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  • 151. Namer, B.
    et al.
    Barta, B.
    Ørstavik, K.
    Schmidt, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Carr, R.
    Schmelz, M.
    Handwerker, H. O.
    Microneurographic assessment of C-fibre function in aged healthy subjects2009In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 587, no Pt 2, p. 419-428Article in journal (Refereed)
    Abstract [en]

    Physiological changes in the nervous system occur with ageing. Both a decline of function and a decrease in the number of C-fibres in the skin have been reported for healthy aged subjects. With the use of microneurographic recordings from single C-fibres in humans we have compared the sensory and axonal properties of these neurones in young and aged healthy subjects. A total of 146 C-fibres were recorded from the common peroneal nerve in young subjects (mean age 24.7 years) and 230 C-fibres were recorded in aged subjects (mean age 56.2 years). In aged subjects, changes were found in the composition of the C-fibre population and in sensory and axonal properties. The relative incidence of afferent to efferent C-fibres was relatively constant independent of the age of subjects. The ratio of mechano-responsive to mechano-insensitive nociceptors was approximately 8 : 2 in the young controls while in aged subjects it was 7 : 3. In aged subjects 13% of the fibres showed atypical discharge characteristics, while this was not observed in young subjects. Spontaneous activity, sensitization and loss of sensory function were found regularly. Changes in functions of the conductile membrane were also observed in fibres from aged subjects. The degree of activity-dependent conduction velocity slowing in response to high frequency stimulation (2 Hz) was more pronounced, while the normalization of conduction velocity subsequent to high frequency stimulation was protracted. We found that both sensitization and desensitization or degeneration of afferent C-fibres occur with age, but are still rare compared to patients with neuropathy. The changes in the axonal properties of C-fibres in aged subjects are compatible with hypoexcitability of the fibres. These findings are important for the understanding and differential diagnoses regarding pathological processes and normal ageing.

  • 152. Namer, B.
    et al.
    Schick, M.
    Kleggetveit, I. P.
    Orstavik, K.
    Schmidt, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Jorum, E.
    Torebjörk, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Handwerker, H.
    Schmelz, M.
    Differential sensitization of silent nociceptors to low pH stimulation by prostaglandin E2 in human volunteers2015In: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 19, no 2, p. 159-166Article in journal (Refereed)
    Abstract [en]

    BackgroundInflammatory mediators activate and sensitize nociceptors. Tissue acidosis with low pH of 5.5 often accompanies inflammation and could enhance inflammatory pain and sensitization. MethodsAction potentials from single mechano-responsive (CM) and mechano-insensitive (CMi) C-nociceptors of cutaneous fascicles of the peroneal nerve in healthy volunteers were recorded by microneurography. Low pH solutions with and without prostaglandin E2 (PGE2) were injected twice (with an interval of approximately 5min) into two spots of the receptive fields of C-fibres. Heat thresholds of the C-fibres were obtained before and after each injection. ResultsInjections of the low pH solutions immediately induced phasic responses in CM nociceptors, whereas CMi fibres responded after a delay of several seconds with a sustained response. More CMi fibres than CM fibres showed ongoing discharge after low pH injection, but the duration and intensity of the responses to the first low pH injection did not differ between them. Upon repetition, duration and intensity of the pH responses increased more than twofold in CMi fibres only. Furthermore, combined application of pH and PGE2 sensitized the response in CMi fibres only. In contrast, heat activation thresholds were sensitized by the combination of low pH and PGE2 in both fibre classes. ConclusionsOur results confirm nociceptor class independent heat sensitization by PGE2 which is probably mediated by transient receptor potential vanilloid 1 phosphorylation. However, prolonged and increased pain responses in humans upon low pH/PGE2 stimulation appear to be primarily dependent on CMi fibres, whereas CM nociceptors appear crucial for phasic responses.

  • 153. Namer, Barbara
    et al.
    Hilliges, Marita
    Ørstavik, Kristin
    Schmidt, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Torebjörk, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Handwerker, Hermann
    Schmelz, Martin
    Endothelin 1 activates and sensitizes human C-nociceptors2008In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 137, no 1, p. 41-49Article in journal (Refereed)
    Abstract [en]

    Microneurography was used to record action potentials from afferent C-fibers in cutaneous fascicles of the peroneal nerve in healthy volunteers. Afferent fibers were classified according to their mechanical responsiveness to von Frey stimulation (75 g) into mechano-responsive and mechano-insensitive nociceptors. Various concentrations of Endothelin1 (ET1) and Histamine were injected into the receptive fields of C-fibers. Activation and heat sensitization were monitored. Axon reflex flare and psychophysical ratings were assessed after injection of ET1 and codeine into the forearms after pre-treatment with an H1 blocker or sodium chloride. 65% of mechanosensitive nociceptors were activated by ET1. One-third showed long lasting responses (>15 min). In contrast, none of thirteen mechano-insensitive fibers were activated. Sensitization to heat was observed in 62% of mechanosensitive and in 46% of mechano-insensitive fibers. Injection of ET1 produced a widespread axon reflex flare, which was suppressed by pre-treatment with an H1 receptor blocker. In addition, pain sensations were induced more often than itching by ET1 in contrast to codeine. No wheal was observed after injection of ET1. Both itching and pain were decreased after H1 blocker treatment. In summary: (1) In humans ET1 activates mechanosensitive, but not mechano-insensitive, nociceptors. (2) Histamine released from mast cells is not responsible for all effects of ET1 on C-nociceptors. (3) ET1 could have a differential role in pain compared to other chemical algogens which activate additionally or even predominantly mechano-insensitive fibers.

  • 154.
    Namer, Barbara
    et al.
    Univ Erlangen Nurnberg, Dept Physiol & Pathophysiol, D-91054 Erlangen, Germany..
    Orstavik, Kristin
    Univ Oslo, Rikshosp, Oslo Univ Hosp, Dept Neurol, N-0027 Oslo, Norway..
    Schmidt, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Kleggetveit, Inge-Petter
    Univ Oslo, Rikshosp, Oslo Univ Hosp, Dept Neurol, N-0027 Oslo, Norway..
    Weidner, Christian
    Univ Erlangen Nurnberg, Dept Physiol & Pathophysiol, D-91054 Erlangen, Germany..
    Mork, Cato
    Norwegian Univ Sci & Technol, Inst Canc Res & Mol Med, N-7034 Trondheim, Norway..
    Kvernebo, Mari Skylstad
    Oslo Univ Hosp, Dept Rheumatol Skin & Infect Dis, Oslo, Norway..
    Kvernebo, Knut
    Oslo Univ Hosp, Dept Vasc Surg, Oslo, Norway..
    Salter, Hugh
    Karolinska Inst, AstraZeneca Translat Sci Ctr, Dept Clin Neurosci, S-10401 Stockholm, Sweden..
    Carr, Thomas Hedley
    AstraZeneca R&D, Macclesfield, Cheshire, England..
    Segerdahl, Marta
    Karolinska Inst, AstraZeneca Translat Sci Ctr, Dept Clin Neurosci, S-10401 Stockholm, Sweden..
    Quiding, Hans
    Karolinska Inst, AstraZeneca Translat Sci Ctr, Dept Clin Neurosci, S-10401 Stockholm, Sweden..
    Waxman, Stephen George
    Yale Univ, Sch Med, Ctr Neurosci & Regenerat Res, New Haven, CT USA..
    Handwerker, Hermann Otto
    Univ Erlangen Nurnberg, Dept Physiol & Pathophysiol, D-91054 Erlangen, Germany..
    Torebjörk, Hans Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Jorum, Ellen
    Univ Oslo, Rikshosp, Oslo Univ Hosp, Dept Neurol, N-0027 Oslo, Norway..
    Schmelz, Martin
    Heidelberg Univ, Dept Anesthesiol Mannheim, D-68167 Mannheim, Germany..
    Specific changes in conduction velocity recovery cycles of single nociceptors in a patient with erythromelalgia with the I848T gain-of-function mutation of Na(v)1.72015In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 156, no 9, p. 1637-1646Article in journal (Refereed)
    Abstract [en]

    Seven patients diagnosed with erythromelalgia (EM) were investigated by microneurography to record from unmyelinated nerve fibers in the peroneal nerve. Two patients had characterized variants of sodium channel Na(v)1.7 (I848T, I228M), whereas no mutations of coding regions of Na(v)s were found in 5 patients with EM. Irrespective of Na(v)1.7 mutations, more than 50% of the silent nociceptors in the patients with EM showed spontaneous activity. In the patient with mutation I848T, all nociceptors, but not sympathetic efferents, displayed enhanced early subnormal conduction in the velocity recovery cycles and the expected late subnormality was reversed to supranormal conduction. The larger hyperpolarizing shift of activation might explain the difference to the I228M mutation. Sympathetic fibers that lack Na(v)1.8 did not show supranormal conduction in the patient carrying the I848T mutation, confirming in human subjects that the presence of Na(v)1.8 crucially modulates conduction in cells expressing EM mutant channels. The characteristic pattern of changes in conduction velocity observed in the patient with the I848T gain-of function mutation in Na(v)1.7 could be explained by axonal depolarization and concomitant inactivation of Na(v)1.7. If this were true, activity-dependent hyperpolarization would reverse inactivation of Na(v)1.7 and account for the supranormal CV. This mechanism might explain normal pain thresholds under resting conditions.

