Dokument

Zusammenfassung:
Das Fibromyalgiesyndrom (FMS) stellt eine generalisierte Tendomyopathie dar und ist beim Menschen durch großflächige, vorzugsweise muskuläre und chronische Schmerzen von mindestens drei Monaten Dauer gekennzeichnet. Die Ursache und Ätiopathogenese dieser Erkrankung sind nach wie vor unbekannt und die Diagnosestellung erfolgt klinisch anhand von Klassifikationskriterien. Die Behandlung ist symptomatisch und führt nicht zu einer Ausheilung der Erkrankung. Das intermittierende Kältestressmodell (ICS-Model) von Nishiyori et al. gilt als etabliertes Mausmodell zur Induktion von fibromyalgie-ähnlicher Schmerzsymptomatik. Auf der Basis muskulärer und mitochondrialer Veränderungen bei Patienten mit FMS, wurden in der vorliegenden Arbeit Effekte des intermittierenden Kältestresses auf molekularer und morphologischer Ebene in C57BL/6J Mäusen untersucht. Dazu wurden jeweils 9 männliche und 9 weibliche Mäuse nach dem ICS-Model behandelt und mit Kontrollgruppen der gleichen Anzahl an Tieren verglichen. Aufgrund von aus der Literatur bekannten metabolischen Veränderungen im Rahmen des FMS, wurden verschiedene Parameter untersucht. Eine Blutgasanalyse zeigte in den ICS-Tieren Unterschiede hinsichtlich Parameter wie CO2, Na+, Glucose, Cl-, K+, Ca2+, MetHb und O2 auf. Lichtmikroskopisch zeigten männliche ICS-Tiere einen geringfügig niedrigeren Glykogenanteil im Muskelgewebe und eine signifikante Reduktion desselben im Lebergewebe. Die LDH-Aktivität in mitochondrialen Proben männlicher und weiblicher ICS-Tiere war im Vergleich zur Kontrollgruppe erhöht. Um Aufschluss über den Einfluss des Kältestresses auf die mitochondriale Funktion zu gewinnen, wurde die Expression des Coenzyms Q10B (COQ10B) und der Cytochrom-c- Oxidase 4 (COX4I1) untersucht. Mittels qRT-PCR konnte gezeigt werden, dass weibliche ICS-Tiere eine erhöhte Expression von Coq10b auf Transkriptionsebene aufwiesen. Die Expression des Cox4i1-Transkriptes zeigte bei den männlichen ICS-Tieren eine signifikante Erniedrigung. Des Weiteren konnte in mitochondrialen Proteinproben eine verminderte Expression von COQ10B als auch COX4I1festgestellt werden. Ebenso wie in der Literatur, zeigten elektronenmikroskopische Analysen deutliche Anzeichen ablaufender autophagischer Prozesse, die wiederum durch molekularbiologische Verfahren verifiziert wurden. qRT-PCR-Analysen zeigten in den ICS-Tieren signifikant erhöhte Expressionen der Autophagie-relevanten Gene Map1lc3b (mikrotubulus- assoziiertes Protein 1 light chain 3 b) und Beclin1 (Becn1) an. Im Muskelgewebe von männlichen ICS-Tieren konnte densitometrisch eine Erhöhung von SqSTM1/p62- Protein (p62) gezeigt werden. Außerdem wies MAP1LC3B immunhistochemisch eine deutlich aggregierte Distribution in den ICS-Tieren auf, was wiederum für das vermehrte Vorkommen von Autophagosomen im Rahmen der Autophagie spricht. Die durchgeführte Arbeit schafft erste Einblicke hinsichtlich der Auswirkungen intermittierenden Kältestresses auf den Stoffwechsel und die Zellfunktion von C57BL/6J Mäusen und gibt Hinweise auf die Bedeutung autophagischer Prozesse sowie mitochondrialer und metabolischer Veränderungen im Muskelgewebe.

Bibliographie / References

1. Garrabou, G., et al., Reversible inhibition of mitochondrial protein synthesis during linezolid-related hyperlactatemia. Antimicrob Agents Chemother, 2007. 51(3): p. 962-7.
2. Aaron, L.A., M.M. Burke, and D. Buchwald, Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arch Intern Med, 2000. 160(2): p. 221-7.
3. Sprott, H., et al., Increased DNA fragmentation and ultrastructural changes in fibromyalgic muscle fibres. Ann Rheum Dis, 2004. 63(3): p. 245-51.
