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Search for "inclusion body myositis" English only.

[There is always overlap in these lists but they should be inclusive as a result]

1: Muscle Nerve. 2009 Jul 22. [Epub ahead of print] Nature of "Tau" immunoreactivity in normal myonuclei and inclusion body myositis. Salajegheh M, Pinkus JL, Nazareno R, Amato AA, Parker KC, Greenberg SA. Department of Neurology, Division of Neuromuscular Disease, Brigham and Women's Hospital, 75 Francis Street, and Harvard Medical School, Boston, Massachusetts 02115, USA. Sarcoplasmic accumulation of phosphorylated-tau has been widely stated to occur in and contribute to the pathogenesis of muscle disease in inclusion body myositis. Twenty inflammatory myopathy and 10 normal muscle samples along with a range of other tissues were stained with anti-"tau" antibodies (tau-5, pS422, and SMI-31). Myonuclear and sarcoplasmic fractions were prepared using differential solubilization and laser-capture microdissection, and immunoblots were performed using pS422 and SMI-31 antibodies. All three antibodies demonstrated anti-tau immunoreactivity in myonuclei from normal and diseased muscle, but not in nuclei from other tissues. Western blots showed pS422 and SMI-31 immunoreactivity against nuclear proteins outside the region expected for phosphorylated-tau. Antibodies previously reported to indicate abnormal accumulation of phosphorylated-tau in IBM myofibers react to normal myonuclei and recognize proteins other than tau. Normal myonuclei contain neurofilament H or other unidentified 200 kDa proteins with similar phosphorylated motifs accounting for SMI-31 immunoreactivity. Muscle Nerve, 2009. PMID: 19626672 [PubMed - as supplied by publisher]

2: Muscle Nerve. 2009 Jul 21. [Epub ahead of print] Dermatomyositis with inclusion body myositis pathology. Layzer R, Lee HS, Iverson D, Margeta M. Department of Neurology, Box 0114, UCSF, University of California, San Francisco, California 94143, USA. The pathogenic role of inflammation in inclusion body myositis (IBM) remains uncertain. A 63-year-old man developed a severe, rapidly progressive myopathy with clinical features typical of dermatomyositis (DM), but muscle pathology was typical of IBM. Treatment with prednisone and methotrexate resulted in complete remission of symptoms. Together with two similar cases reported previously, this case suggests that the inflammatory process of DM may trigger the pathologic changes of IBM. Muscle Nerve, 2009. PMID: 19623629 [PubMed - as supplied by publisher]

3: BMJ. 2009 Jul 20;339:b2680. doi: 10.1136/bmj.b2680. Comment in: BMJ. 2009;339:b2049. How citation distortions create unfounded authority: analysis of a citation network. Greenberg SA. Children's Hospital Informatics Program and Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. sagreenberg@partners.org OBJECTIVE: To understand belief in a specific scientific claim by studying the pattern of citations among papers stating it. DESIGN: A complete citation network was constructed from all PubMed indexed English literature papers addressing the belief that beta amyloid, a protein accumulated in the brain in Alzheimer's disease, is produced by and injures skeletal muscle of patients with inclusion body myositis. Social network theory and graph theory were used to analyse this network. MAIN OUTCOME MEASURES: Citation bias, amplification, and invention, and their effects on determining authority. RESULTS: The network contained 242 papers and 675 citations addressing the belief, with 220,553 citation paths supporting it. Unfounded authority was established by citation bias against papers that refuted or weakened the belief; amplification, the marked expansion of the belief system by papers presenting no data addressing it; and forms of invention such as the conversion of hypothesis into fact through citation alone. Extension of this network into text within grants funded by the National Institutes of Health and obtained through the Freedom of Information Act showed the same phenomena present and sometimes used to justify requests for funding. CONCLUSION: Citation is both an impartial scholarly method and a powerful form of social communication. Through distortions in its social use that include bias, amplification, and invention, citation can be used to generate information cascades resulting in unfounded authority of claims. Construction and analysis of a claim specific citation network may clarify the nature of a published belief system and expose distorted methods of social citation. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PMID: 19622839 [PubMed - in process]

4: J Neurol. 2009 Jul 15. [Epub ahead of print] Detecting dysphagia in inclusion body myositis. Cox FM, Verschuuren JJ, Verbist BM, Niks EH, Wintzen AR, Badrising UA. Department of Neurology, Leiden University Medical Centre, P.O. Box 9600, 2300 RC, Leiden, The Netherlands, f.cox@lumc.nl. Dysphagia is an important yet inconsistently recognized symptom of inclusion body myositis (IBM). It can be disabling and potentially life-threatening. We studied the prevalence and symptom-sign correlation of dysphagia. Fifty-seven IBM patients were interviewed using a standard questionnaire for dysphagia and 43 of these underwent swallowing videofluoroscopy (VFS). Symptoms of dysphagia were present in 37 of 57 patients (65%). Nevertheless, only 17 of these patients (46%) had previously and spontaneously complained about swallowing to their physicians. Both symptoms of impaired propulsion (IP) (59%) and aspiration-related symptoms (52%) were frequently mentioned. Swallowing abnormalities on VFS were present in 34 of 43 patients (79%) with IP of the bolus in 77% of this group. The reported feeling of IP was confirmed by VFS in 92% of these patients. Dysphagia in IBM is common but underreported by the vast majority of patients if not specifically asked for. In practice, two questions reliably predict the presence of IP on VFS: 'Does food get stuck in your throat' and 'Do you have to swallow repeatedly in order to get rid of food'. These questions are an appropriate means in selecting IBM patients for further investigation through VFS and eventual treatment. PMID: 19603245 [PubMed - as supplied by publisher]

5: Brain Pathol. 2009 Jul;19(3):493-506. Inclusion body myositis: a degenerative muscle disease associated with intra-muscle fiber multi-protein aggregates, proteasome inhibition, endoplasmic reticulum stress and decreased lysosomal degradation. Askanas V, Engel WK, Nogalska A. USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA 90017-1912, USA. askanas@usc.edu Sporadic inclusion body myositis (s-IBM), the most common muscle disease of older persons, is of unknown cause, and there is no enduring treatment. Abnormal accumulation of intracellular multi-protein inclusions is a characteristic feature of the s-IBM phenotype, and as such s-IBM can be considered a "conformational disorder," caused by protein unfolding/misfolding combined with the formation of inclusion bodies. Abnormal intracellular accumulation of unfolded proteins may lead to their aggregation and inclusion body formation. The present article is focusing on the multiple proteins that are accumulated in the form of aggregates within s-IBM muscle fibers, and it explores the most recent research advances directed toward a better understanding of mechanisms causing their impaired degradation and abnormal aggregation. We illustrate that, among other factors, abnormal misfolding, accumulation and aggregation of proteins are associated with their inadequate disposal-and these factors are combined with, and perhaps provoked by, an aging intracellular milieu. Other concurrent and possibly provocative phenomena known within s-IBM muscle fibers are: endoplasmic reticulum stress and unfolded protein response, mitochondrial abnormalities, proteasome inhibition, lysosome abnormality and endodissolution. Together, these appear to lead to the s-IBM-specific vacuolar degeneration, and muscle fiber atrophy, concluding with muscle fiber death. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PMID: 19563541 [PubMed - in process]

6: Acta Neuropathol. 2009 Jun 26. [Epub ahead of print] p62/SQSTM1 is overexpressed and prominently accumulated in inclusions of sporadic inclusion-body myositis muscle fibers, and can help differentiating it from polymyositis and dermatomyositis. Nogalska A, Terracciano C, D'Agostino C, King Engel W, Askanas V. Department of Neurology, USC Neuromuscular Center, Good Samaritan Hospital, University of Southern California Keck School of Medicine, 637 S. Lucas Ave, Los Angeles, CA, 90017-1912, USA. p62, also known as sequestosome1, is a shuttle protein transporting polyubiquitinated proteins for both the proteasomal and lysosomal degradation. p62 is an integral component of inclusions in brains of various neurodegenerative disorders, including Alzheimer disease (AD) neurofibrillary tangles (NFTs) and Lewy bodies in Parkinson disease. In AD brain, the p62 localized in NFTs is associated with phosphorylated tau (p-tau). Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle disease associated with aging, and its muscle tissue has several phenotypic similarities to AD brain. Abnormal accumulation of intracellular multiprotein inclusions, containing p-tau in the form of paired helical filaments, amyloid-beta, and several other "Alzheimer-characteristic proteins", is a characteristic feature of the s-IBM muscle fiber phenotype. Diminished proteasomal and lysosomal protein degradation appear to play an important role in the formation of intra-muscle-fiber inclusions. We now report that: (1) in s-IBM muscle fibers, p62 protein is increased on both the protein and the mRNA levels, and it is strongly accumulated within, and as a dense peripheral shell surrounding, p-tau containing inclusions, by both the light- and electron-microscopy. Accordingly, our studies provide a new, reliable, and simple molecular marker of p-tau inclusions in s-IBM muscle fibers. The prominent p62 immunohistochemical positivity and pattern diagnostically distinguish s-IBM from polymyositis and dermatomyositis. (2) In normal cultured human muscle fibers, experimental inhibition of either proteasomal or lysosomal protein degradation caused substantial increase of p62, suggesting that similar in vivo mechanisms might contribute to the p62 increase in s-IBM muscle fibers. PMID: 19557423 [PubMed - as supplied by publisher]

7: Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11125-30. Epub 2009 Jun 19. Secretion of amyloidogenic gelsolin progressively compromises protein homeostasis leading to the intracellular aggregation of proteins. Page LJ, Suk JY, Bazhenova L, Fleming SM, Wood M, Jiang Y, Guo LT, Mizisin AP, Kisilevsky R, Shelton GD, Balch WE, Kelly JW. Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Familial amyloidosis of Finnish type (FAF) is a systemic amyloid disease associated with the deposition of proteolytic fragments of mutant (D187N/Y) plasma gelsolin. We report a mouse model of FAF featuring a muscle-specific promoter to drive D187N gelsolin synthesis. This model recapitulates the aberrant endoproteolytic cascade and the aging-associated extracellular amyloid deposition of FAF. Amyloidogenesis is observed only in tissues synthesizing human D187N gelsolin, despite the presence of full-length D187N gelsolin and its 68-kDa cleavage product in blood-demonstrating the importance of local synthesis in FAF. Loss of muscle strength was progressive in homozygous D187N gelsolin mice. The presence of misfolding-prone D187N gelsolin appears to exacerbate the age-associated decline in cellular protein homeostasis (proteostasis), reflected by the intracellular deposition of numerous proteins, a characteristic of the most common degenerative muscle disease of aging humans, sporadic inclusion body myositis. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PMID: 19549824 [PubMed - in process]

8: Muscle Nerve. 2009 Jul;40(1):19-31. Sarcoplasmic redistribution of nuclear TDP-43 in inclusion body myositis. Salajegheh M, Pinkus JL, Taylor JP, Amato AA, Nazareno R, Baloh RH, Greenberg SA. Department of Neurology, Division of Neuromuscular Disease, Brigham and Women's Hospital, and Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA. The nucleic acid binding protein TDP-43 was recently identified in normal myonuclei and in the sarcoplasm of inclusion body myositis (IBM) muscle. Here we found TDP-43 sarcoplasmic immunoreactivity in 23% of IBM myofibers, while other reported IBM biomarkers were less frequent, with rimmed vacuoles in 2.8%, fluorescent Congo red material in 0.57%, SMI-31 immunoreactivity in 0.83%, and focal R1282 beta-amyloid immunoreactivity in 0.00% of myofibers. The presence of as little as >1% of myofibers with nonnuclear sarcoplasmic TDP-43 was highly sensitive (91%) and specific (100%) to IBM among 50 inflammatory myopathy patient samples, although some patients with hereditary inclusion body myopathies and myofibrillar myopathy also had sarcoplasmic TDP-43. TDP-43 mutations were sought, and none were identified. TDP-43 could be one of many nucleic acid binding proteins that are abnormally present in IBM sarcoplasm. They could potentially interfere with the normal function of extranuclear RNAs that maintain myofiber protein production. Muscle Nerve 40: 19-31, 2009. PMID: 19533646 [PubMed - in process]

9: Muscle Nerve. 2009 Jul;40(1):8-9. TDP-43: A reliable immunohistochemistry marker for inclusion body myositis? Verma A, Tandan R. Department of Neurology, University of Miami Miller School of Medicine, Clinical Research Building, 1120 NW 14 Street, Suite 1317 Miami, FL 33136. PMID: 19533631 [PubMed - in process]

10: Clin Exp Dermatol. 2009 Jun;34(4):451-5. Epub 2009 Apr 14. Defining cancer risk in dermatomyositis. Part I. Madan V, Chinoy H, Griffiths CE, Cooper RG. Dermatology Centre, Salford Royal Hospital NHS Foundation Trust, University of Manchester, Manchester, UK. vishalmadan@doctors.org.uk The idiopathic inflammatory myopathies (IIMs) comprise polymyositis, myositis overlapping with another connective tissue disease, dermatomyositis (DM) and inclusion-body myositis (IBM). IIMs are characterized by the presence of proximal muscle weakness, increased levels of muscle-specific enzymes, specific electromyographic abnormalities, and the presence of inflammatory cell infiltrates in skeletal muscle. Clinical, serological and histological criteria can be used to define individual IIM subtypes. In the first of this two-part review series, we examine the evidence for the existence of cancer-associated myositis (CAM), and in part 2, we discuss recent discoveries that provide insight into identification of patients with DM, who may be most at risk of developing CAM. Publication Types: Research Support, Non-U.S. Gov't PMID: 19522981 [PubMed - in process] 11: Acta Neuropathol. 2009 Jun 6. [Epub ahead of print] Increased plasma amyloid-beta(42) protein in sporadic inclusion body myositis. Abdo WF, van Mierlo T, Hengstman GJ, Schelhaas HJ, van Engelen BG, Verbeek MM. Institute of Neurology, Neuromuscular Centre Nijmegen, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands, f.abdo@neuro.umcn.nl. PMID: 19504113 [PubMed - as supplied by publisher]