  • 155.
    Namer, Barbara
    et al.
    Univ Erlangen Nurnberg, Dept Physiol & Pathophysiol, Erlangen, Germany.;Heidelberg Univ, Dept Anesthesiol, Mannheim, Germany..
    Ørstavik, Kirstin
    Oslo Univ Hosp, Sect Clin Neurophysiol, Dept Neurol, Rikshosp, Oslo, Norway..
    Schmidt, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Mair, Norbert
    Med Univ Innsbruck, Div Physiol, Dept Physiol & Med Phys, Innsbruck, Austria..
    Kleggetveit, Inge Petter
    Oslo Univ Hosp, Sect Clin Neurophysiol, Dept Neurol, Rikshosp, Oslo, Norway..
    Zeidler, Maximillian
    Med Univ Innsbruck, Div Physiol, Dept Physiol & Med Phys, Innsbruck, Austria..
    Martha, Theresa
    Med Univ Innsbruck, Div Physiol, Dept Physiol & Med Phys, Innsbruck, Austria..
    Jorum, Ellen
    Heidelberg Univ, Dept Anesthesiol, Mannheim, Germany.;Univ Oslo, Inst Clin Med, Fac Med, Oslo, Norway..
    Schmelz, Martin
    Heidelberg Univ, Dept Anesthesiol, Mannheim, Germany..
    Kalpachidou, Theodora
    Med Univ Innsbruck, Div Physiol, Dept Physiol & Med Phys, Innsbruck, Austria..
    Kress, Michaela
    Med Univ Innsbruck, Div Physiol, Dept Physiol & Med Phys, Innsbruck, Austria..
    Langeslag, Michiel
    Med Univ Innsbruck, Div Physiol, Dept Physiol & Med Phys, Innsbruck, Austria..
    Changes in Ionic Conductance Signature of Nociceptive Neurons Underlying Fabry Disease Phenotype2017In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 8, article id 335Article in journal (Refereed)
    Abstract [en]

    The first symptom arising in many Fabry patients is neuropathic pain due to changes in small myelinated and unmyelinated fibers in the periphery, which is subsequently followed by a loss of sensory perception. Here we studied changes in the peripheral nervous system of Fabry patients and a Fabry mouse model induced by deletion of a-galactosidase A (Gla(-/0)). The skin innervation of Gla(-/0) mice resembles that of the human Fabry patients. In Fabry diseased humans and Gla(-/0) mice, we observed similar sensory abnormalities, which were also observed in nerve fiber recordings in both patients and mice. Electrophysiological recordings of cultured Gla(-/0) nociceptors revealed that the conductance of voltage-gated Na+ and Ca2+ currents was decreased in Gla(-/0) nociceptors, whereas the activation of voltage-gated K+ currents was at more depolarized potentials. Conclusively, we have observed that reduced sensory perception due to small-fiber degeneration coincides with altered electrophysiological properties of sensory neurons.

  • 156.
    Nandedkar, Sanjeev D.
    et al.
    Natus Med Inc, Hopewell Jct, NY USA.
    Barkhaus, Paul E.
    Med Coll Wisconsin, Milwaukee, WI 53226 USA.
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology. Univ Hosp, Uppsala, Sweden.
    Neuwirth, Christoph
    Kantonsspital St Gallen, St Gallen, Switzerland.
    Weber, Markus
    Kantonsspital St Gallen, St Gallen, Switzerland.
    Motor unit number index: Guidelines for recording signals and their analysis2018In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 58, no 3, p. 374-380Article in journal (Refereed)
    Abstract [en]

    Introduction: This study proposes guidelines for motor unit number index (MUNIX) recording and analysis. Methods: MUNIX was measured in control participants and in patients with amyotrophic lateral sclerosis. Changes in MUNIX values due to E1 electrode position, number of surface electromyography interference pattern (SIP) epochs, SIP epoch duration, force of contraction, and outlier data points were investigated. Results: MUNIX depends on optimized compound muscle action potential (CMAP) amplitude. Individual muscles showed variations when the number of epochs was low or when the SIP duration was short. Longer SIP duration allowed better recognition of artifacts. MUNIX results were affected by SIP values at all force levels but was more affected when SIP area was low. Discussion: We recommend changing the E1 electrode position to maximize CMAP amplitude. Twenty or more SIP signals of 500-ms duration should be recorded by using force levels ranging from slight to maximum. Traces should be reviewed to identify and exclude signals with tremor or solitary spikes.

  • 157. Nandedkar, Sanjeev D.
    et al.
    Barkhaus, Paul E.
    Stålberg, Erik V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Cumulative Motor Index: An Index to Study Progression of Amyotrophic Lateral Sclerosis2015In: Journal of clinical neurophysiology, ISSN 0736-0258, E-ISSN 1537-1603, Vol. 32, no 1, p. 79-85Article in journal (Refereed)
    Abstract [en]

    Purpose:To study disease progression in patients with amyotrophic lateral sclerosis (ALS), we have developed the cumulative motor index (CMI) using the compound muscle action potential amplitude recorded in multiple upper and lower limb muscles.Methods:To study its reproducibility, CMI was measured by 2 operators in 10 healthy subjects on 2 occasions. In 15 patients with ALS, CMI and ALS functional rating score (revised) were measured at 3- to 6-month interval for 12 months or longer.Results:The CMI had good reproducibility in healthy subjects. In one patient with ALS, CMI and ALS functional rating score (revised) remained relatively unchanged. In all remaining 14 patients with disease progression, CMI decreased in a relatively monotonic manner. At 1 year after baseline study, CMI was reduced more than ALS functional rating score (revised) in 10 patients. CMI measurements were possible for longer time period, than analysis from a single distal muscle recording.Conclusions:The CMI can be measured using standard equipment and software available in most electrodiagnostic laboratories. This may be a simple measurement that can be used for clinical studies of ALS progression over longer time periods.

  • 158. Nandedkar, Sanjeev D.
    et al.
    Barkhaus, Paul E.
    Stålberg, Erik V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Motor unit number index (MUNIX): principle, method, and findings in healthy subjects and in patients with motor neuron disease2010In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 42, no 5, p. 798-807Article in journal (Refereed)
    Abstract [en]

    The motor unit number index (MUNIX) is a method for assessment of number and size (MUSIX) of motor units (MUs) using the compound muscle action potential (CMAP) and surface electromyographic interference pattern (SIP). This method was used to study the hypothenar muscle in 34 healthy subjects to define normal range, and to study reproducibility. Four healthy subjects and 13 patients with amyotrophic lateral sclerosis (ALS) were studied serially over a 1-year period. In healthy subjects, MUNIX showed good reproducibility. In serial studies, healthy subjects showed no change in the CMAP amplitude and MUNIX. ALS patients with minimal change in CMAP amplitude had a significant drop in MUNIX and increase in MUSIX, indicating MU loss compensated by reinnervation. When the CMAP changed significantly (>30%) in 1 year, the CMAP and MUNIX decreased in parallel. MUNIX would be useful to study MU loss in degenerative diseases of motor neurons.

  • 159. Nandedkar, Sanjeev D.
    et al.
    Barkhaus, Paul E.
    Stålberg, Erik V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Reproducibility of munix in patients with amyotrophic lateral sclerosis2011In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 44, no 6, p. 919-922Article in journal (Refereed)
    Abstract [en]

    Introduction: In this study we investigated the reproducibility of motor unit number index (MUNIX) in patients with amyotrophic lateral sclerosis (ALS). Methods: MUNIX was recorded in patients with ALS. Studies were performed in 18 thenar and 18 hypothenar muscles by two operators. The reproducibility was assessed using mean MUNIX values, linear regression, correlation coefficient, and coefficient of variation (COV) in individual studies. Results: The mean values showed no significant difference. The linear regression showed a strong correlation. Most patients had low COV. A high COV was seen when MUNIX was very low. The COV was higher in thenar than in hypothenar muscles. Conclusions: MUNIX has very good reproducibility in ALS patients. COV may exaggerate interoperator variation when MUNIX is very low. The higher variability in the thenar muscle is also due to variability in compound muscle action potential amplitude. Although both muscles show good reproducibility, the hypothenar is better suited for serial studies in individual patients.

  • 160.
    Nandedkar, Sanjeev D.
    et al.
    Natus Medical Inc, New York.
    Sanders, Donald B.
    Duke University, Medical Center, Department of Neurology.
    Hobson-Webb, Lisa D.
    Duke University, Medical Center, Department of Neurology.
    Billakota, Santoshi
    Duke University, Medical Center, Department of Neurology.
    Barkhaus, Paul E.
    Medical College of Wisconsin, Department of Neurology.
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    THE EXTRAPOLATED REFERENCE VALUES PROCEDURE: THEORY, ALGORITHM, AND RESULTS IN PATIENTS AND CONTROL SUBJECTS2018In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 57, no 1, p. 90-95Article in journal (Refereed)
    Abstract [en]

    Introduction: Reference values (RVs) are required to separate normal from abnormal values obtained in electrodiagnostic (EDx) testing. However, it is frequently impractical to perform studies on control subjects to obtain RVs. The Extrapolated Reference Values (E-Ref) procedure extracts RVs from data obtained during clinically indicated EDx testing. We compared the E-Ref results with established RVs in several sets of EDx data.

    Methods: The mathematical basis for E-Ref was explored to develop an algorithm for the E-Ref procedure. To test the validity of this algorithm, it was applied to simulated and real jitter measurements from control subjects and patients with myasthenia gravis, and to nerve conduction studies from patients with various conditions referred for EDx studies.

    Results: There was good concordance between E-Ref and RVs for all evaluated data sets.

    Discussion: E-Ref is a promising method to develop RVs.

  • 161.
    Nandedkar, Sanjeev D.
    et al.
    Natus Med Inc, Hopewell Jct, NY USA.
    Sanders, Donald B.
    Duke Univ, Med Ctr, Durham, NC USA.
    Hobson-Webb, Lisa D.
    Duke Univ, Med Ctr, Durham, NC USA.
    Billlakota, Santoshi
    Duke Univ, Med Ctr, Durham, NC USA.
    Barkhaus, Paul E.
    Med Coll Wisconsin, Milwaukee, WI 53226 USA.
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Estimation of Reference Intervals for Transcranial Magnetic Stimulation: Derived Parameters Via the Hoffman Indirect Method Reply2018In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 58, no 4, p. E31-E32Article in journal (Other academic)
  • 162. Nandedkar, Sanjeev D.
    et al.
    Stålberg, Erik V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Quantitative measurements and analysis in electrodiagnostic studies: present and future2008In: Future neurology, ISSN 1748-6971, Vol. 3, no 6, p. 745-764Article in journal (Refereed)
    Abstract [en]

    Electrodiagnostic studies (nerve conduction and needle electromyography) are powerful methods to study diseases of nerves and muscles. Conduction studies are performed to assess the continuity, anatomic course, excitability, number of axons and their synaptic connections, while needle electromyography examination is performed to assess the ‘electrical stability’ of the muscle fiber membrane, and the study of motor units (architecture, activation and number). We have reviewed the relationship between the quantitative measurements and the generators of the recorded potentials. Based on these relationships, the expected patterns of abnormalities for different pathologies are tabulated. This gives us a better appreciation of the sensitivity, specificity and usefulness of different tests when planning and conducting an electrodiagnostic examination. The limitations of current methods are indicated to suggest the need for future development.