4. Cordero, M.D., et al., Mitochondrial dysfunction and mitophagy activation in blood mononuclear cells of fibromyalgia patients: implications in the pathogenesis of the disease. Arthritis Res Ther, 2010. 12(1): p. R17.
5. Cordero, M.D., et al., Clinical symptoms in fibromyalgia are better associated to lipid peroxidation levels in blood mononuclear cells rather than in plasma. PLoS One, 2011. 6(10): p. e26915.
6. Barth, S., D. Glick, and K.F. Macleod, Autophagy: assays and artifacts. J Pathol, 2010. 221(2): p. 117- 24.
7. Battino, M., et al., Oxidative injury and inflammatory periodontal diseases: the challenge of anti- oxidants to free radicals and reactive oxygen species. Crit Rev Oral Biol Med, 1999. 10(4): p. 458-76.
8. Winarni, T.I., et al., Immune-mediated disorders among women carriers of fragile X premutation alleles. Am J Med Genet A, 2012. 158A(10): p. 2473-81.
9. Ozgocmen, S., et al., Antioxidant status, lipid peroxidation and nitric oxide in fibromyalgia: etiologic and therapeutic concerns. Rheumatol Int, 2006. 26(7): p. 598-603.
10. Park, J.H., K.J. Niermann, and N. Olsen, Evidence for metabolic abnormalities in the muscles of patients with fibromyalgia. Curr Rheumatol Rep, 2000. 2(2): p. 131-40.
11. Goldenberg, D.L., Pharmacological treatment of fibromyalgia and other chronic musculoskeletal pain. Best Pract Res Clin Rheumatol, 2007. 21(3): p. 499-511.
12. Mizushima, N. and M. Komatsu, Autophagy: renovation of cells and tissues. Cell, 2011. 147(4): p. 728-41.
13. Cordero, M.D., et al., Coenzyme Q10 in salivary cells correlate with blood cells in Fibromyalgia: improvement in clinical and biochemical parameter after oral treatment. Clin Biochem, 2012. 45(6): p. 509-11.
14. Hauser, W., K. Thieme, and D.C. Turk, Guidelines on the management of fibromyalgia syndrome -a systematic review. Eur J Pain, 2010. 14(1): p. 5-10.
15. Ablin, J.N., Y. Shoenfeld, and D. Buskila, Fibromyalgia, infection and vaccination: two more parts in the etiological puzzle. J Autoimmun, 2006. 27(3): p. 145-52.
16. Schneider, M.J., D.M. Brady, and S.M. Perle, Commentary: differential diagnosis of fibromyalgia syndrome: proposal of a model and algorithm for patients presenting with the primary symptom of chronic widespread pain. J Manipulative Physiol Ther, 2006. 29(6): p. 493-501.
17. Cordero, M.D., et al., Coenzyme Q(10): a novel therapeutic approach for Fibromyalgia? case series with 5 patients. Mitochondrion, 2011. 11(4): p. 623-5.
18. Nishiyori, M., et al., Absence of morphine analgesia and its underlying descending serotonergic activation in an experimental mouse model of fibromyalgia. Neurosci Lett, 2010. 472(3): p. 184-7.
19. Tan, M.L., I. Balabin, and J.N. Onuchic, Dynamics of electron transfer pathways in cytochrome C oxidase. Biophys J, 2004. 86(3): p. 1813-9.
20. Fulle, S., et al., Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome. Free Radic Biol Med, 2000. 29(12): p. 1252-9.
21. Crofford, L.J., N.C. Engleberg, and M.A. Demitrack, Neurohormonal perturbations in fibromyalgia. Baillieres Clin Rheumatol, 1996. 10(2): p. 365-78.
22. Nakatogawa, H., et al., Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol, 2009. 10(7): p. 458-67.
23. Shabalina, I.G., et al., Carboxyatractyloside effects on brown-fat mitochondria imply that the adenine nucleotide translocator isoforms ANT1 and ANT2 may be responsible for basal and fatty- acid-induced uncoupling respectively. Biochem J, 2006. 399(3): p. 405-14.
24. Castro-Marrero, J., et al., Could mitochondrial dysfunction be a differentiating marker between chronic fatigue syndrome and fibromyalgia? Antioxid Redox Signal, 2013. 19(15): p. 1855-60.
25. Fitzcharles, M.A. and P. Boulos, Inaccuracy in the diagnosis of fibromyalgia syndrome: analysis of referrals. Rheumatology (Oxford), 2003. 42(2): p. 263-7.
