogenesis of CIM and VIDD prior to translation to clinical research.

    List of papers
    1. The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction
    Open this publication in new window or tab >>The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction
    Show others...
    2016 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 8, no 350, article id 350ra103Article in journal (Refereed) Published
    Abstract [en]

    Ventilation-induced diaphragm dysfunction (VIDD) is a marked decline in diaphragm function in response to mechanical ventilation, which has negative consequences for individual patients' quality of life and for the health care system, but specific treatment strategies are still lacking. We used an experimental intensive care unit (ICU) model, allowing time-resolved studies of diaphragm structure and function in response to long-term mechanical ventilation and the effects of a pharmacological intervention (the chaperone co-inducer BGP-15). The marked loss of diaphragm muscle fiber function in response to mechanical ventilation was caused by post-translational modifications (PTMs) of myosin. In a rat model, 10 days of BGP-15 treatment greatly improved diaphragm muscle fiber function (by about 100%), although it did not reverse diaphragm atrophy. The treatment also provided protection from myosin PTMs associated with HSP72 induction and PARP-1 inhibition, resulting in improvement of mitochondrial function and content. Thus, BGP-15 may offer an intervention strategy for reducing VIDD in mechanically ventilated ICU patients.

    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-303060 (URN)10.1126/scitranslmed.aaf7099 (DOI)000380780000005 ()
    External cooperation:
    Funder
    The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)Swedish Research Council, 8651; 4423; 4870; 3074EU, European Research Council, CT-223756; COST CM1001The Karolinska Institutet's Research FoundationStockholm County CouncilNovo Nordisk, 100193
    Available from: 2016-09-14 Created: 2016-09-14 Last updated: 2018-01-10Bibliographically approved
    2. Does chaperone co-inducer BGP-15 mitigate the contractile dysfunction of the soleus muscle in a rat ICU model?
    Open this publication in new window or tab >>Does chaperone co-inducer BGP-15 mitigate the contractile dysfunction of the soleus muscle in a rat ICU model?
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Anesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-328594 (URN)
    Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2017-08-31
    3. Mechano-signalling pathways in an experimental intensive critical illness myopathy model
    Open this publication in new window or tab >>Mechano-signalling pathways in an experimental intensive critical illness myopathy model
    Show others...
    2016 (English)In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793Article in journal (Refereed) Published
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-322821 (URN)
    Available from: 2017-08-21 Created: 2017-08-21 Last updated: 2017-08-31
    4. Muscle specific differences in activation of the Janus kinase 2/ Signal Transducer and Activator of Transcription 3 following long-term mechanical ventilation and immobilization in rats
    Open this publication in new window or tab >>Muscle specific differences in activation of the Janus kinase 2/ Signal Transducer and Activator of Transcription 3 following long-term mechanical ventilation and immobilization in rats
    Show others...
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Anesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-328592 (URN)
    Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2017-08-31
  • 231.
    Salah, Heba
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology. Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    Fury, W.
    Regeneron Pharmaceut, Tarrytown, NY USA..
    Gromada, J.
    Regeneron Pharmaceut, Tarrytown, NY USA..
    Bai, Y.
    Regeneron Pharmaceut, Tarrytown, NY USA..
    Tchkonia, T.
    Mayo Clin, Coll Med, Robert & Arlene Kogod Ctr Aging, Rochester, MN USA..
    Kirkland, J. L.
    Mayo Clin, Coll Med, Robert & Arlene Kogod Ctr Aging, Rochester, MN USA..
    Larsson, L.
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.;Karolinska Inst, Dept Clin Neurosci, Clin Neurophysiol, Stockholm, Sweden.;Penn State Univ, Dept Biobehav Hlth, State Coll, PA USA..
    Muscle-specific differences in expression and phosphorylation of the Janus kinase 2/Signal Transducer and Activator of Transcription 3 following long-term mechanical ventilation and immobilization in rats2018In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 222, no 3, article id e12980Article in journal (Refereed)
    Abstract [en]

    Aim: Muscle wasting is one of the factors most strongly predicting mortality and morbidity in critically ill intensive care unit (ICU). This muscle wasting affects both limb and respiratory muscles, but the understanding of underlying mechanisms and muscle-specific differences remains incomplete. This study aimed at investigating the temporal expression and phosphorylation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in muscle wasting associated with the ICU condition to characterize the JAK/STAT proteins and the related changes leading or responding to their activation during exposure to the ICU condition.