  • 163. Navallas, Javier
    et al.
    Rodriguez, Javier
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Scanning electromyography2012In: EMG Methods for evaluating Muscle and Nerve function / [ed] Schwartz M, InTech , 2012, p. 471-490Chapter in book (Refereed)
    Abstract [en]

    The study of the anatomy and physiology of the motor unit has important implications in the diagnosis and follow-up of neuromuscular pathologies. Muscle action potentials allow the use of electrophysiological techniques based on electromyography (EMG) to make inferences about muscle structure, state and behaviour. Scanning EMG is one such technique that can record the temporal and spatial distribution of electrical activity of a single motor unit, allowing for deep insight into the structure and function of motor units. In this chapter, we describe the scanning EMG technique in detail, both from a technical and clinical point of view. A brief review of the motor unit anatomy and physiology is provided in Section 2. The technique, the apparatus setup, the recording procedure and the signal processing required are described in Section 3. Key results of studies using scanning EMG are reviewed in Section 4, including findings related to motor unit organisation in normal muscle and how changes due to pathology are reflected using this electrophysiological technique. Finally, Section 5 provides some hints regarding the use of scanning EMG in research.

  • 164. Navallas, Javier
    et al.
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Studying motor end-plate topography by means of scanning-electromyography2009In: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 120, no 7, p. 1335-1341Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: This study investigates the anatomical and physiological causes of the temporal jumps between motor unit fractions observed in scanning-EMG recordings; i.e., temporal gaps in the distribution of the electrical activity of the motor unit within a transverse section of its territory. METHODS: Scanning-EMG signals were extracted from the biceps brachii. Spatial and temporal aspects of motor unit fractions were characterized. Simulated motor unit potentials (MUPs) were generated under different distributions of the anatomical and physiological parameters. Complexity and latency of the MUPs were calculated. RESULTS: To obtain realistic simulated MUPs it was necessary to reduce the width of the motor end-plate zone and variability of the muscle fiber conduction velocity compared to the overall data available for the entire muscle. To simulate temporal jumps between fractions, motor end-plates must be distributed in sub-bands of narrow width with different mean positions, innervated by separate axonal branches. CONCLUSIONS: Differences in the motor end-plates positions, axonal branches lengths and conduction velocities explain the temporal jumps between fractions. SIGNIFICANCE: Characterization of the motor unit fractions, observable by means of scanning-EMG, can be used to obtain valuable information about the motor end-plate topography and branching pattern of the axon innervating the motor unit.

  • 165. Nebuchennykh, M.
    et al.
    Løseth, S.
    Stålberg, Erik V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Mellgren, S.I.
    Quantitative sensory testing in patients with polyneuropathy and healthy individuals2008In: Acta Neurologica Scandinavica, Supplementum, ISSN 0065-1427, E-ISSN 1600-5449, Vol. 117, no 188, p. 56-61Article in journal (Refereed)
    Abstract [en]

    AIMS

    Elderly individuals and patients with polyneuropathy often feel heat pain or burning sensation on quantitative sensory testing (QST) of warm perception distally in the lower limbs. We therefore studied heat pain threshold (HPT), warm perception threshold (WPT) and the difference between heat pain and warm perception thresholds in 48 patients with symptoms and signs of polyneuropathy matched according to age and gender with 48 healthy persons.

    METHODS

    QST (using method of limits) was performed on the distal calf and the dorsal foot.

    RESULTS

    Particularly in the neuropathy group several individuals (58%) had an unpleasant feeling, often burning, when the thresholds according to the WPT algorithm were recorded. Difference between heat pain and warm perception thresholds in the lower calf of the patients was 3.9 +/- 3.5 and 5.8 +/- 3.4 degrees C in the controls (P = 0.012), and on the foot 3.8 +/- 2.8 vs 5.3 +/- 3.6 degrees C (P = 0.02).

    CONCLUSIONS

    When performing QST it is important to assess also quality features of warm perception, such as burning and heat pain sensation.

  • 166.
    Neuwirth, Christoph
    et al.
    Kantonsspital St Gallen, ALS Clin, Neuromuscular Dis Unit, Rorschacherstr 95, CH-9007 St Gallen, Switzerland..
    Barkhaus, Paul E.
    Med Coll Wisconsin, Milwaukee, WI 53226 USA..
    Burkhardt, Christian
    Kantonsspital St Gallen, ALS Clin, Neuromuscular Dis Unit, Rorschacherstr 95, CH-9007 St Gallen, Switzerland..
    Castro, Jose
    Univ Lisbon, Hosp Santa Maria, Fac Med, Inst Mol Med,Dept Neurosci, P-1699 Lisbon, Portugal..
    Czell, David
    Kantonsspital Winterthur, Winterthur, Switzerland..
    de Carvalho, Mamede
    Univ Lisbon, Hosp Santa Maria, Fac Med, Inst Mol Med,Dept Neurosci, P-1699 Lisbon, Portugal.;Natus Med Inc, Middleton, WI USA..
    Nandedkar, Sanjeev
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Weber, Markus
    Kantonsspital St Gallen, ALS Clin, Neuromuscular Dis Unit, Rorschacherstr 95, CH-9007 St Gallen, Switzerland.;Univ Basel Hosp, Dept Neurol, CH-4031 Basel, Switzerland..
    Motor Unit Number Index (MUNIX) detects motor neuron loss in pre-symptomatic muscles in Amyotrophic Lateral Sclerosis2017In: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 128, no 3, p. 495-500Article in journal (Refereed)
    Abstract [en]

    Objective: Motor Unit Number Index (MUNIX) is a quantitative neurophysiological measure that provides an index of the number of lower motor neurons supplying a muscle. It reflects the loss of motor neurons in patients with Amyotrophic Lateral Sclerosis (ALS). However, it is unclear whether MUNIX also detects motor unit loss in strong, non-wasted muscles. Methods: Three centres measured MUNIX in 49 ALS patients every three months in six different muscles (abductor pollicis brevis, abductor digiti minimi, biceps brachii, tibialis anterior, extensor digitorum brevis, abductor hallucis) on the less affected side. The decline of MUNIX in initially non-wasted, clinically strong muscles (manual muscle testing, MMT grade 5) was analysed before and after onset of weakness. Results: In 49 subjects, 151 clinically strong muscles developed weakness and were included for analysis. The average monthly relative loss of MUNIX was 5.0% before and 5.6% after onset of weakness. This rate of change was significantly higher compared to ALS functional rating scale (ALSFRS-R) and compound muscle action potential (CMAP) change over 12 months prior to the onset of muscle weakness (p = 0.024). Conclusion: MUNIX is an electrophysiological marker that detects lower motor neuron loss in ALS, before clinical weakness becomes apparent by manual muscle testing. Significance: This makes MUNIX a good biomarker candidate for disease progression and possibly pharmacodynamics responds.

  • 167.
    Neuwirth, Christoph
    et al.
    Kantonsspital St Gallen, ALS Clin, Neuromuscular Dis Unit, CH-9007 St Gallen, Switzerland..
    Barkhaus, Paul E.
    Med Coll Wisconsin, Milwaukee, WI 53226 USA..
    Burkhardt, Christian
    Kantonsspital St Gallen, ALS Clin, Neuromuscular Dis Unit, CH-9007 St Gallen, Switzerland..
    Castro, Jose
    Univ Lisbon, Fac Med, Hosp Santa Maria, Dept Neurosci,Inst Med Mol, P-1699 Lisbon, Portugal..
    Czell, David
    Kantonsspital Winterthur, Winterthur, Switzerland..
    de Carvalho, Mamede
    Univ Lisbon, Fac Med, Hosp Santa Maria, Dept Neurosci,Inst Med Mol, P-1699 Lisbon, Portugal..
    Nandedkar, Sanjeev
    Natus Med Inc, Middleton, WI USA..
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Weber, Markus
    Kantonsspital St Gallen, ALS Clin, Neuromuscular Dis Unit, CH-9007 St Gallen, Switzerland.;Univ Basel Hosp, Dept Neurol, CH-4031 Basel, Switzerland..
    Tracking motor neuron loss in a set of six muscles in amyotrophic lateral sclerosis using the Motor Unit Number Index (MUNIX): a 15-month longitudinal multicentre trial2015In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 86, no 11, p. 1172-1179Article in journal (Refereed)
    Abstract [en]

    Background Motor Unit Number Index (MUNIX) is a novel neurophysiological measure that provides an index of the number of functional lower motor neurons in a given muscle. So far its performance across centres in patients with amyotrophic lateral sclerosis (ALS) has not been investigated. Objective To perform longitudinal MUNIX recordings in a set of muscles in a multicentre setting in order to evaluate its value as a marker of disease progression. Methods Three centres applied MUNIX in 51 ALS patients over 15 months. Six different muscles (abductor pollicis brevis, abductor digiti minimi, biceps brachii, tibialis anterior, extensor dig. brevis, abductor hallucis) were measured every 3 months on the less affected side. The decline between MUNIX and ALSFRS-R was compared. Results 31 participants reached month 12. For all participants, ALSFRS-R declined at a rate of 2.3%/month. Using the total score of all muscles, MUNIX declined significantly faster by 3.2%/month (p <= 0.02). MUNIX in individual muscles declined between 2.4% and 4.2%, which differed from ASLFRS-R decline starting from month 3 (p <= 0.05 to 0.002). Subgroups with bulbar, lower and upper limb onset showed different decline rates of ALSFRS-R between 1.9% and 2.8%/month, while MUNIX total scores showed similar decline rates over all subgroups. Mean intraclass correlation coefficient for MUNIX intra-rater reliability was 0.89 and for inter-rater reliability 0.80. Conclusion MUNIX is a reliable electrophysiological biomarker to track lower motor neuron loss in ALS.