26. Carville, S.F., et al., EULAR evidence-based recommendations for the management of fibromyalgia syndrome. Ann Rheum Dis, 2008. 67(4): p. 536-41.
27. Altindag, O. and H. Celik, Total antioxidant capacity and the severity of the pain in patients with fibromyalgia. Redox Rep, 2006. 11(3): p. 131-5.
28. Diaz-Troya, S., et al., The role of TOR in autophagy regulation from yeast to plants and mammals. Autophagy, 2008. 4(7): p. 851-65.
29. Kabeya, Y., et al., LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J, 2000. 19(21): p. 5720-8.
30. Cohen, H., et al., Autonomic nervous system derangement in fibromyalgia syndrome and related disorders. Isr Med Assoc J, 2001. 3(10): p. 755-60.
31. Buskila, D., et al., Fibromyalgia in human immunodeficiency virus infection. J Rheumatol, 1990. 17(9): p. 1202-6.
32. La Rubia, M., et al., Is fibromyalgia-related oxidative stress implicated in the decline of physical and mental health status? Clin Exp Rheumatol, 2013. 31(6 Suppl 79): p. S121-7.
33. Yunus, M.B., et al., Electron microscopic studies of muscle biopsy in primary fibromyalgia syndrome: a controlled and blinded study. J Rheumatol, 1989. 16(1): p. 97-101.
34. Mizushima, N., Autophagy: process and function. Genes Dev, 2007. 21(22): p. 2861-73.
35. Cordero, M.D., et al., Mitochondrial dysfunction in skin biopsies and blood mononuclear cells from two cases of fibromyalgia patients. Clin Biochem, 2010. 43(13-14): p. 1174-6.
36. Vlaeyen, J.W., et al., Cognitive-educational treatment of fibromyalgia: a randomized clinical trial. I. Clinical effects. J Rheumatol, 1996. 23(7): p. 1237-45.
37. Furlan, R., et al., Abnormalities of cardiovascular neural control and reduced orthostatic tolerance in patients with primary fibromyalgia. J Rheumatol, 2005. 32(9): p. 1787-93.
38. Lister, R.E., An open, pilot study to evaluate the potential benefits of coenzyme Q10 combined with Ginkgo biloba extract in fibromyalgia syndrome. J Int Med Res, 2002. 30(2): p. 195-9.
39. Meeus, M., et al., The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia patients: peripheral and central mechanisms as therapeutic targets? Expert Opin Ther Targets, 2013. 17(9): p. 1081-9.
40. Kirisako, T., et al., Formation process of autophagosome is traced with Apg8/Aut7p in yeast. J Cell Biol, 1999. 147(2): p. 435-46.
41. Dubner, R. and K.M. Hargreaves, The neurobiology of pain and its modulation. Clin J Pain, 1989. 5 Suppl 2: p. S1-4; discussion S4-6.
42. Nelson, P.T. and J.N. Keller, RNA in brain disease: no longer just "the messenger in the middle". J Neuropathol Exp Neurol, 2007. 66(6): p. 461-8.
43. Rauchova, H., et al., Coenzyme Q-pool function in glycerol-3-phosphate oxidation in hamster brown adipose tissue mitochondria. J Bioenerg Biomembr, 1992. 24(2): p. 235-41.
44. Bagis, S., et al., Free radicals and antioxidants in primary fibromyalgia: an oxidative stress disorder? Rheumatol Int, 2005. 25(3): p. 188-90.
45. Ozgocmen, S., et al., Current concepts in the pathophysiology of fibromyalgia: the potential role of oxidative stress and nitric oxide. Rheumatol Int, 2006. 26(7): p. 585-97.
46. Sendur, O.F., et al., Serum antioxidants and nitric oxide levels in fibromyalgia: a controlled study. Rheumatol Int, 2009. 29(6): p. 629-33.
47. Pongratz, D.E. and M. Spath, Morphologic aspects of fibromyalgia. Z Rheumatol, 1998. 57 Suppl 2: p. 47-51.
48. Martorell, L., et al., Screening for the presence of FMR1 premutation alleles in a Spanish population with fibromyalgia. Clin Rheumatol, 2012. 31(11): p. 1611-5.
49. Gaziev, A.I., S. Abdullaev, and A. Podlutsky, Mitochondrial function and mitochondrial DNA maintenance with advancing age. Biogerontology, 2014.