    Methods: A novel experimental ICU model allowing long-term exposure to the ICU condition, immobilization and mechanical ventilation, was used in this study. Rats were pharmacologically paralysed by post-synaptic neuromuscular blockade and mechanically ventilated for durations varying between 6hours and 14days to study muscle-specific differences in the temporal activation of the JAK/STAT pathway in plantaris, intercostal and diaphragm muscles.

    Results: The JAK2/STAT3 pathway was significantly activated irrespective of muscle, but muscle-specific differences were observed in the temporal activation pattern between plantaris, intercostal and diaphragm muscles.

    Conclusion: The JAK2/STAT3 pathway was differentially activated in plantaris, intercostal and diaphragm muscles in response to the ICU condition. Thus, JAK2/STAT3 inhibitors may provide an attractive pharmacological intervention strategy in immobilized ICU patients, but further experimental studies are required in the study of muscle-specific effects on muscle mass and function in response to both short- and long-term exposure to the ICU condition prior to the translation into clinical research and practice.

  • 232.
    salah, heba
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Fury, Wen
    Gromada, Jesper
    Bai, Yu
    Tchkonia, Tamar
    Kirkland, James
    Larsson, Lars
    Muscle specific differences in activation of the Janus kinase 2/ Signal Transducer and Activator of Transcription 3 following long-term mechanical ventilation and immobilization in ratsIn: Article in journal (Refereed)
  • 233.
    Salah, Heba
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology. Karolinska Inst, Dept Physiol & Pharmacol, SE-17777 Stockholm, Sweden..
    Li, Meishan
    Karolinska Inst, Dept Physiol & Pharmacol, SE-17777 Stockholm, Sweden..
    Cacciani, Nicola
    Karolinska Inst, Dept Physiol & Pharmacol, SE-17777 Stockholm, Sweden..
    Gastaldello, Stefano
    Karolinska Inst, Dept Physiol & Pharmacol, SE-17777 Stockholm, Sweden..
    Ogilvie, Hannah
    Karolinska Inst, Dept Physiol & Pharmacol, SE-17777 Stockholm, Sweden..
    Akkad, Hazem
    Karolinska Inst, Dept Physiol & Pharmacol, SE-17777 Stockholm, Sweden..
    Namuduri, Arvind Venkat
    Karolinska Inst, Dept Physiol & Pharmacol, SE-17777 Stockholm, Sweden..
    Morbidoni, Valeria
    Univ Padua, Dept Womens & Childrens Hlth, Clin Genet Unit, I-35128 Padua, Italy..
    Artemenko, Konstantin A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Balogh, Gabor
    Hungarian Acad Sci, Biol Res Ctr, Inst Biochem, H-6726 Szeged, Hungary..
    Martinez-Redondo, Vicente
    Karolinska Inst, Dept Physiol & Pharmacol, SE-17777 Stockholm, Sweden..
    Jannig, Paulo
    Karolinska Inst, Dept Physiol & Pharmacol, SE-17777 Stockholm, Sweden..
    Hedström, Yvette
    Karolinska Inst, Dept Physiol & Pharmacol, SE-17777 Stockholm, Sweden..
    Dworkin, Barry
    Karolinska Inst, Dept Physiol & Pharmacol, SE-17777 Stockholm, Sweden.;Penn State Univ, Dept Neurosci, Hershey, PA 17033 USA..
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Utah, Sch Med, Dept Pathol, Salt Lake City, UT 84112 USA.;Binzhou Med Univ, Precis Med, Yantai 264003, Shandong, Peoples R China..
    Ruas, Jorge
    Karolinska Inst, Dept Physiol & Pharmacol, SE-17777 Stockholm, Sweden..
    Vigh, Laszlo
    Hungarian Acad Sci, Biol Res Ctr, Inst Biochem, H-6726 Szeged, Hungary..
    Salviati, Leonardo
    Univ Padua, Dept Womens & Childrens Hlth, Clin Genet Unit, I-35128 Padua, Italy..
    Larsson, Lars
    Karolinska Inst, Dept Physiol & Pharmacol, SE-17777 Stockholm, Sweden.;Penn State Univ, Dept Biobehav Hlth, University Pk, PA 16802 USA.;Karolinska Inst, Clin Neurophysiol, Dept Clin Neurosci, SE-17777 Stockholm, Sweden..
    The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction2016In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 8, no 350, article id 350ra103Article in journal (Refereed)
    Abstract [en]