12: J Clin Neuromuscul Dis. 2009 Jun;10(4):178-84. Improvement in aerobic capacity after an exercise program in sporadic inclusion body myositis. Johnson LG, Collier KE, Edwards DJ, Philippe DL, Eastwood PR, Walters SE, Thickbroom GW, Mastaglia FL. Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Western Australia. ljohnson@meddent.uwa.edu.au OBJECTIVES: The study aimed to investigate the effects of a combined functional and aerobic exercise program on aerobic capacity, muscle strength, and functional mobility in a group of patients with sporadic inclusion body myositis (IBM). METHODS: Aerobic capacity, muscle strength, and functional capacity assessments were conducted on 7 participants with sporadic IBM before and after a 12-week exercise program, which included resistance exercises and aerobic stationary cycling 3 times per week on alternative days. RESULTS: Aerobic capacity of the group increased significantly by 38%, and significant strength improvements were observed in 4 of the muscle groups tested ( p less than 0.05). The exercise program was well tolerated, and there was no significant change in the serum creatine kinase level after the exercise period. CONCLUSIONS: An aerobic exercise program can be safely tolerated by patients with sporadic IBM and can improve aerobic capacity and muscle strength when combined with resistance training. These findings indicate that aerobic and functional muscle strengthening exercise should be considered in the management of patients with IBM. Publication Types: Research Support, Non-U.S. Gov't PMID: 19494728 [PubMed - in process]

13: Acta Reumatol Port. 2009 Apr-Jun;34(2A):161-82. Sporadic inclusion body myositis: an unsolved mystery. Machado P, Miller A, Holton J, Hanna M. Department of Rheumatology, Coimbra University Hospital, Praceta Mota Pinto, 3000-075 Coimbra, Portugal. pedrommcmachado@gmail.com Sporadic inclusion body myositis (sIBM) is considered to be the most common acquired muscle disease associated with aging. It is a disabling disorder still without effective treatment. sIBM causes weakness and atrophy of the distal and proximal muscles. Involvement of quadriceps and deep finger flexors are clues to early diagnosis. Dysphagia in the course of the disease is common. Muscle biopsy shows chronic myopathic features, lymphocytic infiltration invading non-necrotic fibbers, rimmed vacuoles and accumulation of amyloid-related proteins. It remains uncertain whether sIBM is primarily an immune-mediated inflammatory myopathy or a degenerative myopathy with an associated inflammatory component. This review describes the epidemiology and clinical features of the disease as well as the current genetic and pathogenic concepts and therapeutic approaches. Despite recent clues, in many respects sIBM remains an unsolved mystery. Publication Types: Research Support, Non-U.S. Gov't PMID: 19474772 [PubMed - in process]

14: Neuromuscul Disord. 2009 Jun;19(6):406-11. Epub 2009 May 26. Basement membrane remodelling and segmental fibrosis in sporadic inclusion body myositis. Doppler K, Mittelbronn M, Lindner A, Bornemann A. Institute of Brain Research, University of Tübingen, Calwerstr. 3, D-72076 Tübingen, Germany. Sporadic inclusion body myositis (sIBM) is a debilitating idiopathic inflammatory myopathy. Little is known about the pathogenetic mechanisms that lead to myofiber degeneration. In the present study, we evaluated the integrity of the myofiber basement membrane in non-necrotic myofibers invaded by inflammatory infiltrates. We used 100 ten mum thick serial sections obtained from biopsies of 5 patients suffering from sIBM. Biopsies from 5 patients suffering from polymyositis served as controls. We performed sequential HE staining and immunolabeling using anti-CD68, -CD8, -merosin, -laminin alpha4 chain, and -collagen IV antibodies. In sIBM, we detected a total of 89 non-necrotic myofibers that were invaded by inflammatory cells. The invasive process and its sequelae were segmental in nature and included destruction of the myofiber basement membrane, and eventually, partial replacement by fibrosis of the invaded myofiber. In polymyositis, we found only two myofibers that were affected in this way. In sIBM, basement membrane remodelling and irreversible replacement by fibrosis of myofibers appear to represent the end result of a process in which the balance between injury and repair are disrupted. Publication Types: Research Support, Non-U.S. Gov't PMID: 19473842 [PubMed - in process]

15: Brain. 2009 Jun;132(Pt 6):1536-44. Epub 2009 May 19. Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis. Dalakas MC, Rakocevic G, Schmidt J, Salajegheh M, McElroy B, Harris-Love MO, Shrader JA, Levy EW, Dambrosia J, Kampen RL, Bruno DA, Kirk AD. Clinical Neurosciences, Neuromuscular Diseases, Imperial College, London, Hammersmith Hospital Campus, Du Cane Rd, London, UK. m.dalakas@imperial.ac.uk Sporadic inclusion-body myositis (sIBM) is the most common disabling, adult-onset, inflammatory myopathy histologically characterized by intense inflammation and vacuolar degeneration. In spite of T cell-mediated cytotoxicity and persistent, clonally expanded and antigen-driven endomysial T cells, the disease is resistant to immunotherapies. Alemtuzumab is a humanized monoclonal antibody that causes an immediate depletion or severe reduction of peripheral blood lymphocytes, lasting at least 6 months. We designed a proof-of-principle study to examine if one series of Alemtuzumab infusions in sIBM patients depletes not only peripheral blood lymphocytes but also endomysial T cells and alters the natural course of the disease. Thirteen sIBM patients with established 12-month natural history data received 0.3 mg/kg/day Alemtuzumab for 4 days. The study was powered to capture > or =10% increase strength 6 months after treatment. The primary end-point was disease stabilization compared to natural history, assessed by bi-monthly Quantitative Muscle Strength Testing and Medical Research Council strength measurements. Lymphocytes and T cell subsets were monitored concurrently in the blood and the repeated muscle biopsies. Alterations in the mRNA expression of inflammatory, stressor and degeneration-associated molecules were examined in the repeated biopsies. During a 12-month observation period, the patients' total strength had declined by a mean of 14.9% based on Quantitative Muscle Strength Testing. Six months after therapy, the overall decline was only 1.9% ( p less than 0.002), corresponding to a 13% differential gain. Among those patients, four improved by a mean of 10% and six reported improved performance of daily activities. The benefit was more evident by the Medical Research Council scales, which demonstrated a decline in the total scores by 13.8% during the observation period but an improvement by 11.4% ( p less than 0.001) after 6 months, reaching the level of strength recorded 12 months earlier. Depletion of peripheral blood lymphocytes, including the naive and memory CD8+ cells, was noted 2 weeks after treatment and persisted up to 6 months. The effector CD45RA(+)CD62L(-) cells, however, started to increase 2 months after therapy and peaked by the 4th month. Repeated muscle biopsies showed reduction of CD3 lymphocytes by a mean of 50% ( p less than 0.008), most prominent in the improved patients, and reduced mRNA expression of stressor molecules Fas, Mip-1a and alphaB-crystallin; the mRNA of desmin, a regeneration-associated molecule, increased. This proof-of-principle study provides insights into the pathogenesis of inclusion-body myositis and concludes that in sIBM one series of Alemtuzumab infusions can slow down disease progression up to 6 months, improve the strength of some patients, and reduce endomysial inflammation and stressor molecules. These encouraging results, the first in sIBM, warrant a future study with repeated infusions Publication Types: Clinical Trial Research Support, N.I.H., Intramural PMID: 19454532 [PubMed - indexed for MEDLINE]

16: J Neurosci. 2009 May 13;29(19):6132-41. Immunization with amyloid-beta attenuates inclusion body myositis-like myopathology and motor impairment in a transgenic mouse model. Kitazawa M, Vasilevko V, Cribbs DH, LaFerla FM. Department of Neurobiology and Behavior and Neurology, University of California, Irvine, California 92697-4545, USA. Inclusion body myositis (IBM), the most common muscle disease to afflict the elderly, causes slow but progressive degeneration of skeletal muscle and ultimately paralysis. Hallmark pathological features include T-cell mediated inflammatory infiltrates and aberrant accumulations of proteins, including amyloid-beta (Abeta), tau, ubiquitinated-proteins, apolipoprotein E, and alpha-synuclein in skeletal muscle. A large body of work indicates that aberrant Abeta accumulation contributes to the myodegeneration. Here, we investigated whether active immunization to promote clearance of Abeta from affected skeletal muscle fibers mitigates the IBM-like myopathological features as well as motor impairment in a transgenic mouse model. We report that active immunization markedly reduces intracellular Abeta deposits and attenuates the motor impairment compared with untreated mice. Results from our current study indicate that Abeta oligomers contribute to the myopathy process as they were significantly reduced in the affected skeletal muscle from immunized mice. In addition, the anti-Abeta antibodies produced in the immunized mice blocked the toxicity of the Abeta oligomers in vitro, providing a possible key mechanism for the functional recovery. These findings provide support for the hypothesis that Abeta is one of the key pathogenic components in IBM pathology and subsequent skeletal muscle degeneration. Publication Types: Research Support, N.I.H., Extramural PMID: 19439591 [PubMed - indexed for MEDLINE]

17: Expert Opin Pharmacother. 2009 May;10(7):1183-90. Treatment of the inflammatory myopathies: update and practical recommendations. Hengstman GJ, van den Hoogen FH, van Engelen BG. Department of Neurology, Catharina Hospital, PO Box 1350, 5602 ZA Eindhoven, The Netherlands. gerald.hengstman@catharina-ziekenhuis.nl BACKGROUND: The inflammatory myopathies are a heterogeneous group of diseases including dermatomyositis, polymyositis, and inclusion body myositis. Clinical trials in myositis are rare, making it difficult to make clear recommendations on the treatment of these rare disorders. OBJECTIVE: To give an overview of treatment options and strategies and to provide the clinician with a framework that can be used in treating patients with myositis. METHODS: Results of clinical trials in myositis, case series and important case reports are presented and discussed. RESULTS/CONCLUSION: Most patients with dermatomyositis or polymyositis require treatment with oral high-dose prednisone combined with azathioprine or methotrexate to facilitate early tapering of prednisone. In case of treatment failure, intravenous immunoglobulin can be tried, followed by rituximab, mycophenolate mofetil, or tacrolimus depending on the specific clinical situation. A treatment trial with oral prednisone combined with methotrexate is advised in a subgroup of patients with inclusion body myositis. Publication Types: Review PMID: 19405792 [PubMed - indexed for MEDLINE]

18: Clin Rheumatol. 2009 Aug;28(8):947-53. Epub 2009 Apr 23. Concomitant diseases in a cohort of patients with idiopathic myositis during long-term follow-up. Ng KP, Ramos F, Sultan SM, Isenberg DA. Centre for Rheumatology, Department of Medicine, Windeyer Institute, University College London, Room 331, 3rd floor, 46 Cleveland Street, London W1T 4JF, UK. This study aims to report the concomitant diseases observed and damage outcome in a cohort of patients with adult idiopathic inflammatory myositis (IIM) during long-term follow-up. All patients with IIM were identified from a single centre (follow-up between 1979 and 2006) and fulfilled at least three of the four Bohan and Peter criteria. Patients with inclusion body myositis, juvenile-onset myositis and overt overlap syndromes were excluded. Medical notes were retrospectively reviewed. Concomitant diseases identified were divided into 12 different organ systems (bone, cardiac, respiratory, gastrointestinal, renal, central nervous, malignancy, infection, endocrine, eyes, dermatological and haematological). Patient damage index was calculated using the Myositis Damage Index tool. Fifty-five patients (31 polymyositis, 24 dermatomyositis) were identified. The most prevalent organ system involved was lung with 40 events per 1,000 patient years follow-up. There was significant steroid-related complications with 17/18 patients with bone involvement having osteopenia/osteoporosis. Sjogren's syndrome (n = 3) was the most frequent concomitant auto-immune disease observed. Patients with a higher number of organ systems involved had a significantly higher damage index (r = 0.48, p = 0.001). White patients showed a significant trend to develop more than three other organ system involvement ( p less than 0.0001) and myositis-related lung disease ( p less than 0.0001) compared to other races. There is significant steroid-related morbidity in adult IIM patients under long-term follow-up. The prevalence of another concomitant auto-immune disease unlike patients with lupus or Sjogren's syndrome is low. Publication Types: Research Support, Non-U.S. Gov't PMID: 19387765 [PubMed - in process]

19: J Neurol Neurosurg Psychiatry. 2009 May;80(5):583-4. Inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD): clinical features including sphincter disturbance in a large pedigree. Miller TD, Jackson AP, Barresi R, Smart CM, Eugenicos M, Summers D, Clegg S, Straub V, Stone J. Publication Types: Letter PMID: 19372299 [PubMed - indexed for MEDLINE]

20: Folia Neuropathol. 2009;47(1):33-42. Increased expression of cell adhesion molecules in inflammatory myopathies: diagnostic utility and pathogenetic insights. Jain A, Sharma MC, Sarkar C, Bhatia R, Singh S, Handa R. Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110029, India. sharmamehar@yahoo.co.in CONTEXT: Idiopathic inflammatory myopathies (IMs) have been postulated to be of autoimmune origin on the basis of expression of markers like MHC-1 and other mediators involved in autoimmunity such as cell adhesion molecules. AIMS: The present study aims to analyze the expression of cell adhesion molecules ICAM-1 and VCAM-1 and their respective ligands LFA-1 and VLA-4 in IMs, and to assess whether these markers, besides MHC-class 1 antigen and membrane attack complex (MAC), could be of any help in the diagnosis of these diseases. MATERIAL AND METHODS: Retrospective analysis of 119 muscle biopsies consisting of 55 IMs (21 dermatomyositis, 31 polymyositis and 3 inclusion body myositis) and 64 controls received in our department from January 2004 to December 2005 was carried out immunohistochemically using monoclonal antibodies. Statistical analysis: Chi square test and test for validity were used for analysis of differences in expression. RESULTS: Expression of ICAM and VCAM was significantly upregulated on blood vessels and muscle fibres in IMs as compared to controls, in which expression was weak or absent. LFA and VLA-4 were expressed in inflammatory cells in all inflammatory diseases in almost equal numbers. CONCLUSIONS: IMs comprise 6% of all muscle diseases and IBM is not a common IM in India as reported in the Western literature. Our findings support the hypothesis of autoimmune origin of IMs. The difference between expression of these molecules in IMs and controls also has diagnostic implications and these markers should be included along with MHC-1 antigen and membrane attack complex (MAC) in the existing diagnostic armamentarium. PMID: 19353432 [PubMed - indexed for MEDLINE]