50. Thieme, K. and R.H. Gracely, Are psychological treatments effective for fibromyalgia pain? Curr Rheumatol Rep, 2009. 11(6): p. 443-50.
51. Patricia Boya, P.C., Autophagy: Molecular Mechanisms, Physiology and Pathology, in Tocris Bioscience Scientific Review Series 2012.
52. Russell, I.J., et al., Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis. Arthritis Rheum, 1992. 35(5): p. 550-6.
53. Er hat mich stets unterstützt, wo er nur konnte. Vielen, vielen Dank dafür.
54. Er war als einzig verbliebener der Arbeitsgruppe stets mein Ansprechpartner bei allen Fragen und Problemen und immer sehr hilfsbereit und hat geholfen wo er nur konnte.
55. Arnold, L.M., et al., Family study of fibromyalgia. Arthritis Rheum, 2004. 50(3): p. 944-52.
56. Buskila, D. and L. Neumann, Fibromyalgia syndrome (FM) and nonarticular tenderness in relatives of patients with FM. J Rheumatol, 1997. 24(5): p. 941-4.
57. D.L. Kasper, T.R.H., Harrison's Principles of Internal Medecine. 16th edition ed. "Fibromyalgia, arthritis associated with systemic disease, and other arthritides", ed. B.C. Gilliland. Vol. vol.2. 2005, New York, USA: McGraw-Hill, Medical Publication Division
58. Le Goff, P., Is fibromyalgia a muscle disorder? Joint Bone Spine, 2006. 73(3): p. 239-42.
59. Komatsu, M., et al., Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature, 2006. 441(7095): p. 880-4.
60. Dinerman, H. and A.C. Steere, Lyme disease associated with fibromyalgia. Ann Intern Med, 1992. 117(4): p. 281-5.
61. Mein ganz besonderer Dank gilt meinem Doktorvater und Betreuer Prof. Dr. med. Matthias Ocker für die Vergabe des Themas und die hervorragende Unterstützung während der Erstellung dieser Arbeit. Prof. Ocker hat durch seinen Weitblick und seine Begeisterung für das wissenschaftliche Arbeiten meinen Horizont erweitert und mich stetig motiviert für meine Träume zu kämpfen. Seine Tür stand immer offen und selbst zuletzt hat ihn die räumliche Distanz nie davon abgehalten sich allen Fragen und Problemen anzunehmen und zu lösen.
62. Bengtsson, A., K.G. Henriksson, and J. Larsson, Muscle biopsy in primary fibromyalgia. Light- microscopical and histochemical findings. Scand J Rheumatol, 1986. 15(1): p. 1-6.
63. Kalyan-Raman, U.P., et al., Muscle pathology in primary fibromyalgia syndrome: a light microscopic, histochemical and ultrastructural study. J Rheumatol, 1984. 11(6): p. 808-13.
64. Cordero, M.D., et al., Oxidative stress and mitochondrial dysfunction in fibromyalgia. Neuro Endocrinol Lett, 2010. 31(2): p. 169-73.
65. Staud, R. and M.L. Smitherman, Peripheral and central sensitization in fibromyalgia: pathogenetic role. Curr Pain Headache Rep, 2002. 6(4): p. 259-66.
66. Greenfield, S., M.A. Fitzcharles, and J.M. Esdaile, Reactive fibromyalgia syndrome. Arthritis Rheum, 1992. 35(6): p. 678-81.
67. Komatsu, M. and Y. Ichimura, Selective autophagy regulates various cellular functions. Genes Cells, 2010. 15(9): p. 923-33.
68. Kim, I., S. Rodriguez-Enriquez, and J.J. Lemasters, Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys, 2007. 462(2): p. 245-53.
69. Moscat, J., M.T. Diaz-Meco, and M.W. Wooten, Signal integration and diversification through the p62 scaffold protein. Trends Biochem Sci, 2007. 32(2): p. 95-100.
70. Wood, P.B., Stress and dopamine: implications for the pathophysiology of chronic widespread pain. Med Hypotheses, 2004. 62(3): p. 420-4.
71. Wolfe, F., et al., The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum, 1990. 33(2): p. 160-72.
72. Crofford, L.J., The hypothalamic-pituitary-adrenal axis in the pathogenesis of rheumatic diseases. Endocrinol Metab Clin North Am, 2002. 31(1): p. 1-13.