    Ventilation-induced diaphragm dysfunction (VIDD) is a marked decline in diaphragm function in response to mechanical ventilation, which has negative consequences for individual patients' quality of life and for the health care system, but specific treatment strategies are still lacking. We used an experimental intensive care unit (ICU) model, allowing time-resolved studies of diaphragm structure and function in response to long-term mechanical ventilation and the effects of a pharmacological intervention (the chaperone co-inducer BGP-15). The marked loss of diaphragm muscle fiber function in response to mechanical ventilation was caused by post-translational modifications (PTMs) of myosin. In a rat model, 10 days of BGP-15 treatment greatly improved diaphragm muscle fiber function (by about 100%), although it did not reverse diaphragm atrophy. The treatment also provided protection from myosin PTMs associated with HSP72 induction and PARP-1 inhibition, resulting in improvement of mitochondrial function and content. Thus, BGP-15 may offer an intervention strategy for reducing VIDD in mechanically ventilated ICU patients.

  • 234.
    Sandberg, Arne
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Dynamic Changes in the Peripheral and the Central Nervous Systems in Patients with Prior Polio2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    After the acute spell of poliomyelitis, patients commonly suffers from sequelae of weakness. Some of these patients experience new weakness after a time period of stable symptoms.

    The aim of this thesis was to evaluate the possible mechanisms for persistent weakness and development of new weakness in prior polio patients.

    The usefulness of neurophysiologic methods to study prior polio was evaluated. Also two follow up investigations were performed in the attempt to investigate a possible relationship between development of weakness over time and possible failure in neuromuscular function and relation to muscular activity. In another investigation an evaluation of the exceptional finding of a history of paralytic poliomyelitis without neurophysiologic signs of anterior horn cell death was made. The last investigation dealt with reflex pattern in prior polio and it’s relation to weakness and anterior horn cell loss.

    The weakness in prior polio is mainly due to loss of motor neurons with incomplete compensatory mechanisms of reinnervation. The new weakness is mainly due to exaggerated physiological age dependent loss of whole motor neurons, but also fragmentation of the motor unit is likely when these have reached an upper size. Defective neuromuscular transmission and failure in the central drive contribute to a lesser degree to weakness.

    Neurophysiologic method of choice for the assessment of motor unit size and the micro-physiology of the motor unit is Macro EMG.

    Muscular overuse may accelerate motor unit loss over time in prior polio. Extremely large motor units measured with Macro EMG predict new weakness and Macro EMG can be used for prognostication of development of new weakness in prior polio.