  • 168. Neuwirth, Christoph
    et al.
    Nandedkar, Sanjeev
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Barkhaus, Paul E.
    de Carvalho, Mamede
    Furtula, Jasna
    van Dijk, Johannes P.
    Baldinger, Reto
    Castro, Jose
    Costa, Joao
    Otto, Marit
    Sandberg, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Weber, Markus
    Motor Unit Number Index (MUNIX): A novel neurophysiological marker for neuromuscular disorders; test-retest reliability in healthy volunteers2011In: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 122, no 9, p. 1867-1872Article in journal (Refereed)
    Abstract [en]
    Objective: To investigate the intra-rater and inter-rater test-retest reliability of the Motor Unit Number Index (MUNIX) in healthy subjects in a multicentre setting. Methods: Six study centres applied the MUNIX technique in 66 healthy subjects. Five to six muscles (biceps brachii, BB; abductor digiti minimi, ADM; abductor pollicis brevis, APB; tibialis anterior, TA; extensor digitorum brevis, EDB and abductor hallucis, AH) were measured in each volunteer four times by two independent examiners. Results: The method was easy to perform and well tolerated. The intraclass correlation coefficient (ICC) varied between centres and muscles. Intra-rater reliability was greatest for the AH (ICC 0.83) and EDB (ICC 0.81). Inter-rater reliability was greatest for the AH (ICC 0.69) and ADM muscles (ICC 0.69). The most critical muscle was the APB muscle (ICC 0.52, total variability). This was mostly due to variability in the compound muscle action potential (CMAP) measurements. MUNIX values of the APB, ADM and TA fell into the same range as in other motor unit number estimation (MUNE) studies. Conclusion: MUNIX measurements in multiple muscles show good inter- and intra-rater reliability in healthy subjects. CMAP amplitude must be controlled to optimize reliability. Significance: Results suggest that MUNIX could serve as a reliable marker for motor neuron loss in diseases like amyotrophic lateral sclerosis. (C) 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
  • 169. Neuwirth, Christoph
    et al.
    Nandedkar, Sanjeev
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Barkhaus, Paul E.
    de Carvalho, Mamede
    Furtula, Jasna
    van Dijk, Johannes P.
    Baldinger, Reto
    Costa, Joao
    Otto, Marit
    Sandberg, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Weber, Markus
    Motor Unit Number Index (MUNIX): Reference values of five different muscles in healthy subjects from a multi-centre study2011In: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 122, no 9, p. 1895-1898Article in journal (Refereed)
  • 170. Neuwirth, Christoph
    et al.
    Nandedkar, Sanjeev
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Weber, Markus
    Motor Unit Number Index (MUNIX): A novel neurophysiological technique to follow disease progression in amyotrophic lateral sclerosis2010In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 42, no 3, p. 379-384Article in journal (Refereed)
    Abstract [en]

    Motor unit number estimation techniques in amyotrophic lateral sclerosis (ALS) patients are technically challenging and time-consuming. The Motor Unit Number Index (MUNIX) is a novel technique based on surface-EMG recordings and requires only 3-5 minutes per muscle. The objective was to explore the feasibility of longitudinal MUNIX measurements in ALS patients. In seven patients enrolled in a clinical trial, eight muscles were studied every 2 months for up to 15 months in addition to the revised ALS-functional rating scale, slow vital capacity, and compound muscle action potentials. The method was well tolerated and easy to perform. Initial MUNIX measures were significantly reduced compared to controls (487 +/- 194 vs. 1459 113; P < 0.001). Relative drop from baseline paralleled the clinical course and was greater than the drop of other markers of disease progression. MUNIX measurements in multiple muscles are suitable for serial neurophysiologic investigations in ALS. Further longitudinal data are needed for reliability validation.

  • 171. Nicole, Sophie
    et al.
    Chaouch, Amina
    Torbergsen, Torberg
    Bauche, Stephanie
    de Bruyckere, Elodie
    Fontenille, Marie-Josephine
    Horn, Morten A.
    van Ghelue, Marijke
    Loseth, Sissel
    Issop, Yasmin
    Cox, Daniel
    Mueller, Juliane S.
    Evangelista, Teresinha
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Ioos, Christine
    Barois, Annie
    Brochier, Guy
    Sternberg, Damien
    Fournier, Emmanuel
    Hantai, Daniel
    Abicht, Angela
    Dusl, Marina
    Laval, Steven H.
    Griffin, Helen
    Eymard, Bruno
    Lochmueller, Hanns
    Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy2014In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 137, no P9, p. 2429-2443Article in journal (Refereed)
    Abstract [en]

    Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of rare diseases resulting from impaired neuromuscular transmission. Their clinical hallmark is fatigable muscle weakness associated with a decremental muscle response to repetitive nerve stimulation and frequently related to postsynaptic defects. Distal myopathies form another clinically and genetically heterogeneous group of primary muscle disorders where weakness and atrophy are restricted to distal muscles, at least initially. In both congenital myasthenic syndromes and distal myopathies, a significant number of patients remain genetically undiagnosed. Here, we report five patients from three unrelated families with a strikingly homogenous clinical entity combining congenital myasthenia with distal muscle weakness and atrophy reminiscent of a distal myopathy. MRI and neurophysiological studies were compatible with mild myopathy restricted to distal limb muscles, but decrement (up to 72%) in response to 3Hz repetitive nerve stimulation pointed towards a neuromuscular transmission defect. Post-exercise increment (up to 285%) was observed in the distal limb muscles in all cases suggesting presynaptic congenital myasthenic syndrome. Immunofluorescence and ultrastructural analyses of muscle end-plate regions showed synaptic remodelling with denervation-reinnervation events. We performed whole-exome sequencing in two kinships and Sanger sequencing in one isolated case and identified five new recessive mutations in the gene encoding agrin. This synaptic proteoglycan with critical function at the neuromuscular junction was previously found mutated in more typical forms of congenital myasthenic syndrome. In our patients, we found two missense mutations residing in the N-terminal agrin domain, which reduced acetylcholine receptors clustering activity of agrin in vitro. Our findings expand the spectrum of congenital myasthenic syndromes due to agrin mutations and show an unexpected correlation between the mutated gene and the associated phenotype. This provides a good rationale for examining patients with apparent distal myopathy for a neuromuscular transmission disorder and agrin mutations.

  • 172.
    Nilsson, Daniel T.
    et al.
    Gothenburg Univ, Sahlgrenska Acad, Inst Neurosci & Physiol, Epilepsy Res Grp, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Neurosurg, Bla Str 5,3 Tr, S-41345 Gothenburg, Sweden..
    Malmgren, Kristina
    Gothenburg Univ, Sahlgrenska Acad, Inst Neurosci & Physiol, Epilepsy Res Grp, Gothenburg, Sweden..
    Flink, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Rydenhag, Bertil
    Gothenburg Univ, Sahlgrenska Acad, Inst Neurosci & Physiol, Epilepsy Res Grp, Gothenburg, Sweden..
    Outcomes of multilobar resections for epilepsy in Sweden 1990-2013: a national population-based study2016In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 158, no 6, p. 1151-1157Article in journal (Refereed)
    Abstract [en]

    Reports on outcome after multilobar resection (MLR) are scarce and most are retrospective single-centre studies or case studies with few patients. The aim of this study is to present seizure and complication outcomes 2 years after MLR in a prospective population-based series. The Swedish National Epilepsy Surgery Registry (SNESUR) provides prospective population-based data on outcome and complications after epilepsy surgery. For this study, we have analysed data on seizure outcome and complications after MLR from the SNESUR between 1990 and 2013. Fifty-seven patients underwent MLR; 40/57 surgeries were performed between 1990 and 2000. Sixteen operations were classified as partial hemispherotomy. Resections were right-sided in 33 (58 %) patients. Mean age was 17.3 years (range, 0.3-63.4 years) and mean duration of epilepsy before surgery was 11.0 years (range, 0.2-37 years). Preoperative neurological deficits were seen in 19 patients (33.3 %). Learning disability (LD) was seen in 18 patients (31.6 %), six had severe LD (IQ < 50). Seizure outcome after 2 years was available for 53 patients. Thirteen (24.5 %) were seizure-free and 12 (22.6 %) had > 75 % seizure frequency reduction. Three (5.3 %) patients suffered major complications: infarction of the middle cerebral artery, epidural abscess and hemiparesis. Minor complications were seen in ten patients. There was no mortality. This prospective, population-based study provides data on seizure outcome and complications after MLR. In selected patients MLR can be considered, but expectations for seizure freedom should not be too high and patients and parents should be counselled appropriately.

  • 173.
    Nordgren, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Rehabilitation Medicine.
    Falck, Björk
    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.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Waldenström, A
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Hemmingson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Postpolio muscular dysfunction: relationships between muscle energy metabolism, subjective symptoms, magnetic resonance imaging, electromyography, and muscle strength1997In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 20, no 11, p. 1341-1351Article in journal (Refereed)
    Abstract [en]

    Eleven patients with previous polio were studied. The concentration of energy-related metabolites and energy charge was measured from the vastus lateralis muscle, as was isometric muscle strength of knee extension. Cross-sectional area of the quadriceps femoris muscle was calculated from magnetic resonance imaging. Reinnervation was studied using macroelectromyography. Muscle weakness, pain, and newly acquired muscle weakness in the legs was estimated by the patients. The findings in the legs in which the patients experienced new loss of muscle function were compared with the stable legs. There were no significant differences between these groups in any of the objectively measured variables. Only hip pain correlated with new loss of muscle function. Creatine phosphate was decreased in 5 patients. The symptoms and subjective muscle strength did not correlate with any of the objective measurements. There were no significant relationships between energy-related metabolites and postpolio symptoms.