21: Front Neurol Neurosci. 2009;26:126-46. Epub 2009 Apr 6. Idiopathic inflammatory myopathies. Dimachkie MM, Barohn RJ. University of Kansas Medical Center, Kansas City, Kans., USA. mdimachkie@kumc.edu Since the description of the first case of dermatomyositis over a century ago, our understanding of myositis has evolved. Bohan and Peter in 1975 established diagnostic criteria for polymyositis and dermatomyositis. Subsequent investigations by Arahata and Engel delineated differences in the lymphocyte subsets on muscle histopathology distinguishing polymyositis and dermatomyositis. Following that, myositis-specific antibodies have been reported in association with various myositis subtypes and with interstitial lung disease. Polymyositis and dermatomyositis are in general responsive to immunosuppressive therapy. Inclusion body myositis (IBM) became recognized as a distinct entity nearly half a century ago. IBM is clinically and pathologically distinct from the other inflammatory myopathies. The weakness in IBM is characteristic, involving both the proximal and distal muscle groups, such as finger flexion, knee extension and ankle dorsiflexion. Vacuolated fibers, amyloid deposition, and filaments on electron microscopy are pathologic hallmarks of IBM. IBM is refractory to corticosteroids and intravenous gamma globulins. This clinical observation and the pathologic features support the hypothesis that IBM is a muscle-degenerative disease. Most recently, a fourth inflammatory myopathy subtype called necrotizing myopathy was described. Necrotizing myopathy may be related to malignancy, other autoimmune diseases, toxic exposure or can be idiopathic. The key histopathologic findings of this entity are necrotic fibers undergoing phagocytosis. Though patients ultimately respond to immunosuppressive therapy, they tend to be more refractory and therefore often require a more aggressive treatment approach. Copyright (c) 2009 S. Karger AG, Basel. Publication Types: Review PMID: 19349710 [PubMed - indexed for MEDLINE]

22: Curr Opin Rheumatol. 2009 Mar;21(2):158-63. Exercise effects in patients with adult idiopathic inflammatory myopathies. Alexanderson H. Department of Physical Therapy, Karolinska University Hospital, Stockholm, Sweden. helene.alexanderson@karolinska.se PURPOSE OF REVIEW: To give an update on recent findings on effects of exercise in patients with adult inflammatory myopathies. RECENT FINDINGS: Although responding to treatment, a majority of patients with polymyositis and dermatomyositis develop sustained disability. The reason for this is not clear. However, a recent study further supports the hypothesis of hypoxia in muscle tissue as a contributor to muscle weakness. The percentage of type I oxygen-dependent muscle fibers increased after a 12-week submaximal home exercise program along with improved muscle endurance in patients with chronic polymyositis or dermatomyositis. Creatine supplements in addition to the same home exercise program are more beneficial than exercise alone in patients with chronic polymyositis or dermatomyositis. Patients with chronic disease tolerate intensive resistance training resulting in improved muscle strength and muscle endurance. This 7-week exercise study also reported reduced disease activity and possibly even reduced muscle inflammation. SUMMARY: These recent studies are in line with earlier ones further supporting safety and efficacy of exercise in patients with polymyositis or dermatomyositis. There is an urgent need for larger randomized controlled trials also including patients with inclusion body myositis to further increase knowledge of disease mechanisms causing disability, exercise effects, and what exercise program is most efficient in patients with different entities of idiopathic inflammatory myopathies. Publication Types: Research Support, Non-U.S. Gov't Review PMID: 19339927 [PubMed - indexed for MEDLINE]

23: Muscle Nerve. 2009 Jun;39(6):739-53. Fast-twitch sarcomeric and glycolytic enzyme protein loss in inclusion body myositis. Parker KC, Kong SW, Walsh RJ; Bch, Salajegheh M, Moghadaszadeh B, Amato AA, Nazareno R, Lin YY, Krastins B, Sarracino DA, Beggs AH, Pinkus JL, Greenberg SA. Harvard-Partners Center for Genetics and Genomics, Proteomics Core, Harvard Medical School, Boston, Massachusetts USA. Inclusion body myositis (IBM) is an inflammatory disease of skeletal muscle of unknown cause. To further understand the nature of the tissue injury in this disease, we developed methods for large-scale detection and quantitation of proteins in muscle biopsy samples and analyzed proteomic data produced by these methods together with histochemical, immunohistochemical, and microarray data. Twenty muscle biopsy samples from patients with inflammatory myopathies (n = 17) or elderly subjects without neuromuscular disease (n = 3) were profiled by proteomic studies using liquid chromatographic separation of peptides followed by mass spectrometry. Thirteen of the diseased samples additionally underwent microarray studies. Seventy muscle specimens from patients with a range of neuromuscular disorders were examined by ATPase histochemical methods. Smaller numbers of samples underwent immunohistochemical and immunoblot studies. Mass spectrometric studies identified and quantified approximately 300 total distinct proteins in each muscle sample. In IBM and to a lesser extent in polymyositis, proteomic studies confirmed by histochemical, immunohistochemical, and immunoblot studies showed loss of many fast-twitch specific structural proteins and glycolytic enzymes despite relative preservation of transcript levels. Increased abundance of a nuclear membrane protein, immunoglobulins, and two calpain-3 substrates were present. The atrophy present in IBM muscle is accompanied by preferential loss of fast-twitch structural proteins and glycolytic enzymes, particularly glycogen debranching enzyme, with relative preservation of the abundance of their respective transcripts. Although muscle atrophy has long been recognized in IBM, these studies are the first to report specific proteins which are reduced in quantity in IBM muscle. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PMID: 19291799 [PubMed - in process]

24: Acta Neuropathol. 2009 May;117(5):569-74. Epub 2009 Mar 12. Amyloid-beta42 is preferentially accumulated in muscle fibers of patients with sporadic inclusion-body myositis. Vattemi G, Nogalska A, King Engel W, D'Agostino C, Checler F, Askanas V. USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA, 90017, USA. Sporadic inclusion-body myositis (s-IBM) is the only muscle disease in which accumulation of amyloid-beta (Abeta) in abnormal muscle fibers appears to play a key pathogenic role. Increased amyloid-beta precursor protein (AbetaPP) and Abeta accumulation have been reported to be upstream steps in the development of the s-IBM pathologic phenotype, based on cellular and animal models. Abeta is released from AbetaPP as a 40 or 42 aminoacid peptide. Abeta42 is considered more cytotoxic than Abeta40, and it has a higher propensity to aggregate and form amyloid fibrils. Using highly specific antibodies, we evaluated in s-IBM muscle biopsies intra-muscle fiber accumulation of Abeta40 and Abeta42-immunoreactive aggregates by light- and electron-microscopic immunocytochemistry, and quantified their amounts by ELISA. In s-IBM, 80-90% of the vacuolated muscle fibers and 5-20% of the non-vacuolated muscle fibers contained plaque-like Abeta42-immunoreactive inclusions, while only 69% of those fibers also contained Abeta40 deposits. By immuno-electronmicroscopy, Abeta42 was associated with 6-10 nm amyloid-like fibrils, small electron-dense floccular clumps and larger masses of amorphous material. Abeta40 was present only on small patches of floccular clumps and amorphous material; it was not associated with 6-10 nm amyloid fibrils. By ELISA, in s-IBM muscle biopsies Abeta42 was present in values 8.53-44.7 pg/ml, while Abeta40 was not detectable; normal age-matched control biopsies did not have any detectable Abeta42 or Abeta40. Thus, in s-IBM muscle fibers, Abeta42 is accumulated more than Abeta40. We suggest that Abeta42 oligomers and their cytotoxicity may play an important role in the s-IBM pathogenesis. PMID: 19280202 [PubMed - indexed for MEDLINE]

25: Autoimmun Rev. 2009 Jun;8(7):627-31. Epub 2009 Feb 20. Idiopathic inflammatory myopathies and the classical NF-kappaB complex: current insights and implications for therapy. Creus KK, De Paepe B, De Bleecker JL. Department of Neurology, Ghent University Hospital, Belgium. The idiopathic inflammatory myopathies (IIM) comprise a heterogeneous group of muscle diseases. The three best-studied subgroups are dermatomyositis (DM), polymyositis (PM) and sporadic inclusion body myositis (IBM). The latter represents a steroid-refractory condition. PM and IBM are characterized by a cell-mediated immune response directed against non-necrotic fibers expressing Major Histocompatibility Complex class I (MHC class I). IBM presents with additional degenerative features, including rimmed vacuoles and depositions of aberrant proteins. DM is a complement-mediated endotheliopathy often accompanied by characteristic skin manifestations. The ubiquitously expressed transcription factor NF-kappaB is considered essential for the development of auto-immunity. This review describes data gathered so far concerning the distribution of the classical heterodimer p65/p50 and its inhibitor I-kappaBalpha in IIM skeletal muscle. Data suggest that the NF-kappaB complex plays a role in the endotheliopathy characterizing DM and might be involved in myofiber regeneration, and appoint CD4+ and CD68+ mononuclear cells with a more prominent role than previously assumed. Fragmentary knowledge of the immunopathogenesis of IIM hampers the development of therapeutic strategies suited to all patient groups. Unravelling the precise involvement of NF-kappaB subunits in IIM immunopathogenesis can shed new light onto the etiology of these diseases and may offer a novel therapeutic target. PMID: 19232550 [PubMed - in process]

26: J Neuropathol Exp Neurol. 2009 Mar;68(3):262-73. TAR DNA-Binding protein 43 accumulation in protein aggregate myopathies. Olivé M, Janué A, Moreno D, Gámez J, Torrejón-Escribano B, Ferrer I. Institut de Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, Spain. Protein aggregate myopathies, including myofibrillar myopathies and sporadic inclusion body myositis (sIBM), are characterized by abnormal protein aggregates composed of various muscular and ectopic proteins. Previous studies have shown the crucial role ofdysregulated transcription factors such as neuron-restrictive silencerfactor in the expression of aberrant proteins in myotilinopathies. Here, we assessed possible aberrant expression of TAR DNA-bindingprotein 43 (TDP-43), another factor involved in transcription regulation. TDP-43-immunoreactive intracytoplasmic inclusions were seen in all cases examined of myotilinopathy, desminopathy, and sIBM, and in 1 case of inclusion body myositis with Paget disease of bone and frontotemporal degeneration (IBMPFD). TAR DNA-binding protein 43 colocalized with myotilin and valosin in myotilinopathies and IBMPFD, respectively, but only occasionally colocalized with ubiquitin in myotilinopathies, desminopathies, sIBM, and IBMPFD; this indicates that accumulated TDP-43 is largely not ubiquitinated. Moreover, phosphorylated TDP-43 at Ser403/404 and Ser409/410 accumulated in the cytoplasm of vulnerable fibers but did not always colocalize with nonphosphorylated TDP-43. Cytoplasmic deposition was accompanied by decreased TDP-43 localization in the nuclei of affected fibers. These findings indicate that TDP-43 not only is another protein accumulated in myofibrillar myopathies, sIBM, and IBMPFD but also likely has a role through altered microRNA processing in the abnormal protein production, modification, and accumulation in protein aggregate myopathies. Publication Types: Research Support, Non-U.S. Gov't PMID: 19225410 [PubMed - indexed for MEDLINE]

27: Neuropathol Appl Neurobiol. 2009 Aug;35(4):442-5. Epub 2009 Feb 11. McArdle disease and sporadic inclusion body myositis. Scarpelli M, Vattemi G, Filosto M, Krause S, Marini M, Tomelleri G, Tonin P. Publication Types: Letter PMID: 19220759 [PubMed - in process]

28: Med J Aust. 2009 Feb 16;190(4):208-9. Intensive rehabilitation in a patient with inclusion body myositis. Datta Gupta A, Quadros N. Department of Rehabilitation Medicine, Queen Elizabeth Hospital, Adelaide, SA, Australia. anupamduttagupta@yahoo.com Publication Types: Case Reports PMID: 19220189 [PubMed - indexed for MEDLINE]

29: Muscle Nerve. 2009 Mar;39(3):283-96. Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease. Rodino-Klapac LR, Haidet AM, Kota J, Handy C, Kaspar BK, Mendell JR. Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, Ohio 43205 USA. In most cases, pharmacologic strategies to treat genetic muscle disorders and certain acquired disorders, such as sporadic inclusion body myositis, have produced modest clinical benefits. In these conditions, inhibition of the myostatin pathway represents an alternative strategy to improve functional outcomes. Preclinical data that support this approach clearly demonstrate the potential for blocking the myostatin pathway. Follistatin has emerged as a powerful antagonist of myostatin that can increase muscle mass and strength. Follistatin was first isolated from the ovary and is known to suppress follicle-stimulating hormone. This raises concerns for potential adverse effects on the hypothalamic-pituitary-gonadal axis and possible reproductive capabilities. In this review we demonstrate a strategy to bypass off-target effects using an alternatively spliced cDNA of follistatin (FS344) delivered by adeno-associated virus (AAV) to muscle. The transgene product is a peptide of 315 amino acids that is secreted from the muscle and circulates in the serum, thus avoiding cell-surface binding sites. Using this approach our translational studies show increased muscle size and strength in species ranging from mice to monkeys. Adverse effects are avoided, and no organ system pathology or change in reproductive capabilities has been seen. These findings provide the impetus to move toward gene therapy clinical trials with delivery of AAV-FS344 to increase size and function of muscle in patients with neuromuscular disease. Publication Types: Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Review PMID: 19208403 [PubMed - indexed for MEDLINE]