    List of papers
    1. Comparison between concentric needle EMG and macro EMG in patients with a history of polio
    Open this publication in new window or tab >>Comparison between concentric needle EMG and macro EMG in patients with a history of polio
    1999 In: Clin Neurophysiol, Vol. 110, no 11, p. 1900-1908Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-92238 (URN)
    Available from: 2004-10-28 Created: 2004-10-28Bibliographically approved
    2. An 8-year longitudinal study of muscle strength, muscle fiber size, and dynamic electromyogram in individuals with late polio
    Open this publication in new window or tab >>An 8-year longitudinal study of muscle strength, muscle fiber size, and dynamic electromyogram in individuals with late polio
    1998 In: Muscle & Nerve, Vol. 21, no November, p. 1428-1437Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-92239 (URN)
    Available from: 2004-10-28 Created: 2004-10-28Bibliographically approved
    3. How to interpret normal electromyographic findings in patients with an alleged history of polio
    Open this publication in new window or tab >>How to interpret normal electromyographic findings in patients with an alleged history of polio
    2004 In: J Rehabil Med, Vol. 36, no July, p. 169-176Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-92240 (URN)
    Available from: 2004-10-28 Created: 2004-10-28Bibliographically approved
    4. Changes in macro electromyography over time in patients with a history of polio: A comparison of 2 muscles
    Open this publication in new window or tab >>Changes in macro electromyography over time in patients with a history of polio: A comparison of 2 muscles
    2004 In: Arch Phys Med Rehabil, Vol. 85, no July, p. 1174-1182Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-92241 (URN)
    Available from: 2004-10-28 Created: 2004-10-28Bibliographically approved
    5. Reflexes in prior polio; changed excitability in motor neuron pool
    Open this publication in new window or tab >>Reflexes in prior polio; changed excitability in motor neuron pool
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-92242 (URN)
    Available from: 2004-10-28 Created: 2004-10-28Bibliographically approved
  • 235.
    Sandberg, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Single fiber EMG Fiber density and its relationship to Macro EMG amplitude in reinnervation2014In: Journal of Electromyography & Kinesiology, ISSN 1050-6411, E-ISSN 1873-5711, Vol. 24, no 6, p. 941-946Article in journal (Refereed)
    Abstract [en]

    The objective was to elucidate the relation between the Macro EMG parameters fiber density (FD) and Macro amplitude in reinnervation in the purpose to use the FD parameter as a surrogate marker for reinnervation instead of the Macro amplitude. Macro EMG with FD was performed in 278 prior polio patients. The Biceps Brachii and the Tibialis anterior muscles were investigated. FD was more sensitive for detection of signs of reinnervation but showed lesser degree of abnormality than the Macro amplitude. FD and Macro MUP amplitude showed a non-linear relation with a great variation in FD for given Macro amplitude level. The relatively smaller increase in FD compared to Macro amplitude in addition to the non-linear relationship between the FD and the Macro amplitude regarding reinnervation in prior polio can be due to technical reasons and muscle fiber hypertrophy. The FD parameter has a relation to Macro MUP amplitude but cannot alone be used as a quantitative marker of the degree of reinnervation.

  • 236.
    Sandberg, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    The standard concentric needle cannula cannot replace the Macro EMG electrode2014In: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 125, no 2, p. 406-410Article in journal (Refereed)
    Abstract [en]

    Objective:

    To establish the usefulness of the single use and affordable standard concentric EMG electrode as a substitute for the expensive standard macro electrode.

    Methods:

    Macro EMG performed with macro electrode is compared with recordings from the uninsulated cannula of a standard EMG electrode at two different recording depths in the tibialis anterior muscle. This was performed both in muscles with signs of collateral reinnervation and without.

    Results

    The amplitude of the motor units recorded with the uninsulated concentric needle cannula were lower for the deeply recorded motor units compared to motor unit potential (MUP) amplitudes recorded with the standard macro electrode. The deeply recorded concentric needle (CN) cannula recorded MUPs amplitudes were also lower than superficially recorded CN cannula MUPs. The standard Macro EMG signals show no difference between deeply and superficially recorded motor units.

    Conclusion

    The uninsulated cannula of the concentric needle electrode cannot replace the standard Macro EMG electrode due to technical reasons, probably from different effects of shunting of the bare cannula in deep vs. superficially recorded motor units.

    Significance

    The standard CN electrode could not be used as substitute for the standard Macro EMG needle.

  • 237.
    Sandberg, Arne
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Hansson, Björn
    Stålberg, Erik
    Comparison between concentric needle EMG and macro EMG in patients with a history of polio1999In: Clin Neurophysiol, Vol. 110, no 11, p. 1900-1908Article in journal (Refereed)
  • 238.
    Sandberg, Arne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Nandedkar, Sanjeev D.
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Macro electromyography and motor unit number index in the tibialis anterior muscle: Differences and similarities in characterizing motor unit properties in prior polio2011In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 43, no 3, p. 335-341Article in journal (Refereed)
    Abstract [en]