  • 174.
    Norman, Holly
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Kandala, Krishna
    Kolluri, Raghu
    Zackrisson, Håkan
    Nordquist, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Walther, Sten
    Eriksson, Lars
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    A porcine model of Acute Quadriplegic Myopathy: A feasibility study2006In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 50, no 9, p. 1058-1067Article in journal (Refereed)
    Abstract [en]

    Background: The mechanisms underlying acute quadriplegic myopathy (AQM) are poorly understood, partly as a result of the fact that patients are generally diagnosed at a late stage of the disease. Accordingly, there is a need for relevant experimental animal models aimed at identifying underlying mechanisms.

    Methods: Pigs were mechanically ventilated and exposed to various combinations of agents, i.e. pharmacological neuromuscular blockade, corticosteroids and/or sepsis, for a period of 5 days. Electromyography and myofibrillar protein and mRNA expression were analysed using sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), confocal microscopy, histochemistry and real-time polymerase chain reaction (PCR).

    Results: A decreased compound muscle action potential, normal motor nerve conduction velocities, and intact sensory nerve function were observed. Messenger RNA expression, determined by real-time PCR, of the myofibrillar proteins myosin and actin decreased in spinal and cranial nerve innervated muscles, suggesting that the loss of myosin observed in AQM patients is not solely the result of myofibrillar protein degradation.

    Conclusion: The present porcine AQM model demonstrated findings largely in accordance with results previously reported in patients and offers a feasible approach to future mechanistic studies aimed at identifying underlying mechanisms and developing improved diagnostic tests and intervention strategies.

  • 175.
    Norman, Holly
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Zahrisson, Håkan
    Hedström, Yvette
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Andersson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Nordquist, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Eriksson, Lars I
    Libelius, Rolf
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Myofibrillar protein and gene expression in acute quadriplegic myopathy2009In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 285, no 1-2, p. 28-38Article in journal (Refereed)
    Abstract [en]

    The dramatic muscle wasting, preferential loss of myosin and impaired muscle function in intensive care unit (ICU) patients with acute quadriplegic myopathy (AQM) have traditionally been suggested to be the result of proteolysis via specific proteolytic pathways. In this study we aim to investigate the mechanisms underlying the preferential loss of thick vs. thin filament proteins and the reassembly of the sarcomere during the recovery process in muscle samples from ICU patients with AQM. Quantitative and qualitative analyses of myofibrillar protein and mRNA expression were analyzed using SDS-PAGE, confocal microscopy, histochemistry and real-time PCR. The present results demonstrate that the transcriptional regulation of myofibrillar protein synthesis plays an important role in the loss of contractile proteins, as well as the recovery of protein levels during clinical improvement, myosin in particular, presumably in concert with proteolytic pathways, but the mechanisms are specific to the different thick and thin filament proteins studied.

  • 176.
    Ochala, Julien
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Ca2+ sensitizers: An emerging class of agents for counterbalancing weakness in skeletal muscle diseases?2010In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 20, no 2, p. 98-101Article, review/survey (Refereed)
    Abstract [en]

    Ca(2+) ions are key regulators of skeletal muscle contraction. By binding to contractile proteins, they initiate a cascade of molecular events leading to cross-bridge formation and ultimately, muscle shortening and force production. The ability of contractile proteins to respond to Ca(2+) attachment, also known as Ca(2+) sensitivity, is often compromised in acquired and congenital skeletal muscle disorders. It constitutes, undoubtedly, a major physiological cause of weakness for patients. In this review, we discuss recent studies giving strong molecular and cellular evidence that pharmacological modulators of some of the contractile proteins, also termed Ca(2+) sensitizers, are efficient agents to improve Ca(2+) sensitivity and function in diseased skeletal muscle cells. In fact, they compensate for the impaired contractile proteins response to Ca(2+) binding. Currently, such Ca(2+) sensitizing compounds are successfully used for reducing problems in cardiac disorders. Therefore, in the future, under certain conditions, these agents may represent an emerging class of agents to enhance the quality of life of patients suffering from skeletal muscle weakness.

  • 177.
    Ochala, Julien
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Thin filament proteins mutations associated with skeletal myopathies: defective regulation of muscle contraction2008In: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 86, no 11, p. 1197-1204Article in journal (Refereed)
    Abstract [en]

    In humans, more than 140 different mutations within seven genes (ACTA1, TPM2, TPM3, TNNI2, TNNT1, TNNT3, and NEB) that encode thin filament proteins (skeletal alpha-actin, beta-tropomyosin, gamma-tropomyosin, fast skeletal muscle troponin I, slow skeletal muscle troponin T, fast skeletal muscle troponin T, and nebulin, respectively) have been identified. These mutations have been linked to muscle weakness and various congenital skeletal myopathies including nemaline myopathy, distal arthrogryposis, cap disease, actin myopathy, congenital fiber type disproportion, rod-core myopathy, intranuclear rod myopathy, and distal myopathy, with a dramatic negative impact on the quality of life. In this review, we discuss studies that use various approaches such as patient biopsy specimen samples, tissue culture systems or transgenic animal models, and that demonstrate how thin filament proteins mutations alter muscle structure and contractile function. With an enhanced understanding of the cellular and molecular mechanisms underlying muscle weakness in patients carrying such mutations, better therapy strategies can be developed to improve the quality of life.

  • 178.
    Ochala, Julien
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Ahlbeck, Karsten
    Radell, Peter J
    Eriksson, Lars I
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Factors underlying the early limb muscle weakness in acute quadriplegic myopathy using an experimental ICU porcine model2011In: PloS one, ISSN 1932-6203, Vol. 6, no 6, p. e20876-Article in journal (Refereed)
    Abstract [en]

    The basic mechanisms underlying acquired generalized muscle weakness and paralysis in critically ill patients remain poorly understood and may be related to prolonged mechanical ventilation/immobilization (MV) or to other triggering factors such as sepsis, systemic corticosteroid (CS) treatment and administration of neuromuscular blocking agents (NMBA). The present study aims at exploring the relative importance of these factors by using a unique porcine model. Piglets were all exposed to MV together with different combinations of endotoxin-induced sepsis, CS and NMBA for five days. Peroneal motor nerve conduction velocity and amplitude of the compound muscle action potential (CMAP) as well as biceps femoris muscle biopsy specimens were obtained immediately after anesthesia on the first day and at the end of the 5-day experimental period. Results showed that peroneal nerve motor conduction velocity is unaffected whereas the size of the CMAP decreases independently of the type of intervention, in all groups after 5 days. Otherwise, despite a preserved size, muscle fibre specific force (maximum force normalized to cross-sectional area) decreased dramatically for animals exposed to MV in combination with CS or/and sepsis. These results suggest that the rapid declines in CMAP amplitude and in force generation capacity are triggered by independent mechanisms with significant clinical and therapeutic implications.

  • 179.
    Ochala, Julien
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Carpén, Olli
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Maintenance of muscle mass, fiber size, and contractile function in mice lacking the Z-disc protein myotilin2009In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 114, no 4, p. 235-241Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Myofibrillar myopathies constitute a rare group of congenital neuromuscular disorders, frequently associated with mutations in Z-disc proteins such as myotilin. Myotilin location and interactions with other Z-disc proteins are clearly defined, but its role in the regulation of muscle structure and function remains unknown. The present study aims at investigating this specific role of myotilin. METHODS: Skeletal and cardiac muscles were collected from adult mice with a targeted deletion of myotilin (myo(-/-)) and wild-type animals (myo(+/+)). RESULTS AND CONCLUSION: Similar skeletal and cardiac muscle weights were observed in myo(-/-) and myo(+/+) mice. At the muscle cell level, the size and force production of single membrane permeabilized fibers were identical between myo(-/-) and myo(+/+) rodents. Thus, myotilin does not have a significant influence on muscle mass, muscle fiber size, or regulation of muscle contraction. Alternatively, compensatory over-expressions of other elements including proteins from the same subfamily, or Z-disc proteins such as telethonin, or intermediate filaments may compensate for the lack of myotilin.

  • 180.
    Ochala, Julien
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology. Muscle Cell Physiology Laboratory, Department of Physical Medicine and RehabilitationSpaulding Rehabilitation Hospital and Harvard Medical School.; Equipe INSERM- ERM 207 Motricité-Plasticité, Faculté des Sciences du SportUniversité de Bourgogne .
    Dorer, D. J.
    Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA.
    Frontera, W. R.
    Muscle Cell Physiology Laboratory, Department of Physical Medicine and RehabilitationSpaulding Rehabilitation Hospital and Harvard Medical School.
    Krivickas, L. S.
    Muscle Cell Physiology Laboratory, Department of Physical Medicine and RehabilitationSpaulding Rehabilitation Hospital and Harvard Medical School.
    Single skeletal muscle fiber behavior after a quick stretch in young and older men: a possible explanation of the relative preservation of eccentric force in old age2006In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 452, no 4, p. 464-470Article in journal (Refereed)
    Abstract [en]

    The origins of the smaller age-related decrease in eccentric force compared to isometric and concentric conditions in vivo remain unclear. Could this originate from contractile elements of muscle cells? The main intent of the current investigation was to assess the force behavior of muscle cells with aging, during lengthening. Chemically skinned single muscle fibers (n=235) from m. vastus lateralis of six young (mean age 31.6 years) and six older men (mean age 66.1 years) were maximally activated with pCa 4.5 at 15 degrees C. Maximal isometric force and cross-sectional area were measured allowing the calculation of the tension (T-0). A quick stretch (2 nm per half-sarcomere length) was applied and caused an immediate increase in tension followed by a decrease and a secondary delayed and transient rise in tension (phase 3); finally, the tension recovered a steady state value (phase 4). The tension enhancements during phase 3 (Delta T (3)) and phase 4 (Delta T (4)) were evaluated. The myosin heavy-chain isoform composition of each single fiber was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Delta T (3) and Delta T (4) were preserved in older men for both type I and IIa fibers despite a reduction in T-0. Therefore, the age-related preservation of the tension increments after a quick stretch in single muscle fibers could explain in part the smaller decrease in force during eccentric contractions compared to isometric and concentric conditions in vivo with aging usually observed.