73. Haas, R.H., et al., The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metab, 2008. 94(1): p. 16-37.
74. Lemasters, J.J., et al., The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta, 1998. 1366(1-2): p. 177-96.
75. Seibenhener, M.L., et al., Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol Cell Biol, 2004. 24(18): p. 8055-68.
76. Cordero, M.D., et al., Can coenzyme q10 improve clinical and molecular parameters in fibromyalgia? Antioxid Redox Signal, 2013. 19(12): p. 1356-61.
77. Lin, X., et al., Interaction domains of p62: a bridge between p62 and selective autophagy. DNA Cell Biol, 2013. 32(5): p. 220-7.
78. Fu, X., R. Ji, and J. Dam, Antifatigue effect of coenzyme Q10 in mice. J Med Food, 2010. 13(1): p. 211- 5.
79. Toda, K., Preliminary diagnostic criteria for fibromyalgia should be partially revised: comment on the article by Wolfe et al. Arthritis Care Res (Hoboken), 2011. 63(2): p. 308-9; author reply 309-10.
80. Giesecke, T., et al., Subgrouping of fibromyalgia patients on the basis of pressure-pain thresholds and psychological factors. Arthritis Rheum, 2003. 48(10): p. 2916-22.
81. Leventhal, L.J., S.J. Naides, and B. Freundlich, Fibromyalgia and parvovirus infection. Arthritis Rheum, 1991. 34(10): p. 1319-24.
82. Pillemer, S.R., et al., The neuroscience and endocrinology of fibromyalgia. Arthritis Rheum, 1997. 40(11): p. 1928-39.
83. Glick, D., S. Barth, and K.F. Macleod, Autophagy: cellular and molecular mechanisms. J Pathol, 2010. 221(1): p. 3-12.
84. Stisi, S., et al., Etiopathogenetic mechanisms of fibromyalgia syndrome. Reumatismo, 2008. 60 Suppl 1: p. 25-35.
85. Auvinet, B. and D. Chaleil, Identification of subgroups among fibromyalgia patients. Reumatismo, 2012. 64(4): p. 250-60.
86. Rivera, J., et al., Fibromyalgia-associated hepatitis C virus infection. Br J Rheumatol, 1997. 36(9): p. 981-5.
87. Baraniuk, J.N., et al., Cerebrospinal fluid levels of opioid peptides in fibromyalgia and chronic low back pain. BMC Musculoskelet Disord, 2004. 5: p. 48.
88. Kundu, M., et al., Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation. Blood, 2008. 112(4): p. 1493-502.
89. Reggiori, F. and D.J. Klionsky, Autophagic processes in yeast: mechanism, machinery and regulation. Genetics, 2013. 194(2): p. 341-61.
90. Pankiv, S., et al., p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem, 2007. 282(33): p. 24131-45.
91. Harris, R.E., et al., Decreased central mu-opioid receptor availability in fibromyalgia. J Neurosci, 2007. 27(37): p. 10000-6.
92. McBeth, J., et al., Features of somatization predict the onset of chronic widespread pain: results of a large population-based study. Arthritis Rheum, 2001. 44(4): p. 940-6.
93. Nishiyori, M. and H. Ueda, Prolonged gabapentin analgesia in an experimental mouse model of fibromyalgia. Mol Pain, 2008. 4: p. 52.
94. Hara, T., et al., Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature, 2006. 441(7095): p. 885-9.
95. White, E., Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer, 2012. 12(6): p. 401-10.
96. Klionsky, D.J., Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol, 2007. 8(11): p. 931-7.
97. Arnarez, C., S.J. Marrink, and X. Periole, Identification of cardiolipin binding sites on cytochrome c oxidase at the entrance of proton channels. Sci Rep, 2013. 3: p. 1263.
98. DiMauro, S., C.M. Quinzii, and M. Hirano, Mutations in coenzyme Q10 biosynthetic genes. J Clin Invest, 2007. 117(3): p. 587-9.
99. Yoshida, Y., et al., Negligible direct lactate oxidation in subsarcolemmal and intermyofibrillar mitochondria obtained from red and white rat skeletal muscle. J Physiol, 2007. 582(Pt 3): p. 1317-35.
100. Axe, E.L., et al., Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol, 2008. 182(4): p. 685-701.
101. Chung, C.P., et al., Oxidative stress in fibromyalgia and its relationship to symptoms. Clin Rheumatol, 2009. 28(4): p. 435-8.