    Our objective was to establish the usefulness of the noninvasive method of the motor unit number index (MUNIX) in a large muscle and to study how macro electromyography (EMG) and MUNIX complement each other in describing the motor units (MUs) in prior polio. MUNIX and macro EMG were performed in 48 tibialis anterior muscles in 33 prior polio patients. In addition, the reproducibility of MUNIX was investigated. It is shown that MUNIX can be used to characterize MUs with high reproducibility, even in a large muscle. As judged by MUNIX values, the patients had a 25% reduction of motor neurons, whereas the macro EMG indicated a loss of 60% of the neurons. Macro EMG showed more pronounced changes compared with control material than the MUNIX. One of the reasons for this finding may be the difference in MU populations studied with the two methods.

  • 239.
    Sandberg, Arne
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Stålberg, Erik
    Changes in macro electromyography over time in patients with a history of polio: A comparison of 2 muscles2004In: Arch Phys Med Rehabil, Vol. 85, no July, p. 1174-1182Article in journal (Refereed)
  • 240.
    Sandberg, Arne
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Stålberg, Erik
    How to interpret normal electromyographic findings in patients with an alleged history of polio2004In: J Rehabil Med, Vol. 36, no July, p. 169-176Article in journal (Refereed)
  • 241.
    Sandberg, Arne
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Stålberg, Erik
    Reflexes in prior polio; changed excitability in motor neuron poolArticle in journal (Refereed)
  • 242. Sandri, M
    et al.
    Barberi, L
    Bijlsma, A Y
    Blaauw, B
    Dyar, K A
    Milan, G
    Mammucari, C
    Meskers, C G M
    Pallafacchina, G
    Paoli, A
    Pion, D
    Roceri, M
    Romanello, V
    Serrano, A L
    Toniolo, L
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Maier, A B
    Muñoz-Cánoves, P
    Musarò, A
    Pende, M
    Reggiani, C
    Rizzuto, R
    Schiaffino, S
    Signalling pathways regulating muscle mass in ageing skeletal muscle: The role of the IGF1-Akt-mTOR-FoxO pathway2013In: Biogerontology (Dordrecht), ISSN 1389-5729, E-ISSN 1573-6768, Vol. 14, no 3 SI, p. 303-323Article in journal (Refereed)
    Abstract [en]

    During ageing skeletal muscles undergo a process of structural and functional remodelling that leads to sarcopenia, a syndrome characterized by loss of muscle mass and force and a major cause of physical frailty. To determine the causes of sarcopenia and identify potential targets for interventions aimed at mitigating ageing-dependent muscle wasting, we focussed on the main signalling pathway known to control protein turnover in skeletal muscle, consisting of the insulin-like growth factor 1 (IGF1), the kinase Akt and its downstream effectors, the mammalian target of rapamycin (mTOR) and the transcription factor FoxO. Expression analyses at the transcript and protein level, carried out on well-characterized cohorts of young, old sedentary and old active individuals and on mice aged 200, 500 and 800 days, revealed only modest age-related differences in this pathway. Our findings suggest that during ageing there is no downregulation of IGF1/Akt pathway and that sarcopenia is not due to FoxO activation and upregulation of the proteolytic systems. A potentially interesting result was the increased phosphorylation of the ribosomal protein S6, indicative of increased activation of mTOR complex1 (mTORC1), in aged mice. This result may provide the rationale why rapamycin treatment and caloric restriction promote longevity, since both interventions blunt activation of mTORC1; however, this change was not statistically significant in humans. Finally, genetic perturbation of these pathways in old mice aimed at promoting muscle hypertrophy via Akt overexpression or preventing muscle loss through inactivation of the ubiquitin ligase atrogin1 were found to paradoxically cause muscle pathology and reduce lifespan, suggesting that drastic activation of the IGF1-Akt pathway may be counterproductive, and that sarcopenia is accelerated, not delayed, when protein degradation pathways are impaired.