  • 181.
    Ochala, Julien
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Gokhin, David S.
    Penisson-Besnier, Isabelle
    Quijano-Roy, Susana
    Monnier, Nicole
    Lunardi, Joel
    Romero, Norma B.
    Fowler, Velia M.
    Congenital myopathy-causing tropomyosin mutations induce thin filament dysfunction via distinct physiological mechanisms2012In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 21, no 20, p. 4473-4485Article in journal (Refereed)
    Abstract [en]

    In humans, congenital myopathy-linked tropomyosin mutations lead to skeletal muscle dysfunction, but the cellular and molecular mechanisms underlying such dysfunction remain obscure. Recent studies have suggested a unifying mechanism by which tropomyosin mutations partially inhibit thin filament activation and prevent proper formation and cycling of myosin cross-bridges, inducing force deficits at the fiber and whole-muscle levels. Here, we aimed to verify this mechanism using single membrane-permeabilized fibers from patients with three tropomyosin mutations (TPM2-null, TPM3-R167H and TPM2-E181K) and measuring a broad range of parameters. Interestingly, we identified two divergent, mutation-specific pathophysiological mechanisms. (i) The TPM2-null and TPM3-R167H mutations both decreased cooperative thin filament activation in combination with reductions in the myosin cross-bridge number and force production. The TPM3-R167H mutation also induced a concomitant reduction in thin filament length. (ii) In contrast, the TPM2-E181K mutation increased thin filament activation, cross-bridge binding and force generation. In the former mechanism, modulating thin filament activation by administering troponin activators (CK-1909178 and EMD 57033) to single membrane-permeabilized fibers carrying tropomyosin mutations rescued the thin filament activation defect associated with the pathophysiology. Therefore, administration of troponin activators may constitute a promising therapeutic approach in the future.

  • 182.
    Ochala, Julien
    et al.
    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.
    Diez, Monica Llano
    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.
    Li, Meishan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Aare, Sudhakar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Qaisar, Rizwan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Banduseela, Varuna C.
    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.
    Tang, Xiaorui
    Dworkin, Barry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Ford, G. Charles
    Nair, K. Sreekumaran
    Perera, Sue
    Gautel, Mathias
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Preferential skeletal muscle myosin loss in response to mechanical silencing in a novel rat intensive care unit model: underlying mechanisms2011In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 589, no 8, p. 2007-2026Article in journal (Refereed)
    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.

  • 183.
    Ochala, Julien
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Iwamoto, Hiroyuki
    Myofilament lattice structure in presence of a skeletal myopathy-related tropomyosin mutation2013In: Journal of Muscle Research and Cell Motility, ISSN 0142-4319, E-ISSN 1573-2657, Vol. 34, no 3-4, p. 171-175Article in journal (Refereed)
    Abstract [en]

    Human tropomyosin mutations deregulate skeletal muscle contraction at the cellular level. One key feature is the slowing of the kinetics of force development. The aim of the present study was to characterize the potential underlying molecular mechanisms by recording and analyzing the X-ray diffraction patterns of human membrane-permeabilized muscle cells expressing a particular beta-tropomyosin mutation (E41K). During resting conditions, the d(1,0) lattice spacing, Delta(1,0) and I-1,I-1 to I-1,I-0 ratio were not different from control values. These results suggest that, in presence of the E41K beta-tropomyosin mutation, the myofilament lattice geometry is well maintained and therefore may not have any detrimental influence on the contraction mechanisms and thus, on the rate of force generation.

  • 184.
    Ochala, Julien
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Iwamoto, Hiroyuki
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Yagi, Naoto
    A myopathy-linked tropomyosin mutation severely alters thin filament conformational changes during activation2010In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 21, p. 9807-9812Article in journal (Refereed)
    Abstract [en]

    Human point mutations in alpha- and beta-tropomyosin induce contractile deregulation, skeletal muscle weakness, and congenital myopathies. The aim of the present study was to elucidate the hitherto unknown underlying molecular mechanisms. Hence, we recorded and analyzed the X-ray diffraction patterns of human membrane-permeabilized muscle cells expressing a particular beta-tropomyosin mutation (R133W) associated with a loss in cell force production, in vivo muscle weakness, and distal arthrogryposis. Upon addition of calcium, we notably observed less intensified changes, compared with controls, (i) in the second (1/19 nm(-1)), sixth (1/5.9 nm(-1)), and seventh (1/5.1 nm(-1)) actin layer lines of cells set at a sarcomere length, allowing an optimal thin-thick filament overlap; and (ii) in the second actin layer line of overstretched cells. Collectively, these results directly prove that during activation, switching of a positive to a neutral charge at position 133 in the protein partially hinders both calcium- and myosin-induced tropomyosin movement over the thin filament, blocking actin conformational changes and consequently decreasing the number of cross-bridges and subsequent force production.

  • 185.
    Ochala, Julien
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Lehtokari, Vilma-Lotta
    Iwamoto, Hiroyuki
    Li, Meishan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Feng, Han-Zhong
    Jin, Jian-Ping
    Yagi, Naoto
    Wallgren-Pettersson, Carina
    Pénisson-Besnier, Isabelle
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Disrupted myosin cross-bridge cycling kinetics triggers muscle weakness in nebulin-related myopathy2011In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 25, no 6, p. 1903-1913Article in journal (Refereed)
    Abstract [en]

    Nebulin is a giant protein expressed at high levels in skeletal muscle. Mutations in the nebulin gene (NEB) lead to muscle weakness and various congenital myopathies. Despite increasing clinical and scientific interest, the pathogenesis of weakness remains unknown. The present study, therefore, aims at unraveling the underlying molecular mechanisms. Hence, we recorded and analyzed the mechanics as well as the X-ray diffraction patterns of human membrane-permeabilized single muscle fibers expressing nebulin mutations. Results demonstrated that, during contraction, the cycling rate of myosin heads attaching to actin is dramatically perturbed, causing a reduction in the fraction of myosin-actin interactions in the strong binding state. This phenomenon prevents complete thin-filament activation, more especially proper and full tropomyosin movement, further limiting additional binding of myosin cross-bridges. At the cell level, this reduces the force-generating capacity and, overall, provokes muscle weakness. To reverse such a negative cascade of events, future potential therapeutic interventions should, therefore, focus on the triggering component, the altered myosin cross-bridge cycling kinetics.

  • 186.
    Ochala, Julien
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Li, Mingxin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Tajsharghi, Homa
    Kimber, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Tulinius, Mar
    Oldfors, Anders
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Effects of a R133W beta-tropomyosin mutation on regulation of muscle contraction in single human muscle fibres2007In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 581, no 3, p. 1283-1292Article in journal (Refereed)
    Abstract [en]

    A novel R133W β-tropomyosin (β-Tm) mutation, associated with muscle weakness and distal limb deformities, has recently been identified in a woman and her daughter. The muscle weakness was not accompanied by progressive muscle wasting or histopathological abnormalities in tibialis anterior muscle biopsy specimens. The aim of the present study was to explore the mechanisms underlying the impaired muscle function in patients with the β-Tm mutation. Maximum force normalized to fibre cross-sectional area (specific force, SF), maximum velocity of unloaded shortening (V0), apparent rate constant of force redevelopment (ktr) and force–pCa relationship were evaluated in single chemically skinned muscle fibres from the two patients carrying the β-Tm mutation and from healthy control subjects. Significant differences in regulation of muscle contraction were observed in the type I fibres: a lower SF (P < 0.05) and ktr (P < 0.01), and a faster V0 (P < 0.05). The force–pCa relationship did not differ between patient and control fibres, indicating an unaltered Ca2+ activation of contractile proteins. Collectively, these results indicate a slower cross-bridge attachment rate and a faster detachment rate caused by the R133W β-Tm mutation. It is suggested that the R133W β-Tm mutation induces alteration in myosin–actin kinetics causing a reduced number of myosin molecules in the strong actin-binding state, resulting in overall muscle weakness in the absence of muscle wasting.

  • 187.
    Ochala, Julien
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Radell, Peter J
    Eriksson, Lars I
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    EMD 57033 partially reverses ventilator-induced diaphragm muscle fibre calcium desensitisation2010In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 459, no 3, p. 475-483Article in journal (Refereed)
    Abstract [en]

    In critically ill patients, ventilator-induced diaphragm muscle fibre dysfunction (VIDD) contributes to weaning problems, increasing hospitalisation time and related costs. VIDD pathophysiology remains partially unknown, especially the characterisation of the contractile dysfunction. In the present study, it was hypothesised that Ca(2+) activation is affected during VIDD. Ca(2+) sensitivity of contraction was therefore evaluated at the single skinned diaphragm muscle fibre level in piglets randomised into sham operation or 5-day mechanical ventilation. Ca(2+) sensitivities of force and stiffness in fibres were significantly impaired in all mechanically ventilated piglets compared with sham-operated controls, suggesting a less efficient Ca(2+) activation of cells, i.e. a lower relative number of strongly attached cross-bridges for each sub-maximal concentration of Ca(2+). In an attempt to test whether this negative effect of VIDD is reversible, single muscle fibres were exposed to the EMD 57033 Ca(2+) sensitiser. EMD 57033 (30 microM) improved the Ca(2+) sensitivity of force and stiffness in fibres from animals that were mechanically ventilated for 5 days as well as in sham-operated piglets. Thus, EMD 57033 partly restored the Ca(2+) activation of cells, reducing VIDD. This finding offers a strong basis for evaluating the effect of Ca(2+) sensitisers on diaphragm function in vivo.

  • 188.
    Ochala, Julien
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Ravenscroft, Gianina
    Laing, Nigel G.
    Nowak, Kristen J.
    Nemaline Myopathy-Related Skeletal Muscle alpha-Actin (ACTA1) Mutation, Asp286Gly, Prevents Proper Strong Myosin Binding and Triggers Muscle Weakness2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, p. e45923-Article in journal (Refereed)
    Abstract [en]

    Many mutations in the skeletal muscle alpha-actin gene (ACTA1) lead to muscle weakness and nemaline myopathy. Despite increasing clinical and scientific interest, the molecular and cellular pathogenesis of weakness remains unclear. Therefore, in the present study, we aimed at unraveling these mechanisms using muscles from a transgenic mouse model of nemaline myopathy expressing the ACTA1 Asp286Gly mutation. We recorded and analyzed the mechanics of membranepermeabilized single muscle fibers. We also performed molecular energy state computations in the presence or absence of Asp286Gly. Results demonstrated that during contraction, the Asp286Gly acts as a "poison-protein'' and according to the computational analysis it modifies the actin-actin interface. This phenomenon is likely to prevent proper myosin crossbridge binding, limiting the fraction of actomyosin interactions in the strong binding state. At the cell level, this decreases the force-generating capacity, and, overall, induces muscle weakness. To counterbalance such negative events, future potential therapeutic strategies may focus on the inappropriate actin-actin interface or myosin binding.