30: Muscle Nerve. 2009 Mar;39(3):389-91. A novel mutation in the VCP gene (G157R) in a German family with inclusion-body myopathy with Paget disease of bone and frontotemporal dementia. Djamshidian A, Schaefer J, Haubenberger D, Stogmann E, Zimprich F, Auff E, Zimprich A. Department of Neurology, Medical University of Vienna; Währinger Gürtel 18-20, Vienna A-1097, Austria. Mutations in the valosin-containing protein (VCP) are known to cause autosomal-dominant inclusion-body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD). We report a novel missense mutation (G157R) in the N-terminal region of the VCP gene in a German family. Family members presented with mild to moderate proximal muscle weakness, Paget disease of bone, and signs of early cognitive decline, with onset in the fourth decade. Two family members also showed signs of early hearing impairment, which was confirmed to be sensorineural in one person, a symptom not yet described in the context of IBMPFD. PMID: 19208399 [PubMed - indexed for MEDLINE]

31: Ann Neurol. 2009 Jan;65(1):7-11. Sporadic inclusion body myositis: pathogenic considerations. Karpati G, O'Ferrall EK. Department of Neurology, McGill University, Montreal Neurological Institute, Montreal, Quebec, Canada. george.karpati@mcgill.ca Sporadic inclusion body myositis is the commonest acquired disease of skeletal muscles after 50 years of age, and as such it has commanded a great deal of attention of investigators over the past 25 years. As a result, a large amount of information has accumulated concerning its clinical profile, myopathology, and immunopathology. In the myopathology and immunopathology, there is general agreement that the characteristic features could be divided into a degenerative and an inflammatory group. However, there has been controversy about the possible role of these changes in the pathogenesis of muscle fiber damage. In particular, there is no agreement whether a cause-and-effect relationship exists between these two groups of changes, and if so, which is the primary one. In this brief overview, we examine the validity of the various controversial observations and critically review the justification for the two major hypotheses for the primary role of inflammation versus degeneration. Publication Types: Review PMID: 19194875 [PubMed - indexed for MEDLINE]

32: J Neurol Sci. 2009 Apr 15;279(1-2):47-52. Epub 2009 Jan 25. CCR7+ myeloid dendritic cells together with CCR7+ T cells and CCR7+ macrophages invade CCL19+ nonnecrotic muscle fibers in inclusion body myositis. Tateyama M, Fujihara K, Misu T, Itoyama Y. Department of Neurology, Tohoku University School of Medicine, Sendai, Japan. mtateyama@em.neurol.med.tohoku.ac.jp CCR7 and its ligands CCL19 and CCL21 are a key chemokine system in T cell priming in secondary lymphoid organs, and are rarely expressed in normal muscle tissue. We immunohistochemically investigated the expression of this chemokine system in the muscles of seven patients with inclusion body myositis (IBM). In all cases, CCR7+ mononuclear cells infiltrated in the endomysium, preferentially surrounded and invaded nonnecrotic muscle fibers. Double immunostaining revealed that such CCR7+ mononuclear cells included BDCA-1+ myeloid dendritic cells as well as CD8+ cells, CD4+ cells and CD68+ macrophages. On the other hand, CCL19 was widely expressed on muscle fibers including those invaded by mononuclear cells. CCL19 was also expressed diffusely on endomysial mononuclear cells and endothelium of vessels. Immunoreactivities of CCL21 were detected on some muscle fibers and mononuclear cells. By RT-PCR analyses, mRNA of CCR7 was detected in all the patients and that of CCL19 and CCL21 was detected in six. These findings showed that the CCL19, CCL21/CCR7 chemokine system is expressed in muscles of IBM. The chemokine mediated attraction in dendritic and other immune cells and muscle cells may be crucial in sustained antigen presentation, T cell activation and immune attack to muscles in the pathogenesis of IBM. Publication Types: Research Support, Non-U.S. Gov't PMID: 19171354 [PubMed - indexed for MEDLINE]

33: J Clin Neuromuscul Dis. 2008 Dec;10(2):79-82. Neuromuscular pathology case. Lacomis D. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. lacomisd@upmc.edu Publication Types: Case Reports PMID: 19169096 [PubMed - indexed for MEDLINE]

34: Mol Biol Cell. 2009 Mar;20(5):1533-44. Epub 2009 Jan 14. The insulin/Akt signaling pathway is targeted by intracellular beta-amyloid. Lee HK, Kumar P, Fu Q, Rosen KM, Querfurth HW. Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA. Intraneuronal beta-amyloid (Abeta(i)) accumulates early in Alzheimer's disease (AD) and inclusion body myositis. Several organelles, receptor molecules, homeostatic processes, and signal transduction components have been identified as sensitive to Abeta. Although prior studies implicate the insulin-PI3K-Akt signaling cascade, a specific step within this or any essential metabolic or survival pathway has not emerged as a molecular target. We tested the effect of Abeta42 on each component of this cascade. In AD brain, the association between PDK and Akt, phospho-Akt levels and its activity were all decreased relative to control. In cell culture, Abeta(i) expression inhibited both insulin-induced Akt phosphorylation and activity. In vitro experiments identified that beta-amyloid (Abeta), especially oligomer preparations, specifically interrupted the PDK-dependent activation of Akt. Abeta(i) also blocked the association between PDK and Akt in cell-based and in vitro experiments. Importantly, Abeta did not interrupt Akt or PI3K activities (once stimulated) nor did it affect more proximal signal events. These results offer a novel therapeutic strategy to neutralize Abeta-induced energy failure and neuronal death. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PMID: 19144826 [PubMed - indexed for MEDLINE]

35: Clin Neuropathol. 2008 Nov-Dec;27(6):424-9. Altered distribution of lamin and emerin in muscle nuclei of sIBM patients. Fidzianska A, Glinka Z, Kaminska A, Niebroj-Dobosz I. Neuromuscular Unit, Medical Research Center, Polish Academy of Sciences, Pawinskiego 5 str., 02-106 Warsaw, Poland. neurmyol@cmdik.pan.pl OBJECTIVE: Sporadic inclusion body myositis (sIBM) is a chronic acquired inflammatory myopathy. The cause of sIBM remains unknown and its pathogenesis is controversial. There is a hypothesis [Karpati and Carpenter 1993] that the rimmed vacuoles result from nuclear breakdown, and IBM filaments are formed from components of the nuclear matrix. MATERIAL AND METHODS: For nuclear membrane protein detection, six IBM patients were studied using immunohistochemical and immunochemical techniques. RESULTS: It was demonstrated that in the interior of 10-15% myonuclei emerin and lamin A/C inclusions appeared constantly. This finding indicated an abberant localization of lamin A/C epitopes, the presence of presumptive lamin A (67 KDu) and emerin as in the affected nuclei. CONCLUSION: We support the suggestion that truncated, changed lamin A protein takes part in nuclear disintegration and rimmed vacuole formation. PMID: 19130741 [PubMed - indexed for MEDLINE]

36: Mol Neurodegener. 2009 Jan 6;4(1):2. Intracellular amyloid formation in muscle cells of Abeta-transgenic Caenorhabditis elegans: determinants and physiological role in copper detoxification. Minniti AN, Rebolledo DL, Grez PM, Fadic R, Aldunate R, Volitakis I, Cherny RA, Opazo C, Masters C, Bush AI, Inestrosa NC. Centro de Regulación Celular y Patología "Joaquín V, Luco" (CRCP), MIFAB, Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, 8331010 Santiago, Chile. ninestrosa@bio.puc.cl. ABSTRACT: BACKGROUND: The amyloid beta-peptide is a ubiquitous peptide, which is prone to aggregate forming soluble toxic oligomers and insoluble less-toxic aggregates. The intrinsic and external/environmental factors that determine Abeta aggregation in vivo are poorly understood, as well as the cellular meaning of this process itself. Genetic data as well as cell biological and biochemical evidence strongly support the hypothesis that Abeta is a major player in the onset and development of Alzheimer's disease. In addition, it is also known that Abeta is involved in Inclusion Body Myositis, a common myopathy of the elderly in which the peptide accumulates intracellularly. RESULTS: In the present work, we found that intracellular Abeta aggregation in muscle cells of Caenorhabditis elegans overexpressing Abeta peptide is affected by two single amino acid substitutions, E22G (Arctic) and V18A (NIC). Both variations show decrease intracellular amyloidogenesis compared to wild type Abeta. We show that intracellular amyloid aggregation of wild type Abeta is accelerated by Cu2+ and diminished by copper chelators. Moreover, we demonstrate through toxicity and behavioral assays that Abeta-transgenic worms display a higher tolerance to Cu2+ toxic effects and that this resistance may be linked to the formation of amyloid aggregates. CONCLUSION: Our data show that intracellular Abeta amyloid aggregates may trap excess of free Cu2+ buffering its cytotoxic effects and that accelerated intracellular Abeta aggregation may be part of a cell protective mechanism. PMID: 19126228 [PubMed - as supplied by publisher]

37: Ultrastruct Pathol. 2008 Nov-Dec;32(6):246-51. BACE2 is stored in secretory granules of mouse and rat pancreatic beta cells. Finzi G, Franzi F, Placidi C, Acquati F, Palumbo E, Russo A, Taramelli R, Sessa F, La Rosa S. Department of Pathology, Ospedale di Circolo, Varese, Italy. BACE2 is a protease homologous to BACE1 protein, an enzyme involved in the amyloid formation of Alzheimer disease (AD). However, despite the high homology between these two proteins, the biological role of BACE2 is still controversial, even though a few studies have suggested a pathogenetic role in sporadic inclusion-body myositis and hereditary inclusion-body myopathy, which are characterized by vacuolization of muscular fibers with intracellular deposits of proteins similar to those found in the brain of AD patients. Although BACE2 has also been identified in the pancreas, its function remains unknown and its specific localization in different pancreatic cell types has not been definitively ascertained. For these reasons, the authors have investigated the cellular and subcellular localization of BACE2 in normal rodent pancreases. BACE2 immunoreactivity was found in secretory granules of beta cells, co-stored with insulin and IAPP, while it was lacking in the other endocrine and exocrine cell types. The presence of BACE2 in secretory granules of beta cells suggests that it may play a role in diabetes-associated amyloidogenesis. Publication Types: Research Support, Non-U.S. Gov't PMID: 19117266 [PubMed - indexed for MEDLINE]

38: Neurobiol Aging. 2008 Dec 22. [Epub ahead of print] Amyloid-beta protein impairs Ca(2+) release and contractility in skeletal muscle. Shtifman A, Ward CW, Laver DR, Bannister ML, Lopez JR, Kitazawa M, Laferla FM, Ikemoto N, Querfurth HW. Department of Neurology Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, 736 Cambridge St., Boston, MA 02135, United States. Inclusion body myositis (IBM), the most common muscle disorder in the elderly, is partly characterized by dysregulation of beta-amyloid precursor protein (betaAPP) expression and abnormal, intracellular accumulation of full-length betaAPP and beta-amyloid epitopes. The present study examined the effects of beta-amyloid accumulation on force generation and Ca(2+) release in skeletal muscle from transgenic mice harboring human betaAPP and assessed the consequence of Abeta(1-42) modulation of the ryanodine receptor Ca(2+) release channels (RyRs). beta-Amyloid laden muscle produced less peak force and exhibited Ca(2+) transients with smaller amplitude. To determine whether modification of RyRs by beta-amyloid underlie the effects observed in muscle, in vitro Ca(2+) release assays and RyR reconstituted in planar lipid bilayer experiments were conducted in the presence of Abeta(1-42). Application of Abeta(1-42) to RyRs in bilayers resulted in an increased channel open probability and changes in gating kinetics, while addition of Abeta(1-42) to the rabbit SR vesicles resulted in RyR-mediated Ca(2+) release. These data may relate altered betaAPP metabolism in IBM to reductions in RyR-mediated Ca(2+) release and muscle contractility. PMID: 19108934 [PubMed - as supplied by publisher]

39: J Neurol Sci. 2009 Mar 15;278(1-2):25-9. Epub 2008 Dec 20. Inflammatory myopathies with mitochondrial pathology and protein aggregates. Temiz P, Weihl CC, Pestronk A. Celal Bayar University School of Medicine, Department of Pathology, Manisa, 45010, Turkey. OBJECTIVES: To compare the clinical course and muscle biopsy features of polymyositis with mitochondrial pathology (PM-Mito) to inclusion body myositis (IBM) and steroid-responsive inflammatory myopathies (polymyositis). METHODS: We compared clinical, laboratory and myopathologic features in a retrospective study of patients with PM-Mito (23), IBM (26) and polymyositis (12). RESULTS: Selective weakness in the quadriceps or finger flexors was common in PM-Mito (62%) and IBM (87%). Weakness progressed more slowly in PM-Mito than in IBM. PM-Mito patients with more rapidly progressive weakness had more cytochrome oxidase negative muscle fibers. There was no history of benefit from corticosteroid treatment in any PM-Mito or IBM patients. B-cell foci were absent in IBM and PM-Mito. LC3, an autophagy marker, and alphaB-crystallin were common in aggregates in PM-Mito and IBM, but not polymyositis. SMI-31 and TDP-43 positive aggregates were common in IBM but not in PM-Mito or polymyositis. beta-amyloid showed no differences in aggregates among the three groups. CONCLUSIONS: PM-Mito and IBM may be part of the same disease spectrum. PM-Mito has more slowly progressive weakness than IBM and rarely has TDP-43 or SMI-31 staining aggregates in muscle fibers. The most frequent proteins in aggregates in both PM-Mito and IBM are LC3, an autophagy marker, and alphaB-crystallin. Alterations in autophagic degradation pathways may be a common pathogenic mechanism in PM-Mito and IBM. In pathologically typical polymyositis, staining for mitochondrial enzyme activity, aggregates and B-cells helps to distinguish PM-Mito from inflammatory myopathy syndromes that are more likely to respond to corticosteroid treatment. Publication Types: Research Support, Non-U.S. Gov't PMID: 19101700 [PubMed - indexed for MEDLINE]