  • 243. Santos, S.
    et al.
    Baraibar, M.
    Le Boulch, M.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Friguet, B.
    Optimization of a proteomic approach for evidencing and identifying oxidized proteins during human skeletal muscle aging2013In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 48, no 7, p. 687-688Article in journal (Other academic)
  • 244.
    Sauerstein, Katja
    et al.
    Univ Erlangen Nurnberg, Dept Physiol & Expt Pathophysiol, Nurnberg, Germany; Heidelberg Univ, Med Fac Mannheim, Dept Expt Pain Res, CBTM, Mannheim, Germany.
    Liebelt, Jan
    Univ Erlangen Nurnberg, Dept Physiol & Expt Pathophysiol, Nurnberg, Germany; Heidelberg Univ, Med Fac Mannheim, Dept Expt Pain Res, CBTM, Mannheim, Germany.
    Namer, Barbara
    Univ Erlangen Nurnberg, Dept Physiol & Expt Pathophysiol, Nurnberg, Germany; Heidelberg Univ, Med Fac Mannheim, Dept Expt Pain Res, CBTM, Mannheim, Germany.
    Schmidt, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Rukwied, Roman
    Heidelberg Univ, Med Fac Mannheim, Dept Expt Pain Res, CBTM, Mannheim, Germany.
    Schmelz, Martin
    Heidelberg Univ, Med Fac Mannheim, Dept Expt Pain Res, CBTM, Mannheim, Germany.
    Low-Frequency Stimulation of Silent Nociceptors Induces Secondary Mechanical Hyperalgesia in Human Skin2018In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 387, p. 4-12Article in journal (Refereed)
    Abstract [en]

    Secondary mechanical hyperalgesia to punctate mechanical stimuli and light touch (allodynia) are prominent symptoms in neuropathic pain states. In a combined microneurographic and psychophysical study, we investigated the role of mechano-insensitive (silent) nociceptors regarding induction. Electrical thresholds of mechano-sensitive and silent nociceptors were assessed by microneurography with two closely spaced intracutaneous electrodes (i.c.) and a transcutaneous configuration (t.c.) in the foot dorsum. For t.c. stimulation there was a marked difference between silent (median, quartiles; 60, 50-70 mA, n = 63) and mechano-sensitive fibers (3, 2-5 mA, n = 107). In silent fibers, thresholds were lower for i.c. stimulation (16, 14-19 mA, n = 8), but higher in mechano-sensitive units (6, 5-6 mA, n = 13). Corresponding psychophysical tests showed no difference between the stimulation configuration for pain thresholds, but lower thresholds for the i.c. stimulation in axon reflex erythema (12 vs. 21 mA), punctate hyperalgesia (9 vs. 15 mA) and allodynia (15 vs. 18 mA). Punctate hyperalgesia was evoked at very low stimulation frequencies of 1/20 Hz (7/7 subjects), whereas the induction of an axon reflex flare required stimulation at 1/5 Hz. Electrical stimulation which is sufficient to excite mechano-insensitive C nociceptors can induce secondary mechanical hyperalgesia even at low frequencies supporting a role of such low-level input to clinical pain states. Thus, differential nociceptor class-specific input to the spinal cord adds to the complexity of modulatory mechanisms that determine nociceptive processing in the spinal cord.

  • 245. Schmelz, M.
    et al.
    Schmidt, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Microneurographic single-unit recordings to assess receptive properties of afferent human C-fibers2010In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 470, no 3, p. 158-161Article, review/survey (Refereed)
    Abstract [en]

    Action potentials in unmyelinated peripheral axons can be recorded in awake humans by microneurography with small electrodes placed in a peripheral nerve. This technique provides extracellular recordings of single C-fibers and thus enables characterization of their sensory and axonal properties. By using microneurographical basic properties of afferent C-fibers such as conduction velocities, innervation territories, sensory thresholds and chemical responsiveness were measured. Moreover, axonal excitability changes induced by repetitive activation were assessed. Sensory and axonal properties of the different fiber classes cluster. Based on those specific properties, unitary functional classes of nociceptors (such as polymodal nociceptors and mechano-insensitive nociceptors) and non-nociceptors (such as tactile afferents and warm fibers) were classified. With normal data available, sensitization and desensitization of afferent fibers have been found in pathophysiologic states as detected in chronic pain patients. As subjects and patients are awake during the recording, microneurography provides a unique tool to correlate the discharge behaviour of afferent nerve fibers with the sensation evoked by certain stimuli.