  • 189.
    Ochala, Julien
    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.
    Llano Diez, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Banduseela, Varuna C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Aare, Sudhakar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Ahlbeck, Karsten
    Radell, Peter J
    Eriksson, Lars I
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Diaphragm muscle weakness in an experimental porcine intensive care unit model2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 6, article id e20558Article in journal (Refereed)
    Abstract [en]

    In critically ill patients, mechanisms underlying diaphragm muscle remodeling and resultant dysfunction contributing to weaning failure remain unclear. Ventilator-induced modifications as well as sepsis and administration of pharmacological agents such as corticosteroids and neuromuscular blocking agents may be involved. Thus, the objective of the present study was to examine how sepsis, systemic corticosteroid treatment (CS) and neuromuscular blocking agent administration (NMBA) aggravate ventilator-related diaphragm cell and molecular dysfunction in the intensive care unit. Piglets were exposed to different combinations of mechanical ventilation and sedation, endotoxin-induced sepsis, CS and NMBA for five days and compared with sham-operated control animals. On day 5, diaphragm muscle fibre structure (myosin heavy chain isoform proportion, cross-sectional area and contractile protein content) did not differ from controls in any of the mechanically ventilated animals. However, a decrease in single fibre maximal force normalized to cross-sectional area (specific force) was observed in all experimental piglets. Therefore, exposure to mechanical ventilation and sedation for five days has a key negative impact on diaphragm contractile function despite a preservation of muscle structure. Post-translational modifications of contractile proteins are forwarded as one probable underlying mechanism. Unexpectedly, sepsis, CS or NMBA have no significant additive effects, suggesting that mechanical ventilation and sedation are the triggering factors leading to diaphragm weakness in the intensive care unit.

  • 190. Olsson, I.
    et al.
    Edelvik, A.
    Flink, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Rydenhag, B.
    Malmgren, K.
    Seizure Outcome after Hemispherectomy Data from the Swedish National Epilepsy Surgery Register2012In: Epilepsia, ISSN 0013-9580, E-ISSN 1528-1167, Vol. 53, no S5, p. 110-111Article in journal (Other academic)
  • 191.
    Olsson, M. Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Krüger, Martina
    Meyer, Lars-Henrik
    Ahnlund, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Gransberg, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Linke, Wolfgang A.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Fibre type-specific increase in passive muscle tension in spinal cord-injured subjects with spasticity2006In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 577, no 1, p. 339-352Article in journal (Refereed)
    Abstract [en]

    Patients with spasticity typically present with an increased muscle tone that is at least partly caused by an exaggerated stretch reflex. However, intrinsic changes in the skeletal muscles, such as altered mechanical properties of the extracellular matrix or the cytoskeleton, have been reported in response to spasticity and could contribute to hypertonia, although the underlying mechanisms are poorly understood. Here we examined the vastus lateralis muscles from spinal cord-injured patients with spasticity (n = 7) for their passive mechanical properties at three different levels of structural organization, in comparison to healthy controls (n = 7). We also assessed spasticity-related alterations in muscle protein expression and muscle ultrastructure. At the whole-muscle level in vivo, we observed increased passive tension (PT) in some spasticity patients particularly at long muscle lengths, unrelated to stretch reflex activation. At the single-fibre level, elevated PT was found in cells expressing fast myosin heavy chain (MyHC) isoforms, especially MyHC-IIx, but not in those expressing slow MyHC. Type IIx fibres were present in higher than normal proportions in spastic muscles, whereas type I fibres were proportionately reduced. At the level of the isolated myofibril, however, there were no differences in PT between patients and controls. The molecular size of the giant protein titin, a main contributor to PT, was unchanged in spasticity, as was the titin: MyHC ratio and the relative desmin content. Electron microscopy revealed extensive ultrastructural changes in spastic muscles, especially expanded connective tissue, but also decreased mitochondrial volume fraction and appearance of intracellular amorphous material. Results strongly suggest that the global passive muscle stiffening in spasticity patients is caused to some degree by elevated PT of the skeletal muscles themselves. We conclude that this increased PT component arises not only from extracellular matrix remodelling, but also from structural and functional adaptations inside the muscle cells, which alter their passive mechanical properties in response to spasticity in a fibre type-dependent manner.

  • 192. Padua, Luca
    et al.
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Caliandro, Pietro
    Muscogiuri, Giovanna
    Pazzaglia, Costanza
    Sorice, Gian Pio
    Granata, Giuseppe
    Salomone, Enrica
    Pontecorvi, Alfredo
    Giaccari, Andrea
    Single-fiber conduction velocity test allows earlier detection of abnormalities in diabetes2011In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 43, no 5, p. 652-656Article in journal (Refereed)
    Abstract [en]

    Introduction: The purpose of this study was to determine whether single-fiber conduction velocity (SF-CV) of a small number of axons increases sensitivity for identification of motor nerve conduction alterations in patients with diabetes. Methods: Twenty-one consecutive diabetic patients in good metabolic control were studied. For each patient, conventional (C-CV) and SF-CV results were correlated with the presence of neuropathic symptoms. Results: Nine of 21 patients reported symptoms suggestive of mild nerve impairment. Three patients had abnormal sural nerve CV, 1 of whom also had abnormal motor nerve conduction. Eighteen patients had normal findings on conventional tests, 3 of whom had slowing of SF-CV. Conclusions: SF-CV is able to detect mild myelin damage with higher sensitivity than conventional tests. The use of SF-CV may be a helpful tool in the early identification of diabetic polyneuropathy, and it may be useful for tailoring an approach to diabetic polyneuropathy.

  • 193. Peltola, Maria E.
    et al.
    Liukkonen, Elina
    Granström, Marja-Liisa
    Paetau, Ritva
    Kantola-Sorsa, Elisa
    Valanne, Leena
    Falck, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Blomstedt, Göran
    Gaily, Eija
    The effect of surgery in encephalopathy with electrical status epilepticus during sleep2011In: Epilepsia, ISSN 0013-9580, E-ISSN 1528-1167, Vol. 52, no 3, p. 602-609Article in journal (Refereed)
    Abstract [en]

    P>Purpose: We analyzed clinical and electroencephalography (EEG) outcomes of 13 patients with pharmacoresistant encephalopathy with electrical status epilepticus during sleep (ESES) following epilepsy surgery. Methods: All patients had symptomatic etiology of ESES and preoperative neuropsychological deterioration. Ten patients had daily atypical absences. Clinical outcome was assessed at 6 months and at 2 years after surgery. Clinical and EEG data were reviewed retrospectively. The spike propagation pattern and area and source strength in source montage were analyzed from preoperative and postoperative EEG studies. Key Findings: Preoperative sleep EEG showed electrical status epilepticus during sleep (SES) with one-way interhemispheric propagation in nine patients and with two-way interhemispheric propagation in four. The age of the patients at the time of surgery ranged from 3.6-9.9 years. Focal resection (two patients) or hemispherotomy (one patient with postoperative EEG) either terminated SES or restricted the discharge to one region. Either reduced SES propagation area or source strength was found in four of eight callosotomy patients with postoperative EEG. Of patients who had seizures preoperatively, Engel class I-II seizure outcome was observed in two of three children after focal resection or hemispherotomy and in two of eight children after callosotomy. None of these patients with Engel class I-II outcome had SES with two-way interhemispheric propagation on preoperative EEG. Cognitive deterioration was halted postoperatively in all except one patient. Cognitive catch-up of more than 10 IQ points was seen in three patients, all of whom had shown a first measured IQ of > 75. Significance: Patients with pharmacoresistant ESES based on symptomatic etiology may benefit from resective surgery or corpus callosotomy regarding both seizure outcome and cognitive prognosis.

  • 194. Phillips, W D
    et al.
    Christadoss, P
    Losen, M
    Punga, Anna Rostedt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Shigemoto, K
    Verschuuren, J
    Vincent, A
    Guidelines for pre-clinical animal and cellular models of MuSK-myasthenia gravis2015In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 270, no SI, p. 29-40Article in journal (Refereed)
    Abstract [en]

    Muscle-specific tyrosine kinase (MuSK) autoantibodies are the hallmark of a form of myasthenia gravis (MG) that can challenge the neurologist and the experimentalist. The clinical disease can be difficult to treat effectively. MuSK autoantibodies affect the neuromuscular junction in several ways. When added to muscle cells in culture, MuSK antibodies disperse acetylcholine receptor clusters. Experimental animals actively immunized with MuSK develop MuSK autoantibodies and muscle weakness. Weakness is associated with reduced postsynaptic acetylcholine receptor numbers, reduced amplitudes of miniature endplate potentials and endplate potentials, and failure of neuromuscular transmission. Similar impairments have been found in mice injected with IgG from MG patients positive for MuSK autoantibody (MuSK-MG). The active and passive models have begun to reveal the mechanisms by which MuSK antibodies disrupt synaptic function at the neuromuscular junction, and should be valuable in developing therapies for MuSK-MG. However, translation into new and improved treatments for patients requires procedures that are not too cumbersome but suitable for examining different aspects of MuSK function and the effects of potential therapies. Study design, conduct and analysis should be carefully considered and transparently reported. Here we review what has been learnt from animal and culture models of MuSK-MG, and offer guidelines for experimental design and conduct of studies, including sample size determination, randomization, outcome parameters and precautions for objective data analysis. These principles may also be relevant to the increasing number of other antibody-mediated diseases that are now recognized.