40: J Alzheimers Dis. 2008 Dec;15(4):673-84. Potential mechanisms linking cholesterol to Alzheimer's disease-like pathology in rabbit brain, hippocampal organotypic slices, and skeletal muscle. Ghribi O. Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, ND 58202, USA. oghribi@medicine.nodak.edu Epidemiological, animal, and cellular studies suggest that abnormalities in cholesterol metabolism are important in the pathogenesis of Alzheimer's disease (AD), potentially by increasing amyloid-beta (Abeta) peptide levels. Accumulation of Abeta in the brain is suggested to play a key role in the neurodegenerative processes by triggering the hyperphosphorylation of tau and the neuronal death that develop in the course of AD. However, the mechanisms by which cholesterol increases Abeta levels are still ill-defined. Previous and ongoing work from our laboratory indicates that hypercholesterolemia leads to the increased neuronal content of cholesterol and increased levels and processing of the amyloid-beta protein precursor (AbetaPP). We also have found that the oxidized cholesterol metabolite, 27-hydroxycholesterol, increases Abeta levels in both organotypic hippocampal slices and in neuronal preparations cultured from adult rabbits. This cholesterol metabolite is predominantly formed in the circulation and, in contrast to cholesterol, has the ability to cross into the brain. These results may indicate that 27-hydroxycholesterol is the link between circulating cholesterol and AD-like pathology in the brain. We also have found pathological hallmarks in the skeletal muscle of cholesterol-fed rabbits that are suggestive of inclusion body myositis, a disease that shares some pathological similarities with AD. Publication Types: Research Support, N.I.H., Extramural Review PMID: 19096164 [PubMed - indexed for MEDLINE]

41: Curr Neurol Neurosci Rep. 2009 Jan;9(1):83-9. Inclusion body myositis: review of recent literature. Greenberg SA. Department of Neurology, Brigham and Women's Hospital,75 Francis Street, Boston, MA 02115, USA. sagreenberg@partners.org Inclusion body myositis (IBM) is a progressive inflammatory skeletal muscle disease of unknown cause and without effective treatment. This article discusses existing literature, emphasizing disease mechanisms and models. In particular, it addresses limitations in the beta-amyloid-mediated theory of IBM myofiber injury, flawed rationales of animal models of this disease, and recent reports regarding treatment. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review PMID: 19080758 [PubMed - indexed for MEDLINE]

42: Clin Rheumatol. 2009 Jun;28 Suppl 1:S21-2. Epub 2008 Dec 6. A case of inclusion body myositis responsive to prednisolone therapy. Kalla R, Soumakiyan M, Tuck S. Department of Rheumatology, James Cook University Hospitals, Marton Road, Middlesbrough, TS4 3BW, UK. kallarahul@gmail.com Inclusion body myositis, although rare, is the commonest cause of myopathy in patients aged over 50 years. The suggested pathogenesis remains uncertain and its prognosis remains poor. There have been select case reports of its association with an inflammatory etiology and it is postulated that this group of patients respond better to immunosuppressive therapy. We therefore report a rare case of inclusion body myositis that responded well to immunosuppressive therapy. We also report the possibility of its association with infliximab therapy. PMID: 19067104 [PubMed - in process]

43: Muscle Nerve. 2009 Jan;39(1):16-24. Discriminating neurogenic from myopathic disease via measurement of muscle anisotropy. Garmirian LP, Chin AB, Rutkove SB. Department of Neurology, Division of Neuromuscular Diseases, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. Skeletal muscle is electrically anisotropic, with a tendency for applied electrical current to flow more readily along muscle fibers than across them. In this study, we assessed a method for non-invasive measurement of anisotropy to determine its potential to serve as a new technique for distinguishing neurogenic from myopathic disease. Measurements were made on the biceps brachii and tibialis anterior muscles in 15 normal subjects and 12 patients with neuromuscular disease (6 with amyotrophic lateral sclerosis and 6 with various myopathies) using 50 kHZ applied current. Consistent multi-angle anisotropic patterns were found for reactance and phase in both muscles in normal subjects. Normalized anisotropy differences for each subject were defined, and group average values identified. The amyotrophic lateral sclerosis (ALS) patients demonstrated increased and distorted anisotropy patterns, whereas myopathic patients demonstrated normal or reduced anisotropy. These results suggest that non-invasive measurement of muscle anisotropy has potential for diagnosis of neuromuscular diseases. (c) 2008 Wiley Periodicals, Inc. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PMID: 19058193 [PubMed - indexed for MEDLINE]

44: Clin Exp Rheumatol. 2008 Sep-Oct;26(5):887-93. Clinical outcome following B cell depletion therapy in eight patients with refractory idiopathic inflammatory myopathy. Sultan SM, Ng KP, Edwards JC, Isenberg DA, Cambridge G. University College London Hospital, London, UK. OBJECTIVE: To assess the efficacy of B lymphocyte depletion therapy (BCDT) in patients with refractive idiopathic inflammatory myopathy (IIM). METHODS: Eight patients thought to have IIM were treated with BCDT utilising rituximab. Five were treated as part of an open label trial and three on the basis of perceived clinical need. Rituximab (1 gram) and methylprednisolone (100 mg) were given as intravenous infusions on days 0 and 14. The primary efficacy outcome at 6 months was 15% improvement in muscle strength and 30% reduction in CPK. RESULTS: Two patients with Jo-1 antibody positive dermatomyositis (DM) demonstrated a clinical response. Both achieved >30% improvement in CPK. In one, the CPK remained within the normal range for 10 months, the other had a normalised CPK and stabilisation of lung function tests for 36 months. Muscle strength by myometry, however, did not achieve the primary outcome, although, patient 1, demonstrated an improvement of 20% at 8 months (the patient had elective surgery of the hand during the study period). Jo-1 antibody levels fell modestly in both patients but remained detectable. Re-evaluation of three patients revealed that one had inclusion body myositis, one had sporadic muscular dystrophy and one subsequently developed nodular sclerosing lymphoma. All except one patient showed adequate B cell depletion with re-population occurring 3- >42 months after BCDT. One patient did not deplete and died of an unrelated cause. CONCLUSIONS: This study emphasizes the importance of identifying and selecting the appropriate sub-group of patients with IIM most likely to respond to BCDT. Publication Types: Clinical Trial Research Support, Non-U.S. Gov't PMID: 19032824 [PubMed - indexed for MEDLINE]

45: Neurotherapeutics. 2008 Oct;5(4):633-7. The hereditary inclusion body myopathy enigma and its future therapy. Argov Z, Mitrani-Rosenbaum S. Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. zohara@ekmd.huji.ac.il Hereditary inclusion body myopathy (HIBM) is a genetic muscle disease due to mutations in the gene encoding the enzyme complex UDP-N-acetylglucosamine 2 epimerase-N-acetylmannosamine kinase (GNE), which catalyzes the rate-limiting step in sialic acid production. The review describes some of the disease features that may be relevant for further understanding of the metabolic impairment of HIBM and its future therapy. It also addresses the biochemical basis behind the substrate supplementation therapy designed for this condition. Publication Types: Research Support, Non-U.S. Gov't Review PMID: 19019317 [PubMed - indexed for MEDLINE]

46: Neurotherapeutics. 2008 Oct;5(4):548-57. Idiopathic inflammatory myopathies: current and future therapeutic options. Wiendl H. Department of Neurology, University of Wuerzburg, Wuerzburg, Germany. heinz.wiendl@klinik.uni-wuerzburg.de Idiopathic inflammatory myopathies (notably polymyositis and dermatomyositis) are relatively uncommon diseases with a heterogeneous clinical presentation. Only a few randomized, double-blind, placebo-controlled trials have been performed, measures to assess outcome and response to treatment have to be validated. Initial treatment options of first choice are corticosteroids, although rarely tested in randomized, controlled trials. Unfortunately, not all patients respond to them and many develop undesirable side effects. Thus, second line agents or immunosuppressants given in combination with corticosteroids are used. For dermatomyositis/polymyositis, combination with azathioprine is most common. In case this combination is not sufficient or applicable, intravenous immunoglobulins are justified. Alternative or stronger immunosuppressants, such as cyclosporine A, cyclophosphamide, methotrexate, or mycophenolate are also used. There are no defined guidelines or best treatment protocols agreed on internationally; therefore, the medical approach must be individualized based on the severity of clinical presentation, disease duration, presence of extramuscular features, and prior therapy and contraindications to particular agents. Approximately 25% of patients are nonresponders and continue to experience clinical relapses. Those are candidates for alternative treatment options and experimental therapies. New immunoselective therapies directed toward cytokine modulation, immune cell migration, or modification of certain immune subsets (B- and T-cells) are a promising avenue of research and clinical application. Possible future therapeutic options are presented and discussed. Publication Types: Research Support, Non-U.S. Gov't Review PMID: 19019306 [PubMed - indexed for MEDLINE]

47: Arthritis Rheum. 2008 Nov;58(11):3600-8. Human muscle cells express the costimulatory molecule B7-H3, which modulates muscle-immune interactions. Waschbisch A, Wintterle S, Lochmüller H, Walter MC, Wischhusen J, Kieseier BC, Wiendl H. University of Wuerzburg, Wuerzburg, Germany, and University of Erlangen, Erlangen, Germany. OBJECTIVE: Interactions between the family of B7 ligands and their receptors are increasingly recognized as crucial for stimulation and/or inhibition of immune responses. The present study was undertaken to examine the expression and functional relevance of B7 homolog 3 (B7-H3), a novel B7 homolog attributed significant immunoregulatory functions, in human muscle cells in vivo and in vitro. METHODS: Thirty-five muscle biopsy specimens obtained from patients with polymyositis, dermatomyositis, inclusion body myositis, or noninflammatory myopathies and normal controls were analyzed by immunohistochemistry for B7-H3 expression. The expression of B7-H3 protein on primary human myoblasts and TE671 muscle rhabdomyosarcoma cells was studied by flow cytometry and Western blot analysis. B7-H3 small interfering RNA (siRNA) was used to study the impact of knockdown of B7-H3 on CD8+ cell-mediated lysis in skeletal muscle cells. RESULTS: B7-H3 was not detectable on normal muscle fibers. In contrast, its expression was markedly increased on muscle fibers from patients with inflammatory myopathies. Cell-surface staining was most prominent in the contact areas between muscle fibers and inflammatory cells. B7-H3 protein was detected on myoblasts cultured from control and myositis patient muscle tissue as well as in TE671 muscle rhabdomyosarcoma cells. Knockdown of B7-H3 by siRNA in TE671 cells enhanced CD8+ T cell-specific lysis, indicating a functional role of B7-H3 in the protection of skeletal muscle from immune-mediated lysis. CONCLUSION: Our results demonstrate that human muscle cells express B7-H3, a functional coinhibitory molecule of the B7 family. B7-H3 may play an important role in muscle-immune interactions, providing further evidence of the active role of muscle cells in local immunoregulatory processes. Publication Types: Research Support, Non-U.S. Gov't PMID: 18975328 [PubMed - indexed for MEDLINE]

48: Acta Neuropathol. 2008 Dec;116(6):583-95. Epub 2008 Oct 31. Inclusion-body myositis: muscle-fiber molecular pathology and possible pathogenic significance of its similarity to Alzheimer's and Parkinson's disease brains. Askanas V, Engel WK. Department of Neurology, USC Neuromuscular Center, Good Samaritan Hospital, University of Southern California Keck School of Medicine, 637 South Lucas Avenue, Los Angeles, CA 90017-1912, USA. askanas@usc.edu Sporadic inclusion-body myositis (s-IBM), the most common muscle disease of older persons, is of unknown cause and lacks successful treatment. Here we summarize diagnostic criteria and discuss our current understanding of the steps in the pathogenic cascade. While it is agreed that both degeneration and mononuclear-cell inflammation are components of the s-IBM pathology, how each relates to the pathogenesis remains unsettled. We suggest that the intra-muscle-fiber degenerative component plays the primary role, leading to muscle-fiber destruction and clinical weakness, since anti-inflammatory treatments are not of sustained benefit. We discuss possible treatment strategies aimed toward ameliorating a degenerative component, for example, lithium and resveratrol. Also discussed are the intriguing phenotypic similarities between s-IBM muscle fibers and the brains of Alzheimer and Parkinson's diseases, the most common neurodegenerative diseases associated with aging. Similarities include, in the respective tissues, cellular aging, mitochondrial abnormalities, oxidative and endoplasmic-reticulum stresses, proteasome inhibition and multiprotein aggregates. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review PMID: 18974994 [PubMed - indexed for MEDLINE]

49: Neurol India. 2008 Jul-Sep;56(3):363-7. Major histocompatibility complex class I expression can be used as a diagnostic tool to differentiate idiopathic inflammatory myopathies from dystrophies. Sundaram C, Uppin MS, Meena AK. Department of Pathology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, India. challa_sundaram@yahoo.com AIM: Utility of major histocompatibility complex (MHC) Class I antigen immunostaining was studied to differentiate idiopathic inflammatory myopathies from dystrophies. MATERIALS AND METHODS: Forty muscle biopsies including seven dermatomyositis (DM), six polymyositis (PM), two sporadic inclusion body myositis (sIBM), 20 dystrophies (one Duchenne, three Becker's, four alpha, one gamma sarcoglycanopathy, nine limb girdle, one myotonic and one fascioscapulohumeral muscular dystrophy) and five controls were stained with antibody for MHC Class I antigen (Novocastra clone W6/32 HL 1:100 dilution). RESULTS: Polymyositis and sIBM showed MHC class I antigen positivity along sarcolemma of single and small groups of muscle fibers. The regenerating fibers in the perifascicular area in DM showed intense cytoplasmic positivity of MHC class I antigen. Muscle fibers in all dystrophies except regenerating fibers and control normal muscle were negative for MHC. Capillaries and lymphocytes were positive controls. There were no false positives in the study. CONCLUSION: MHC Class I immunostaining can be used as a complementary diagnostic tool for the diagnosis of idiopathic inflammatory myopathies. PMID: 18974565 [PubMed - indexed for MEDLINE]