  • 246.
    Schmidt, Roland
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Kleggetveit, Inge Petter
    Namer, Barbara
    Helås, Tormod
    Obreja, Otilia
    Schmelz, Martin
    Jørum, Ellen
    Double spikes to single electrical stimulation correlates to spontaneous activity of nociceptors in painful neuropathy patients.2012In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 153, no 2, p. 391-8Article in journal (Refereed)
    Abstract [en]

    Multiple firing of C nociceptors upon a single electrical stimulus has been suggested to be a possible mechanism contributing to neuropathic pain. Because this phenomenon maybe based on a unidirectional conduction block, it might also be related to neuropathic changes without a direct link to pain. We investigated painful neuropathy patients using microneurography and analysed nociceptors for the occurrence of multiple spiking and spontaneous activity. In 11 of 105 nociceptors, double spiking was found, with 1fibre even showing triple spikes on electrical stimulation. The interval between the main action potential and the multiple spikes ranged from 13 to 100ms. There was a significant association between spontaneous activity and multiple spiking in C nociceptors, with spontaneous activity being present in 9 of 11 fibres with multiple spiking, but only in 21 of 94 nociceptors without multiple spiking (P<.005, Fisher exact test). Among the 75 C nociceptors without spontaneous activity, only 2 nociceptors showed multiple spiking. In 8 neuropathy patients without pain, double spiking was found only in 4 of 90 nociceptors. Multiple spiking of nociceptors coincides with spontaneous activity in nociceptors of painful neuropathy patients. We therefore conclude that rather than being a generic sign of neuropathy, multiple spiking is linked to axonal hyperexcitability and spontaneous activity of nociceptors. It is still unclear whether it also is mechanistically related to the clinical pain level.

  • 247.
    Schmidt, Roland
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Weidner, Christian
    Schmelz, Martin
    Time course of acetylcholine-induced activation of sympathetic efferents matches axon reflex sweating in humans2011In: Journal of the peripheral nervous system, ISSN 1085-9489, E-ISSN 1529-8027, Vol. 16, no 1, p. 30-36Article in journal (Refereed)
    Abstract [en]

    Action potentials from postganglionic C-fibres were recorded in healthy volunteers by microneurography in the peroneal nerve. Their responsiveness to mechanical or heat stimuli or to sympathetic reflex provocation tests was determined by transient slowing of conduction velocity following activation. Twenty units were classified as sympathetic efferent units. Acetylcholine (ACh) iontophoresis (10%, 1 mA, 1 min) inside their innervation territory activated 8 of 20 sympathetic fibres with a mean delay of 61 +/- 12 s, peak response at 175 +/- 38 s, and a duration of 240 +/- 42 s, whereas iontophoresis of saline did not activate any of them. The time course of neuronal activation correlated with the axon reflex sweating measured by an evaporimeter in a separate session (delay 76 +/- 9 s, peak at 195 +/- 12 s, decline to 50% of peak 312 +/- 25 s). No ACh-induced vasoconstriction was observed by laser Doppler scanning (n = 11) even after depletion of neuropeptides by chronic topical capsaicin treatment (n = 8). We conclude that ACh iontophoresis activates about half of the sympathetic fibres in human skin and provokes a corresponding axon reflex sweating. The absence of ACh-induced vasoconstriction even after the depletion of neuropeptides by capsaicin suggests that only sudomotor fibres, but not sympathetic vasoconstrictor fibres are activated by this stimulus.

  • 248. Schreurs, Annabel
    et al.
    Stålberg, Erik V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Rostedt Punga, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Indication of peripheral nerve hyperexcitability in adult-onset subacute sclerosing panencephalitis (SSPE)2008In: Neurological Sciences, ISSN 1590-1874, E-ISSN 1590-3478, Vol. 29, no 2, p. 121-124Article in journal (Refereed)
    Abstract [en]

    Subacute sclerosing panencephalitis (SSPE) is a rare chronic, progressive encephalitis that affects primarily children and young adults, caused by a persistent infection of immune-resistant measles virus. Diagnostic hallmarks include widespread cortical dysfunction on EEG, myoclonus, white matter abnormalities on neuroradiological examination and the presence of IgG antimeasles antibodies in the cerebrospinal fluid. We present the first case of SSPE with signs of peripheral nerve hyperexcitability, observed as extra discharges following the compound motor action potential at motor nerve stimulation. In addition we demonstrate the importance of SSPE in the differential diagnosis of adult patients with psychiatric and neurological symptoms.