  • 195. Press, R
    et al.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Svenningsson, A
    Andersen, O
    Axelson, Hans W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Strömberg, U
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Wahlin, A
    Isaksson, C
    Johansson, J-E J
    Hägglund, H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Autologous haematopoietic stem cell transplantation: a viable treatment option for CIDP2014In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 85, no 6, p. 618-624Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Only 70-80% of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) respond satisfactorily to the established first-line immunomodulatory treatments. Autologous haematopoietic stem cell transplantation (AHSCT) has been performed as a last treatment resort in a few therapy-refractory cases with CIDP. We describe the results of AHSCT in 11 consecutive Swedish patients with therapy-refractory CIDP with a median follow-up time of 28 months.

    METHOD: Case data were gathered retrospectively for AHSCT treatments in 11 patients with CIDP refractory to the first-line immunomodulatory treatments, intravenous high-dose immunoglobulin, corticosteroids and plasma exchange and to one or more second-line treatments used in 10 of the 11 patients.

    RESULTS: The median Inflammatory Neuropathy Cause and Treatment (INCAT) score within 1 month prior to AHSCT was 6 and the Rankin score 4. Total INCAT and Rankin scores improved significantly within 2-6 months after AHSCT and continued to do so at last follow-up. The motor action potential amplitudes (CMAP) improved already within 4 months (median) after AHSCT. Three of the 11 patients relapsed during the follow-up period, requiring retransplantation with AHSCT in one. Eight of the 11 patients maintained drug-free remission upon last follow-up. AHSCT was safe but on the short term associated with a risk of cytomegalovirus (CMV) and Epstein-Barr virus reactivation, CMV disease, haemorrhagic cystitis and pancreatitis.

    CONCLUSIONS: Our results though hampered by the limited number of patients and the lack of a control group suggest AHSCT to be efficacious in therapy-refractory CIDP, with a manageable complication profile. Confirmation of these results is necessary through randomised controlled trials.

  • 196. Puksa, L.
    et al.
    Eeg-Olofsson, Karin. Edebol
    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.
    Falck, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Reference values for F wave parameters in healthy 3-20 year old subjects2011In: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 122, no 1, p. 199-204Article in journal (Refereed)
    Abstract [en]

    Objective: To create a reference value database for F wave parameters from healthy subjects aged 3-20 yr. Methods: We studied the following parameters: minimum F wave latency minus distal motor latency (FMINLAT), number of F waves/20 stimuli (FNUMBER) and F wave dispersion (FDISP). The median, ulnar, peroneal and tibial nerves were studied. All four nerves were not analyzed in all subjects, the number of subjects varied from 78 to 118 in each nerve. Results: Age explained 71-87% of the variability of FLATMIN while height explained 80-95% of the variability. The FMINLAT increases by 0.12 ms/cm of height in the upper limb nerves and by 0.28 ms/cm in the lower limb nerves. Gender did not influence the FMINLAT. FDISP was not related with age, height or gender. FNUMBER was not related with age or height, it was somewhat larger in males than females but the difference was not significant in all nerves. Conclusions: The best model for FMINLAT was a linear regression model with height as an independent variable. FDISP and FNUMBER are not related to age, height or gender between the ages of 3 and 20 yr. Significance: We have constructed clinically useful reference values for F wave parameters in healthy subjects aged 3-20 yr for the main motor nerves commonly studied.

  • 197.
    Punga, Anna R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Maj, Marcin
    Lin, Shuo
    Meinen, Sarina
    Rueegg, Markus A.
    MuSK levels differ between adult skeletal muscles and influence postsynaptic plasticity2011In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 33, no 5, p. 890-898Article in journal (Refereed)
    Abstract [en]

    Muscle-specific tyrosine kinase (MuSK) is involved in the formation and maintenance of the neuromuscular junction (NMJ), and is necessary for NMJ integrity. As muscle involvement is strikingly selective in pathological conditions in which MuSK is targeted, including congenital myasthenic syndrome with MuSK mutation and MuSK antibody-seropositive myasthenia gravis, we hypothesized that the postsynaptic response to MuSK-agrin signalling differs between adult muscles. Transcript levels of postsynaptic proteins were compared between different muscles in wild-type adult mice. MuSK expression was high in the soleus and sternomastoid muscles and low in the extensor digitorum longus (EDL) and omohyoid muscles. The acetylcholine receptor (AChR) alpha subunit followed a similar expression pattern, whereas expression of Dok-7, Lrp4 and rapsyn was comparable between the muscles. We subsequently examined muscles in mice that overexpressed a miniaturized form of neural agrin or MuSK. In these transgenic mice, the soleus and sternomastoid muscles responded with formation of ectopic AChR clusters, whereas such clusters were almost absent in the EDL and omohyoid muscles. Electroporation of Dok-7 revealed its important role as an activator of MuSK in AChR cluster formation in adult muscles. Together, our findings indicate for the first time that adult skeletal muscles harbour different endogenous levels of MuSK and that these levels determine the ability to form ectopic AChR clusters upon overexpression of agrin or MuSK. We believe that these findings are important for our understanding of adult muscle plasticity and the selective muscle involvement in neuromuscular disorders in which MuSK is diminished.

  • 198.
    Punga, Anna Rostedt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Alimohammadi, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Fagrell, Dan
    Goteborgs Plastikkirurgiska Ctr, Gothenburg, Sweden..
    Nyberg, Frida
    Galderma A&C, Uppsala, Sweden..
    Rees, Diane
    Zenith Healthcare Commun Ltd, Chester, Cheshire, England..
    Wong, Cindy
    Galderma A&C, Uppsala, Sweden..
    A Randomized, Comparative Study to Evaluate Efficacy and Safety of Two Injection Volumes of AbobotulinumtoxinA in Treatment of Glabellar Lines2016In: Dermatologic Surgery, ISSN 1076-0512, E-ISSN 1524-4725, Vol. 42, no 8, p. 967-976Article in journal (Refereed)
    Abstract [en]

    BACKGROUNDDifferent volumes of 0.9% NaCl may be used to reconstitute abobotulinumtoxinA yielding an injection volume that ranges from 0.05 to 0.1 mL per injection point for treatment of glabellar lines.OBJECTIVETo evaluate the efficacy, safety, and subject satisfaction of 2 different injection volumes to deliver the same unit dose of abobotulinumtoxinA for treatment of glabellar lines.MATERIALS AND METHODSThis randomized comparative study was conducted using 2 different reconstitution volumes to deliver a fixed unit dose of 10 Speywood units (sU) of abobotulinumtoxinA in either 0.05 mL (labeled volume) or 0.1 mL (twofold volume) per injection point. Evaluations included wrinkle severity, neurophysiological assessment by compound muscle action potential (CMAP), and subject satisfaction.RESULTSUse of either injection volume of abobotulinumtoxinA resulted in the early onset of effect, high effectiveness, and long duration of effect. The safety profile and injection pain levels were similar in both groups. The twofold injection volume was shown to be noninferior to the labeled injection volume based on CMAP results.CONCLUSIONA twofold increase in injection volume to 0.1 mL per injection point to deliver 10 sU of abobotulinumtoxinA is effective and safe.

  • 199.
    Punga, Anna Rostedt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Andersson, Mats
    Alimohammadi, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Punga, Tanel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Disease specific signature of circulating miR-150-5p and miR-21-5p in myasthenia gravis patients2015In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 356, no 1-2, p. 90-96Article in journal (Refereed)
    Abstract [en]

    Purpose: Reliable biological markers for patients with the autoimmune neuromuscular disorder myasthenia gravis (MG) are lacking. We determined whether levels of the circulating immuno-microRNAs miR-150-5p and miR-21-5p were elevated in sera from clinically heterogeneous MG patients, with and without immunosuppression, as compared to healthy controls and patients with other autoimmune disorders. Methods: Sera from 71 MG patients and 55 healthy controls (HC) were analyzed for the expression levels of miR-150-5p and miR-21-5p with qRT-PCR. Sera were also assayed from 23 patients with other autoimmune disorders (AID; psoriasis, Addison's and Crohn's diseases). Results: 34 MG patients had no immunosuppressive drug treatment (MG-0) and 37 patients were under stable immunosuppressive drug treatment since a 6 months (MG + IMM). Serum levels of miR-150-5p and miR-21-5p were higher in the MG-0 patients compared to HC (p < 0.0001). Further, miR-150-5p levels were 41% lower and miR-21-5p levels were 25% lower in the MG + IMM compared to MG-0 (p = 0.0051 and 0.0419). In the AID patients, mean miR-150-5p and miR-21-5p were comparable with healthy controls (p = 0.66). Conclusions: The immuno-microRNAs miR-150-5p and miR-21-5p show a disease specific signature, which suggests these microRNAs as possible biological autoimmune markers of MG. (C) 2015 The Authors. Published by Elsevier B.V.

  • 200.
    Punga, Anna Rostedt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Eriksson, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Alimohammadi, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Univ Uppsala Hosp, Dept Dermatol & Venereol, Uppsala, Sweden.
    Regional Diffusion of Botulinum Toxin in Facial Muscles: A Randomised Double-blind Study and a Consideration for Clinical Studies with Split-face Design2015In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 95, no 8, p. 948-951Article in journal (Refereed)
    Abstract [en]

    Despite the extensive use of botulinum toxin A (BoNTA) in medical and cosmetic treatments, the potential spreading of BoNTA to surrounding tissues remains unknown. A patient with hemifacial paralysis upon blepharospasm treatment with low dose of BoNTA, prompted us to investigate the spreading effect. A randomised, double-blind study was conducted in which 5 healthy women (33-52 years) were treated with different doses of onabotulinum toxin unilaterally in the corrugator muscle. Parameters of efficacy and diffusion (CMAP; EMG and jitter analysis) in both glabellar and frontalis muscles were assessed at baseline, 2 and 4 weeks following BoNTA injection. CMAP of the treated glabellar muscles was reduced to approximately 40% in all dose groups. Additionally, contralateral CMAP reduction was observed in 3 of 5 subjects. These data confirm regional diffusion of BoNTA in facial muscle application, which raises question on the reliability of split-face models in BoNTA studies.

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