102. Quinzii, C.M., et al., Respiratory chain dysfunction and oxidative stress correlate with severity of primary CoQ10 deficiency. FASEB J, 2008. 22(6): p. 1874-85.
103. Sluka, K.A., Is it possible to develop an animal model of fibromyalgia? Pain, 2009. 146(1-2): p. 3-4.
104. Kang, R., et al., The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ, 2011. 18(4): p. 571-80.
105. Gostimskaya, I. and A. Galkin, Preparation of highly coupled rat heart mitochondria. J Vis Exp, 2010(43).
106. Lee, J., S. Giordano, and J. Zhang, Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem J, 2012. 441(2): p. 523-40.
107. Frye, C.A., Progesterone attenuates depressive behavior of younger and older adult C57/BL6, wildtype, and progesterone receptor knockout mice. Pharmacol Biochem Behav, 2011. 99(4): p. 525- 31.
108. Yunus, M.B., Towards a model of pathophysiology of fibromyalgia: aberrant central pain mechanisms with peripheral modulation. J Rheumatol, 1992. 19(6): p. 846-50.
109. Yunus, M.B., et al., Pathologic changes in muscle in primary fibromyalgia syndrome. Am J med, 1986. 81(3A): p. 38-42.
110. Caso, G., et al., Effect of coenzyme q10 on myopathic symptoms in patients treated with statins. Am J Cardiol, 2007. 99(10): p. 1409-12.
111. Clauw, D.J., Fibromyalgia: an overview. Am J med, 2009. 122(12 Suppl): p. S3-S13.
112. Koike, M., et al., Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease). Am J Pathol, 2005. 167(6): p. 1713-28.
113. Turunen, M., J. Olsson, and G. Dallner, Metabolism and function of coenzyme Q. Biochim Biophys Acta, 2004. 1660(1-2): p. 171-99.
114. Moreno-Fernandez, A.M., et al., Oral treatment with amitriptyline induces coenzyme Q deficiency and oxidative stress in psychiatric patients. J Psychiatr Res, 2012. 46(3): p. 341-5.
115. Epstein, S.A., et al., Psychiatric disorders in patients with fibromyalgia. A multicenter investigation. Psychosomatics, 1999. 40(1): p. 57-63.
116. Cohen, H., et al., Prevalence of post-traumatic stress disorder in fibromyalgia patients: overlapping syndromes or post-traumatic fibromyalgia syndrome? Semin Arthritis Rheum, 2002. 32(1): p. 38-50.
117. Buskila, D., et al., Familial aggregation in the fibromyalgia syndrome. Semin Arthritis Rheum, 1996. 26(3): p. 605-11.
118. Mizushima, N., T. Yoshimori, and B. Levine, Methods in mammalian autophagy research. Cell, 2010. 140(3): p. 313-26.
119. Malt, E.A., et al., Altered dopamine D2 receptor function in fibromyalgia patients: a neuroendocrine study with buspirone in women with fibromyalgia compared to female population based controls. J Affect Disord, 2003. 75(1): p. 77-82.
120. Sim, J. and S. Madden, Illness experience in fibromyalgia syndrome: a metasynthesis of qualitative studies. Soc Sci Med, 2008. 67(1): p. 57-67.
121. Staud, R., et al., Temporal summation of pain from mechanical stimulation of muscle tissue in normal controls and subjects with fibromyalgia syndrome. Pain, 2003. 102(1-2): p. 87-95.
122. Kosek, E. and P. Hansson, Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects. Pain, 1997. 70(1): p. 41-51.
123. Littarru, G.P. and L. Tiano, Clinical aspects of coenzyme Q10: an update. Nutrition, 2010. 26(3): p. 250-4.
124. Yang, Z. and D.J. Klionsky, Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol, 2010. 22(2): p. 124-31.
125. Clauw, D.J. and L.J. Crofford, Chronic widespread pain and fibromyalgia: what we know, and what we need to know. Best Pract Res Clin Rheumatol, 2003. 17(4): p. 685-701.
126. Eisinger, J., A. Plantamura, and T. Ayavou, Glycolysis abnormalities in fibromyalgia. J Am Coll Nutr, 1994. 13(2): p. 144-8.
127. Rosenfeldt, M.T., et al., Analysis of macroautophagy by immunohistochemistry. Autophagy, 2012. 8(6): p. 963-9.

Das Dokument ist im Internet frei zugänglich - Hinweise zu den Nutzungsrechten