     

  • 249. Sikk, K
    et al.
    Taba, P
    Haldre, S
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Danfors, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Thurfjell, L
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Eriksson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Flink, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Färnstrand, C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Aquilonius, Sten-Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Clinical, neuroimaging and neurophysiological features in addicts with manganese-ephedrone exposure2010In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 121, no 4, p. 237-243Article in journal (Refereed)
    Abstract [en]

    Objective - To identify biomarkers supporting the clinical diagnosis of manganism in patients several years after exposure to manganese (Mn). Methods - Neurophysiological examinations, magnetic resonance imaging (MRI), single-photon emission computed tomography and fluorodeoxyglycose (FDG) positron emission tomography were performed in four former ephedrone addicts with extrapyramidal symptoms. Results - Peripheral nervous system was not affected. No patients had reduced uptake of (123)I Ioflupane in the striatum. MRI signal intensities were slightly changed in the basal ganglia. All patients showed a widespread, but not uniform, pathological pattern of FDG uptake with changes mainly located to the central part of the brain including the basal ganglia and the surrounding white matter. Conclusions - Presynaptic neurons in the nigrostriatal pathway are intact in Mn-induced parkinsonism after prolonged abstinence from ephedrone. The diagnosis is principally based on clinical signs and the history of drug abuse.

  • 250. Smith, R
    et al.
    Ponten, Eva
    Hedström, Yvette
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Ward, R
    Chambers, G
    Subramaniam, Shankar
    Lieber, L
    Novel transcriptional profile in wrist muscles from cerebral palsy patients2009In: BMC Medical Genomics, ISSN 1755-8794, Vol. 2, p. 44-Article in journal (Refereed)
    Abstract [en]

    Background: Cerebral palsy (CP) is an upper motor neuron disease that results in a progressive movement disorder. Secondary to the neurological insult, muscles from CP patients often become spastic. Spastic muscle is characterized by an increased resistance to stretch, but often develops the further complication of contracture which represents a prominent disability in children with CP. This study's purpose is to characterize alterations of spastic muscle on the transcriptional level. Increased knowledge of spastic muscle may lead to novel therapies to improve the quality of life for children with CP. Method: The transcriptional profile of spastic muscles were defined in children with cerebral palsy and compared to control patients using Affymetrix U133A chips. Expression data were verified using quantitative-PCR (QPCR) and validated with SDS-PAGE for select genes. Significant genes were determined using a 2 x 2 ANOVA and results required congruence between 3 preprocessing algorithms. Results: CP patients clustered independently and 205 genes were significantly altered, covering a range of cellular processes. Placing gene expression in the context of physiological pathways, the results demonstrated that spastic muscle in CP adapts transcriptionally by altering extracellular matrix, fiber type, and myogenic potential. Extracellular matrix adaptations occur primarily in the basal lamina although there is increase in fibrillar collagen components. Fiber type is predominately fast compared to normal muscle as evidenced by contractile gene isoforms and decrease in oxidative metabolic gene transcription, despite a paradoxical increased transcription of slow fiber pathway genes. We also found competing pathways of fiber hypertrophy with an increase in the anabolic IGF1 gene in parallel with a paradoxical increase in myostatin, a gene responsible for stopping muscle growth. We found evidence that excitation-contraction coupling genes are altered in muscles from patients with CP and may be a significant component of disease. Conclusion: This is the first transcriptional profile performed on spastic muscle of CP patients and these adaptations were not characteristic of those observed in other disease states such as Duchenne muscular dystrophy and immobilization-induced muscle atrophy. Further research is required to understand the mechanism of muscle adaptation to this upper motor neuron lesion that could lead to the development of innovative therapies.

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