50: Neurol India. 2008 Jul-Sep;56(3):263-70. Inflammatory muscle diseases. Mastaglia FL. Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Queen Elizabeth II Medical Centre, Nedlands 6009, Australia. flmast@cyllene.uwa.edu.au The three major immune-mediated inflammatory myopathies, dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM), each have their own distinctive clinical features, underlying pathogenetic mechanisms and patterns of muscle gene expression. In DM a complement-dependent humoral process thought to be initiated by antibodies to endothelial cells results in a microangiopathy with secondary ischemic changes in muscles. On the other hand, in PM and IBM there is a T-cell response with invasion of muscle fibers by CD8+ lymphocytes and perforin-mediated cytotoxic necrosis. In IBM degenerative changes are also a feature and comprise autophagia with rimmed vacuole formation and inclusions containing beta-amyloid and other proteins whose accumulation may be linked to impaired proteasomal function. The relationship between the inflammatory and degenerative component remains unclear, as does the basis for the selective vulnerability of certain muscles and the resistance to conventional forms of immunotherapy in most cases of IBM. Patients with DM or PM usually respond to treatment with glucocorticoids and immunosuppressive agents but their use remains largely empirical. Intravenous immunoglobulin therapy can be used to achieve disease control in patients with severe weakness or dysphagia, or in patients with immunodeficiency, but its use is limited by expense. Emerging therapies for resistant cases include TNFalpha inhibitors (etanercept, infliximab) and monoclonal antibodies (rituximab, alemtuzumab). However, experience with these therapies is still limited and there is a need for randomized trials to test their efficacy and establish guidelines for their use in clinical practice. Publication Types: Review PMID: 18974552 [PubMed - indexed for MEDLINE]

51: Curr Opin Rheumatol. 2008 Nov;20(6):681-5. Animal models in myositis. Katsumata Y, Ascherman DP. Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan. katsumata@ior.twmu.ac.jp PURPOSE OF REVIEW: The etiology of the idiopathic inflammatory myopathies remains elusive. Delineation of pathogenic mechanisms in humans is hindered by the heterogeneity of different patient populations as well as the complexity and chronicity of the disease. Therefore, appropriate animal models are required to help clarify the immunopathogenesis of these disorders and to explore promising new therapies. The purpose of this review is to discuss recently published animal models in myositis, with a particular focus on idiopathic inflammatory myopathy. RECENT FINDINGS: Over the last few years, there has been considerable progress in the development of animal models for polymyositis and inclusion body myositis, but reports focusing on dermatomyositis have been limited. Although some of these systems are entirely novel, others have elucidated pathogenic mechanisms of existing models. SUMMARY: Several new animal models of myositis have emerged over the last few years that have revealed new insights regarding the pathophysiology of idiopathic inflammatory myopathy and that should set the foundation for development of new, more effective therapies against this often intractable disease. Publication Types: Review PMID: 18946328 [PubMed - indexed for MEDLINE]

52: Curr Opin Rheumatol. 2008 Nov;20(6):669-74. Dendritic cells and the immunopathogenesis of idiopathic inflammatory myopathies. de Padilla CM, Reed AM. Division of Rheumatology, Departments of Medicine, Pediatrics, and Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. PURPOSE OF REVIEW: Mechanisms driving the autoimmune process in idiopathic inflammatory myopathies (IIMs) have not been unraveled, despite extensive studies. In recent times, it has become apparent that heterogeneous populations of dendritic cells have specialized roles in IIM. Here, we will discuss the role of dendritic cells in the induction of adaptive immune response in IIM and review the recent literature addressing the role of dendritic cells in the cause and pathogenesis of inflammatory myopathies. RECENT FINDINGS: Different subsets of immature and mature dendritic cells have been recently identified in skeletal muscle in IIM. Dendritic cells present in inclusion body myositis and polymyositis are primarily myeloid dendritic cells. In contrast, plasmacytoid dendritic cells, a subset of dendritic cells and considered the main source of the interferon-alpha/beta (IFN-alpha/beta), have been found abundantly in muscle tissue of adult dermatomyositis and juvenile dermatomyositis. SUMMARY: Dendritic cells are associated with the chronic infiltration of mononuclear cells in the inflammatory muscle tissue of IIM patients. Increasing evidences point out that dendritic cells are not only crucially involved in the initiation of anti-self immune response but are also essential for the maintenance of autoimmune lesions in inflammatory myopathies. Publication Types: Review PMID: 18946326 [PubMed - indexed for MEDLINE]

53: Curr Opin Rheumatol. 2008 Nov;20(6):662-8. Inclusion body myositis: new insights into pathogenesis. Garlepp MJ, Mastaglia FL. School of Pharmacy, Curtin University of Technology, Australia. mgarlepp@ichr.uwa.edu.au PURPOSE OF REVIEW: The pathogenesis of sporadic inclusion body myositis is complex and the disease has a relentless course. Recent observations regarding possible mechanisms of disease may provide targets for therapy. RECENT FINDINGS: Evidence is strengthening that specific T-cell and B-cell responses are ongoing in skeletal muscle in sporadic inclusion body myositis and that cytokines and chemokines generated by an autoimmune response are likely to influence antigen presentation by intramuscular dendritic cells and muscle cells, expression of amyloid precursor protein and the endoplasmic reticulum stress response. Early beta-amyloid expression and perhaps aberrant expression of protein processing enzymes, such as E3 ligases, seem to be involved in the myopathic process. NF-kappaB activation by endoplasmic reticulum stress and cytokine action further stimulates amyloid precursor protein production, exacerbates endoplasmic reticulum stress and increases myostatin content in muscle contributing to muscle atrophy. SUMMARY: Understanding the paradoxes in sporadic inclusion body myositis is important in determining rational therapy for the disease. Amyloid precursor protein is expressed in muscle in other inflammatory muscle diseases but the cellular distribution differs and inclusions do not form so that other metabolic defects seem to be important. Intramuscular immune cells influence muscle function and viability in inclusion body myositis but immunotherapy is ineffective. A useful target for therapy may be restoration of muscle regenerating capacity. Publication Types: Review PMID: 18946325 [PubMed - indexed for MEDLINE]

54: Curr Opin Rheumatol. 2008 Nov;20(6):656-61. Imaging tools for the clinical assessment of idiopathic inflammatory myositis. Walker UA. Department of Rheumatology, Basel University, Basel, Switzerland. ulrich.walker@fps-basel.ch PURPOSE OF REVIEW: To summarize advances in the imaging of idiopathic inflammatory myopathies. RECENT FINDINGS: T2-weighted MRI with fat suppression or short tau inversion recovery sequences are the most sensitive and specific routine method of polymyositis and dermatomyositis imaging. MRI also represents an important aid in the identification of biopsy sites, with whole-body MRI sensitively visualizing the distribution of muscle involvement throughout the body. Ultrasound may be a cost-effective alternative to MRI, with contrast-enhanced ultrasound also permitting the assessment of muscle vascularization. PET sensitively detects increased muscle metabolism and simultaneously screens for underlying malignancies in dermatomyositis. Most scintigraphic techniques have a low sensitivity and specificity in the detection of muscle involvement, and it is unclear whether they provide an added benefit. New MRI techniques, such as T2 mapping, diffusion-weighted imaging and blood oxygenation level-dependent imaging, can provide information on muscle recruitment, myofibrillar structure and blood supply. SUMMARY: In suspected myositis, muscle imaging should be strongly considered prior to obtaining a muscle biopsy. Future research should prospectively study the use of muscle imaging in the evaluation of treatment response and muscle function. Publication Types: Review PMID: 18946324 [PubMed - indexed for MEDLINE]

55: Am J Phys Med Rehabil. 2008 Nov;87(11):883-9. Dysphagia in inclusion body myositis: clinical features, management, and clinical outcome. Oh TH, Brumfield KA, Hoskin TL, Kasperbauer JL, Basford JR. Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, Minnesota 55905, USA. OBJECTIVE: To evaluate the clinical features, treatment strategies, and outcome of dysphagia in patients with inclusion body myositis. DESIGN: Retrospective review of all 26 patients (20 women, 6 men, mean age of 72.2 yrs) with inclusion body myositis-associated dysphagia seen in 1997-2001 at our institution. RESULTS: Twenty-four patients (92%) had a dysphagia evaluation. Cricopharyngeal muscle dysfunction was noted in all nine patients who had barium swallow studies. Eighteen patients (69%) underwent one or more interventional procedures: cricopharyngeal myotomy (10), pharyngoesophageal dilation (6), percutaneous endoscopic gastrostomy (6), and botulinum injection of the upper esophageal sphincter (2). Dysphagia tended to worsen with time. Symptomatic improvement was noted with cricopharyngeal myotomy (63%) and pharyngoesophageal dilation (33%). The Mendelsohn maneuver seemed helpful in maintaining oral intake in the three patients in whom it was recommended. Thirteen patients died during follow-up at a mean age of 81 yrs. The cause of death was identified in eight and in all cases was because of the respiratory complications of aspiration. CONCLUSIONS: Dysphagia is a progressive condition in patients with inclusion body myositis and often leads to death from aspiration pneumonia. Treatment targeting cricopharyngeal muscle dysfunction, such as the Mendelsohn maneuver, will benefit from further investigation. PMID: 18936555 [PubMed - indexed for MEDLINE]

56: Neurobiol Aging. 2008 Oct 13. [Epub ahead of print] Decreased SIRT1 deacetylase activity in sporadic inclusion-body myositis muscle fibers. Nogalska A, D'Agostino C, Engel WK, Davies KJ, Askanas V. Department of Neurology, USC Neuromuscular Center, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA 90017-1912, USA. SIRT1 belongs to the sirtuin family of NAD(+)-dependent histone/protein deacetylases. Experimentally, increased activity of SIRT1 facilitates calorie-restricted longevity, and decreases NF-kappaB activation and the amount of the amyloid-beta (Abeta). We studied SIRT1 in an aging-associated muscle disease, sporadic inclusion-body myositis (s-IBM), whose muscle fibers contain increased NF-kappaB activation and abnormal accumulation of Abeta. We show that, as compared to the age-matched controls, in s-IBM muscle fibers: (1) SIRT1 activity and deacetylation of SIRT1 targets, H4, NF-kappaB and p53 were decreased; (2) SIRT1 mRNA and protein were significantly increased; (3) in the cytoplasm, SIRT1 protein was accumulated in the form of cytoplasmic aggregates; (4) in the nuclei, SIRT1 protein was decreased. To our knowledge, this is the first demonstration of SIRT1 abnormalities, including decreased SIRT1 deacetylase activity, in human disease associated with aging. We propose that in s-IBM muscle fibers, inadequate activity of SIRT1 may be detrimental by increasing NF-kappaB activation and contributing to abnormal Abeta accumulation. Improving SIRT1 action by treatment with known SIRT1 activators might benefit s-IBM patients. PMID: 18922603 [PubMed - as supplied by publisher]

57: Neurobiol Aging. 2008 Sep 25. [Epub ahead of print] Increased aging in primary muscle cultures of sporadic inclusion-body myositis. Morosetti R, Broccolini A, Sancricca C, Gliubizzi C, Gidaro T, Tonali PA, Ricci E, Mirabella M. Department of Neuroscience, Catholic University, Rome, Italy; Fondazione Don Carlo Gnocchi, Rome, Italy. Ageing is thought to participate to the pathogenesis of sporadic inclusion-body myositis (s-IBM). Although the regenerative potential of s-IBM muscle is reduced in vivo, age-related abnormalities of satellite cells possibly accounting for the decline of muscle repair have not been demonstrated. Here we show that proliferation rate and clonogenicity of s-IBM myoblasts are significantly lower and doubling time is longer than normal age-matched controls, indicating that proliferative capacity of s-IBM muscles becomes exhausted earlier. Telomere shortening is detected in s-IBM cells suggesting premature senescence. Differently from controls, s-IBM myoblasts show increased active beta-catenin mainly localized within myonuclei, indicating active Wnt stimulation. After many rounds of muscle growth, only s-IBM myoblasts accumulate congophilic inclusions and immunoreactive Abeta(1-40) deposits. Therefore, s-IBM myoblasts seem to have a constitutively impaired regenerative capacity and the intrinsic property, upon sufficient aging in vitro, to accumulate Abeta. Our results might be valuable in understanding molecular mechanisms associated with muscle aging underlying the defective regeneration of s-IBM muscle and provide new clues for future therapeutic strategies. PMID: 18823681 [PubMed - as supplied by publisher]

58: Arthritis Rheum. 2008 Oct;58(10):3216-23. Expression of the CD85j (leukocyte Ig-like receptor 1, Ig-like transcript 2) receptor for class I major histocompatibility complex molecules in idiopathic inflammatory myopathies. Schleinitz N, Cognet C, Guia S, Laugier-Anfossi F, Baratin M, Pouget J, Pelissier JF, Harle JR, Vivier E, Figarella-Branger D. Department of Internal Medicine, CHU La Conception, Marseille, France. nicolas.schleinitz@ap-hm.fr OBJECTIVE: Expression of class I major histocompatibility complex (MHC) molecules on the surface of muscle cells is a biologic feature of idiopathic inflammatory myopathies (IIM). Class I MHC-transgenic mouse models support a causative role for class I MHC expression by muscle cells in the pathogenesis of IIM. The muscle lesions are characterized by leukocyte infiltration. We undertook this study to analyze the expression in muscle lesions of various class I MHC-specific receptors on leukocytes and natural killer (NK) cells. METHODS: We generated a panel of cell transfectants to control the immunofluorescence analysis of class I MHC receptor expression. We then analyzed the expression of CD158 (killer cell Ig-like receptors [KIRs]) and CD85j (leukocyte Ig-like receptor 1, Ig-like transcript 2) on muscle sections prepared from 14 patients with IIM (5 with dermatomyositis [DM], 5 with polymyositis [PM], and 4 with sporadic inclusion body myositis [IBM]). RESULTS: We could not detect the presence of NK cells in inflammatory lesions. However, the class I MHC receptor CD85j, but no KIRs, was expressed by inflammatory cells infiltrating muscle lesions in IIM. CONCLUSION: CD85j is expressed in PM and sporadic IBM at the sites of partial invasion and in DM in perivascular inflammation, paving the way for dissecting the role of CD85j in the pathogenesis of inflammatory myopathies. Publication Types: Research Support, Non-U.S. Gov't PMID: 18821690 [PubMed - indexed for MEDLINE]

59: J Clin Neurosci. 2008 Dec;15(12):1350-3. Epub 2008 Sep 23. Prevalence of sporadic inclusion body myositis and factors contributing to delayed diagnosis. Needham M, Corbett A, Day T, Christiansen F, Fabian V, Mastaglia FL. Centre for Neuromuscular and Neurological Disorders, Australian Neuromuscular Research Institute (ANRI), University of Western Australia, Queen Elizabeth II Medical Centre, Nedlands, Perth 6009, Australia. Needhm01@student.uwa.edu.au The prevalence of sporadic inclusion body myositis (sIBM) is variable in different populations and ethnic groups. A previous survey in Western Australia in 2000 found a prevalence of 9.3 per million population. We have now performed a follow-up survey to determine whether there has since been any change in prevalence. The current prevalence was found to be 14.9 per million population, with a prevalence of 51.3 per million population in people over 50 years of age. This is the highest reported prevalence of sIBM and correlates with a high frequency of HLA-DR3 and the 8.1 major histocompatibility complex ancestral haplotype in this population. Review of a combined cohort of 57 sIBM cases from three Australian centres revealed a high rate of initial misdiagnosis and a mean time to diagnosis of 5.2 years, which suggests that even the latest prevalence figure may be an underestimate, and emphasising the need to increase the level of awareness of the condition among the medical community. Publication Types: Research Support, Non-U.S. Gov't PMID: 18815046 [PubMed - indexed for MEDLINE]

60: J Neurol. 2008 Jul;255 Suppl 3:12-6. IVIg in other autoimmune neurological disorders: current status and future prospects. Dalakas M. Neuromuscular Division, Dept. of Neurology, 900 Walnut St., 2nd Floor, Philadelphia, PA 19107, USA. marinos.dalakas@jefferson.edu A number of autoimmune disorders have been identified in which IVIg treatment may be beneficial. Evidence for the use of IVIg in inflammatory myopathies comes from controlled trials in dermatomyositis (DM) and sporadic-inclusion body myositis (s-IBM). In DM, muscle strength was increased and neuromuscular scores and skin rashes improved. Results for s-IBM have not been as encouraging as those observed for DM. Subsequently, IVIg should be recommended as a second-line therapy in DM and used for life-threatening dysphagia in s-IBM. Using an animal model of experimental autoimmune myasthenia gravis (MG), studies also indicate that IVIg can significantly improve clinical symptoms and affect pathogenic idiotypic antibodies. In human MG, studies indicate that IVIg exhibited equal efficacy compared to plasmapheresis. IVIg can therefore be recommended for use in an MG crisis or in lieu of plasmapheresis. The role of IVIg in the chronic management of MG has not been studied. IVIg has also been investigated in autoimmune CNS disorders. In a controlled study in patients with stiff person syndrome IVIg was effective, with improvements in the distribution of stiffness index and heightened sensitivity scores. For neurodegenerative diseases such as Alzheimer's disease, post-polio syndrome, pain, fibrosis, and autoimmune sleep disorders, some early promising results for the use of IVIg are emerging, but remain to be fully investigated. In conclusion, IVIg appears to be an effective treatment for a number of autoimmune disorders, however, optimal dosing and pharmacogenetic studies are necessary. Publication Types: Review PMID: 18685921 [PubMed - indexed for MEDLINE]

61: J Neurol Neurosurg Psychiatry. 2008 Oct;79(10):1186-9. TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia. Weihl CC, Temiz P, Miller SE, Watts G, Smith C, Forman M, Hanson PI, Kimonis V, Pestronk A. Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA. weihlc@neuro.wustl.edu TAR DNA binding protein-43 (TDP-43) is found in ubiquitinated inclusions (UBIs) in some frontotemporal dementias (FTD-U). One form of FTD-U, due to mutations in the valosin containing protein (VCP) gene, occurs with an inclusion body myopathy (IBMPFD). Since IBMPFD brain has TDP-43 in UBIs, we looked for TDP-43 inclusions in IBMPFD muscle. In normal muscle, TDP-43 is present in nuclei. In IBMPFD muscle, TDP-43 is additionally present as large inclusions within UBIs in muscle cytoplasm. TDP-43 inclusions were also found in 78% of sporadic inclusion body myositis (sIBM) muscles. In IBMPFD and sIBM muscle, TDP-43 migrated with an additional band on immunoblot similar to that reported in FTD-U brains. This study adds sIBM and hereditary inclusion body myopathies to the growing list of TDP-43 positive inclusion diseases. PMID: 18796596 [PubMed - indexed for MEDLINE]

62: J Histochem Cytochem. 2009 Jan;57(1):29-39. Epub 2008 Sep 15. Secreted protein acidic and rich in cysteine (SPARC) in human skeletal muscle. Jørgensen LH, Petersson SJ, Sellathurai J, Andersen DC, Thayssen S, Sant DJ, Jensen CH, Schrøder HD. Institute of Clinical Research (LHJ, SJP, JS, HDS), Odense, Denmark. Secreted protein acidic and rich in cysteine (SPARC)/osteonectin is expressed in different tissues during remodeling and repair, suggesting a function in regeneration. Several gene expression studies indicated that SPARC was expressed in response to muscle damage. Studies on myoblasts further indicated a function of SPARC in skeletal muscle. We therefore found it of interest to study SPARC expression in human skeletal muscle during development and in biopsies from Duchenne and Becker muscular dystrophy and congenital muscular dystrophy, congenital myopathy, inclusion body myositis, and polymyositis patients to analyze SPARC expression in a selected range of inherited and idiopathic muscle wasting diseases. SPARC-positive cells were observed both in fetal and neonatal muscle, and in addition, fetal myofibers were observed to express SPARC at the age of 15-16 weeks. SPARC protein was detected in the majority of analyzed muscle biopsies (23 of 24), mainly in mononuclear cells of which few were pax7 positive. Myotubes and regenerating myofibers also expressed SPARC. The expression-degree seemed to reflect the severity of the lesion. In accordance with these in vivo findings, primary human-derived satellite cells were found to express SPARC both during proliferation and differentiation in vitro. In conclusion, this study shows SPARC expression both during muscle development and in regenerating muscle. The expression is detected both in satellite cells/myoblasts and in myotubes and muscle fibers, indicating a role for SPARC in the skeletal muscle compartment. Publication Types: Research Support, Non-U.S. Gov't PMID: 18796407 [PubMed - indexed for MEDLINE]

63: Mol Neurobiol. 2008 Oct;38(2):178-98. Epub 2008 Sep 5. Inclusion body myositis: a view from the Caenorhabditis elegans muscle. Rebolledo DL, Minniti AN, Grez PM, Fadic R, Kohn R, Inestrosa NC. Centro de Envejecimiento y Regeneración (CARE), Centro de Regulación Celular y Patología Joaquín V. Luco, MIFAB, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Alameda 340, Santiago, Chile. Inclusion body myositis (IBM) is the most common myopathy in people over 50 years of age. It involves an inflammatory process that, paradoxically, does not respond to anti-inflammatory drugs. A key feature of IBM is the presence of amyloid-beta-peptide aggregates called amyloid deposits, which are also characteristic of Alzheimer's disease. The use of animals that mimic at least some characteristics of a disease has become very important in the quest to elucidate the molecular mechanisms underlying this and other pathogeneses. Although there are some transgenic mouse strains that recreate some aspects of IBM, in this review, we hypothesize that the great degree of similarity between nematode and human genes known to be involved in IBM as well as the considerable conservation of biological mechanisms across species is an important feature that must be taken into consideration when deciding on the use of this nematode as a model. Straightforward laboratory techniques (culture, transformation, gene knockdown, genetic screenings, etc.) as well as anatomical, physiological, and behavioral characteristics add to the value of this model. In the present work, we review evidence that supports the use of Caenorhabditis elegans as a biological model for IBM. Publication Types: Review PMID: 18773311 [PubMed - indexed for MEDLINE]

64: Curr Opin Neurol. 2008 Oct;21(5):596-600. Recent advances in distal myopathy with rimmed vacuoles (DMRV) or hIBM: treatment perspectives. Malicdan MC, Noguchi S, Nishino I. National Institute of Neurosciences, National Center of Neurology and Psychiatry, Tokyo, Japan. PURPOSE OF REVIEW: Distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy is an adult-onset autosomal recessive, slowly progressive and debilitating myopathy due to mutations in the gene that regulates the synthesis of sialic acid. This review aims to update our knowledge of this myopathy and to review studies about pathomechanism and therapeutic strategies. RECENT FINDINGS: Owing to the mutated gene, it was expected that the pathomechanism of this myopathy would be based on hyposialylation, a highly controversial phenomenon. This concept has been supported by findings in two recently generated animal models. In addition, the intracellular amyloid-beta accumulation in a distal myopathy with rimmed vacuole mouse model is relevant to similar findings in patients. SUMMARY: Clarifying the role of hyposialylation in distal myopathy with rimmed vacuole/hereditary inclusion body myopathy could potentially lead to a therapeutic strategy for this progressive myopathy. In addition, strategies aimed at preventing amyloid-beta deposition or enhancing its clearance could also be beneficial, as this epiphenomenon is now known to occur early in the course of the disease. Publication Types: Research Support, Non-U.S. Gov't Review PMID: 18769255 [PubMed - indexed for MEDLINE]

65: Hum Mol Genet. 2008 Dec 1;17(23):3663-74. Epub 2008 Aug 23. Mitochondrial processes are impaired in hereditary inclusion body myopathy. Eisenberg I, Novershtern N, Itzhaki Z, Becker-Cohen M, Sadeh M, Willems PH, Friedman N, Koopman WJ, Mitrani-Rosenbaum S. Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel. Hereditary inclusion body myopathy (HIBM) is an adult onset, slowly progressive distal and proximal myopathy. Although the causing gene, GNE, encodes for a key enzyme in the biosynthesis of sialic acid, its primary function in HIBM remains unknown. To elucidate the pathological mechanisms leading from the mutated GNE to the HIBM phenotype, we attempted to identify and characterize early occurring downstream events by analyzing the genomic expression patterns of muscle specimens from 10 HIBM patients carrying the M712T Persian Jewish founder mutation and presenting mild histological changes, compared with 10 healthy matched control individuals, using GeneChip expression microarrays. When analyzing the expression profile data sets by the intersection of three statistic methods (Student's t-test, TNoM and Info score), we found that the HIBM-specific transcriptome consists of 374 differentially expressed genes. The specificity of the HIBM transcriptome was assessed by the minimal transcript overlap found between HIBM and the transcriptome of nine additional muscle disorders including adult onset limb girdle myopathies, inflammatory myopathies and early onset conditions. A strikingly high proportion (18.6%) of the overall differentially expressed mRNAs of known function were found to encode for proteins implicated in various mitochondrial processes, revealing mitochondria pathways dysregulation. Mitochondrial morphological analysis by video-rate confocal microscopy showed a high degree of mitochondrial branching in cells of HIBM patients. The subtle involvement of mitochondrial processes identified in HIBM reveals an unexpected facet of HIBM pathophysiology which could at least partially explain the slow evolution of this disorder and give new insights in the disease mechanism. Publication Types: Research Support, Non-U.S. Gov't PMID: 18723858 [PubMed - indexed for MEDLINE]

66: Postgrad Med J. 2008 Jul;84(993):382-4. What to do ... When the treatment does not work: polymyositis. Mastaglia FL. Centre for Neuromuscular and Neurological Disorders. University of Western Australia, Queen Elizabeth II Medical Centre, Nedlands 6009, Australia. flmast@cyllene.uwa.edu.au Publication Types: Review PMID: 18716019 [PubMed - indexed for MEDLINE]

67: J ECT. 2009 Jun;25(2):125-8. Electroconvulsive treatment for a patient with psychotic depression and inclusion body myositis. Ntatsaki E, D'Mello O, Lewis J, Underwood BR, Smith M, Head L. Department of Old Age Psychiatry, Redwald Unit, St Clement's Hospital, Ipswich, UK. ntatsakie@doctors.org.uk A patient with inclusion body myositis (IBM) and psychotic depression required inpatient psychiatric care. The patient's mental and physical health continued to deteriorate despite maximal treatment with medication. After careful consideration and psychiatric, neurological, and anesthetic review, electroconvulsive therapy was initiated. We present, what is to our knowledge, the first documented case of a patient with inclusion body myositis requiring a course of electroconvulsive therapy for psychotic depression. PMID: 18708945 [PubMed - in process]

68: Med Hypotheses. 2008 Nov;71(5):788-801. Epub 2008 Aug 13. Paleoneurology: neurodegenerative diseases are age-related diseases of specific brain regions recently developed by Homo sapiens. Ghika J. CHCVs, Division of Neurology, Avenue Grand Champsec 80, CH-1951 Sion (VS), Switzerland. joseph.ghika@rsv-gnw.ch Bipedal locomotion and fine motility of hand and larynx of humans introduced musculoskeletal adaptations, new pyramidal, corticostriatal, corticobulbar, nigrostriatal, and cerebellar pathways and expansions of prefrontal, cingular, parieto-temporal and occipital cortices with derived new brain capabilities. All selectively degenerate in aged homo sapiens following 16 syndromic presentations: (1) Parkinsonism: nigrostriatal control for fast automatic movements of hand, larynx, bipedal posture and gait ("simian gait and hand"). (2) Frontal (highest level) gait disorders (lower body parkinsonism, gait apraxia, retropulsion): prefrontostriatal executive control of bipedal locomotion. (3) ataxia: new synergistic coordination of bipedal gait and fine motility. (4) Dyskinesias (chorea, dystonia, tremor...): intrusions of simian basal ganglia motor subroutines. (5) motoneuron diseases: new proximo-distal and bulbar motoneurones, preserving older ones (oculomotor, abdominal...). (6) Archaic reflexes: prefrontal disinhibition of old mother/tree-climbing-oriented reflexes (sucking, grasping, Babinski/triple retraction, gegenhalten), group alarms (laughter, crying, yawning, grunting...) or grooming (tremor=scratching). (7) Dysautonomia: contextual regulation (orthostatism...). (8) REM sleep disorders of new cortical functions. (9) Corticobasal syndrome: melokinetic control of hand prehension-manipulation and language (retrocession to simian patterns). (10) Frontal/temporal lobe degeneration: medial-orbitofrontal behavioural variant: self monitoring of internal needs and social context: apathy, loss of personal hygiene, stereotypia, disinhibition, loss of concern for consequences of acts, social rules, danger and empathy; dorsolateral executive variant: inadequacy to the context of action (goal, environmental changes...); progressive non-fluent aphasia: executive and praxic processing of speech; temporal variant: abstract concepts for speech, gestures and vision (semantic dementia, progressive nonfluent aphasia) (11) Temporomesial-limbic-paralimbic-associative cortical dementias (Alzheimer's disease, Lewy body, progressive amnesia): processing of explicit cognition: amnesic syndrome, processing of hand, larynx and eye: disorientation, ideomotor apraxia, agnosia, visuospatial processing, transcortical aphasia. (12) Focal posterior atrophy (Benson, progressive apraxia): visuomotor processing of what and where. (13) Macular degeneration: retinal "spot" for explicit symbols. (14) "Psychiatric syndromes": metacognition, self monitoring and regulation of hierarchical processing of metacognition: hallucinations, delusions, magic and mystic logic, delusions, confabulations; drive: impulsivity, obsessive-compulsive disorders, mental automatisms; social interactions: theory of mind, autism, Asperger. (15) Mood disorders: control on emotions: anxio-depressive and bipolar disorders, moria, emotional lability. (16) Musculoskeletal: inclusion body myositis: muscles for bipedal gait and fine motility. Paget's disease: bones for bipedal gait and cranium. Understanding of the genetic mechanisms underlying the evolution of these recent human brain regions and paleoneurology my be the key to the focal, asymmetrical or systemic character of neurodegeneration, the pathologic heterogeneity/overlap of syndromic presentations associating gait, hand, language, cognition, mood and behaviour disorders. PMID: 18703290 [PubMed - indexed for MEDLINE]

69: Ultrastruct Pathol. 2008 Jul-Aug;32(4):123-6. Tubuloreticular structures in different types of myositis: implications for pathogenesis. Bronner IM, Hoogendijk JE, Veldman H, Ramkema M, van den Bergh Weerman MA, Rozemuller AJ, de Visser M. Department of Neurology, Flevoziekenhuis, Almere, The Netherlands. In dermatomyositis (DM) there is strong histopathological evidence of a microvascular pathogenesis, including endothelial microtubular inclusions. In nonspecific myositis, perimysial and perivascular infiltrates in the muscle biopsy similar to DM are found. Microtubular inclusions in endothelial cells were systematically searched for and found in 4 of the 20 muscle biopsies of nonspecific myositis patients (20%). Three had a CTD (SLE, scleroderma, and Sjogren syndrome). Ten patients with DM and 5 patients with sporadic inclusion body myositis served as positive and negative controls, respectively. Publication Types: Research Support, Non-U.S. Gov't PMID: 18696397 [PubMed - indexed for MEDLINE]

70: Arq Neuropsiquiatr. 2008 Jun;66(2B):428-30. Inclusion body myositis and HIV infection. de Freitas MR, Neves MA, Nascimento OJ, de Mello MP, Botelho JP, Chimelli L. Neurology Department, Fluminense Federal University, Niteroi, RJ, Brazil. mgdefreitas@hotmail.com PMID: 18641890 [PubMed - in process] 71: Physiol Genomics. 2008 Sep 17;35(1):106-15. Epub 2008 Jul 15. Muscle weakness correlates with muscle atrophy and precedes the development of inclusion body or rimmed vacuoles in the mouse model of DMRV/hIBM. Malicdan MC, Noguchi S, Hayashi YK, Nishino I. Department of Neuromuscular Research and Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan. Distal myopathy with rimmed vacuoles (DMRV), also called hereditary inclusion body myopathy (hIBM), is characterized clinically by weakness and atrophy that initially involves the distal muscles and pathologically by the presence of rimmed vacuoles (RVs) or intracellular protein deposits in myofibers. It is caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene that is important in sialic acid synthesis. Recently, we generated a mouse model (Gne(-/-)hGNED176VTg) that exhibits muscle weakness and pathological changes similar to DMRV patients. To gain better understanding of the pathomechanism of DMRV, we determined temporal changes in the overall motor performance of this model mouse for DMRV in correlation with the structure and function of isolated skeletal muscles and muscle pathology. These DMRV mice exhibited muscle weakness, decreased whole muscle mass and cross-sectional area (CSA), and reduced contractile power in an age-related manner. Single-fiber CSA further supported the finding of muscle atrophy that involved both type I and type II fibers. These results suggest that atrophy is highly correlated with reduced production of force at young age, both in vivo and ex vivo, thereby implicating the important role of atrophy in the pathomechanism of DMRV. In older age, and particularly in gastrocnemius muscles, RVs and intracellular inclusions were seen in type IIA fibers, further aggravating reduction of force and specific increase in twitch-tetanus ratio. Publication Types: Research Support, Non-U.S. Gov't PMID: 18628337 [PubMed - indexed for MEDLINE]

72: Ann Rheum Dis. 2009 Jun;68(6):836-43. Epub 2008 Jul 15. Increased serum levels of B cell activating factor (BAFF) in subsets of patients with idiopathic inflammatory myopathies. Krystufková O, Vallerskog T, Helmers SB, Mann H, Putová I, Belácek J, Malmström V, Trollmo C, Vencovsky J, Lundberg IE. Institute of Rheumatology, Prague, Czech Republic. krys@revma.cz OBJECTIVE: To investigate serum levels of B cell activating factor (BAFF) in patients with myositis and correlate these to autoantibody profile, clinical phenotype and treatment. METHODS: BAFF levels in sera from 49 patients with dermatomyositis, 44 with polymyositis, 6 with inclusion body myositis and 30 matched controls were measured by ELISA. Specific autoantibodies were detected by line blot and western blot assays. RESULTS: Serum levels of BAFF were significantly higher in patients compared to healthy controls (p = 0.003). Patients with anti-Jo-1 autoantibodies had higher BAFF levels than control individuals ( p less than0.003) or patients without any specific autoantibodies ( p less than0.05). Patients with dermatomyositis had higher BAFF levels compared to polymyositis ( p less than0.05). Patients with interstitial lung disease (ILD) had higher BAFF levels than patients without ILD ( p less than0.05) or controls ( p less than0.01) but this could be explained by presence of anti-Jo-1 autoantibodies. BAFF levels correlated with serum creatine kinase (CK) (rs = 0.365, p = 0.0005) but not with C-reactive protein (CRP) levels. A negative correlation of BAFF levels with glucocorticoid daily dose for all patients (rs = -0.292, p = 0.003) and with cumulative glucocorticoid doses in early myositis cases (rs = -0.659, p less than0.001) was recorded. CONCLUSION: Our finding of elevated serum levels of BAFF in patients with myositis with described phenotypes together with the correlations between levels of BAFF and CK and a negative correlation with dose of glucocorticoids, indicate that BAFF could be a potential therapeutic target in such cases. Publication Types: Research Support, Non-U.S. Gov't PMID: 18628284 [PubMed - indexed for MEDLINE]

73: Ann Neurol. 2008 Jul;64(1):1-3. Comment on: Ann Neurol. 2008 Jul;64(1):15-24. Interplay between inflammation and degeneration: using inclusion body myositis to study "neuroinflammation". Dalakas MC. Publication Types: Comment Editorial PMID: 18626972 [PubMed - indexed for MEDLINE]

74: Rheumatology (Oxford). 2008 Sep;47(9):1433-5. Epub 2008 Jul 8. Sarcoidosis and inclusion body myositis. Vattemi G, Tonin P, Marini M, Guadagnin ML, Dal Pra B, Simonati A, Filosto M, Tomelleri G. Publication Types: Case Reports Letter PMID: 18611922 [PubMed - indexed for MEDLINE]

75: Free Radic Biol Med. 2008 Sep 15;45(6):773-9. Epub 2008 Jun 14. In inclusion-body myositis muscle fibers Parkinson-associated DJ-1 is increased and oxidized. Terracciano C, Nogalska A, Engel WK, Wojcik S, Askanas V. Department of Neurology, USC Neuromuscular Center, University of Southern California Keck School of Medicine, Good Samaritan Hospital, 637 S. Lucas Avenue, Los Angeles, CA 90017-1912, USA. Sporadic inclusion-body myositis (s-IBM) is the most common muscle disease of older persons. The muscle-fiber molecular phenotype exhibits similarities to both Alzheimer-disease (AD) and Parkinson-disease (PD) brains, including accumulations of amyloid-beta, phosphorylated tau, alpha-synuclein, and parkin, as well as evidence of oxidative stress and mitochondrial abnormalities. Early-onset autosomal-recessive PD can be caused by mutations in the DJ-1 gene, leading to its inactivation. DJ-1 has antioxidative and mitochondrial-protective properties. In AD and PD brains, DJ-1 is increased and oxidized. We studied DJ-1 in 17 s-IBM and 18 disease-control and normal muscle biopsies by: (1) immunoblots of muscle homogenates and mitochondrial fractions; (2) real-time PCR; (3) oxyblots evaluating DJ-1 oxidation; (4) light- and electron-microscopic immunocytochemistry. Compared to controls, in s-IBM muscle fibers DJ-1 was: (a) increased in the soluble fraction, monomer 2-fold (P = 0.01), and dimer 2.8-fold (P = 0.004); (b) increased in the mitochondrial fraction; (c) highly oxidized; and (d) aggregated in about 15% of the abnormal muscle fibers. DJ-1 mRNA was increased 3.5-fold (P = 0.034). Accordingly, DJ-1 might play a role in human muscle disease, and thus not be limited to human CNS degenerations. In s-IBM muscle fibers, DJ-1 could be protecting these fibers against oxidative stress, including protection of mitochondria. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PMID: 18601999 [PubMed - indexed for MEDLINE]

76: J Neuropathol Exp Neurol. 2008 Jul;67(7):711-9. Endothelial and myogenic differentiation of hematopoietic progenitor cells in inflammatory myopathies. Hollemann D, Budka H, Löscher WN, Yanagida G, Fischer MB, Wanschitz JV. Department of Blood Group Serology and Transfusion Medicine, Institute of Neurology, Medical University Vienna, Austria. Incorporation of circulating hematopoietic progenitor cells (HPCs) into damaged skeletal muscle has been proposed as a novel mechanism of tissue repair complementary to satellite cell-dependent regeneration. We studied the occurrence and myoendothelial differentiation of HPCs in muscle of patients with inflammatory myopathies. Muscle biopsies from untreated patients with dermatomyositis, polymyositis, inclusion body myositis, and controls were investigated for the expression of endothelial (CD31, von Willebrand factor, vascular endothelial growth factor receptor 2), hematopoietic (CD34, CD133, CD45), and myogenic (Pax7, MyoD) markers by immunohistochemistry and reverse-transcriptase-polymerase chain reaction. Confocal laser scanning microscopy was used to visualize coexpression of CD34, CD133, von Willebrand factor, or Pax7 on individual cells. Morphometric analysis revealed significantly increased numbers of CD133 cells per square millimeter in polymyositis and inclusion body myositis compared with controls ( p less than 0.001); this correlated with the density of CD45 infiltrates ( p less than 0.001). By confocal laser scanning microscopy, we detected several mononuclear cells that coexpressed either CD34/von Willebrand factor or CD133/Pax7 with or without CD34 reactivity, indicating endothelial or myogenic commitment of some HPCs in skeletal muscle. Rarely, CD133/CD34/Pax7 cells seemed to occupy satellite cell niches or to incorporate into preexisting myofibers. Our findings suggest that circulating HPCs colonize skeletal muscle in inflammatory conditions and provide evidence for in situ myoendothelial differentiation of some of these cells. Publication Types: Research Support, Non-U.S. Gov't PMID: 18596542 [PubMed - indexed for MEDLINE]

77: Neuromuscul Disord. 2008 Jun;18(6):493-500. Epub 2008 Jun 4. Distal inflammatory myopathy: unusual presentation of polymyositis or new entity? Dimitri D, Dubourg O, Maisonobe T, Fournier E, Ranque B, Laforêt P, Mussini JM, Pagnoux C, Béhin A, Papo T, Benveniste O, Eymard B, Herson S. Centre de Référence des Maladies Neuromusculaires Garches-Necker-Mondor-Hendaye, APHP, INSERM U841, CHU Henri Mondor, 51 boulevard du Maréchal de Lattre de Tassigny, 94010 Créteil, France. New classification of idiopathic inflammatory myopathy (IIM) defined three major entities, polymyositis (PM), dermatomyositis (DM) and sporadic inclusion body myositis (s-IBM). We report the clinical, electrophysiological and pathological characteristics of three patients with a rare form of IIM not fulfilling the diagnostic criteria for any of these three major entities. The three patients presented with a subacute, distal asymmetrical weakness in upper limbs. Muscle biopsy showed an active myositis, with necrosis and regeneration, T cell infiltrates with invasion of non-necrotic fibers, without rimmed vacuoles, and diffuse major histocompatibility complex-I (MHC-I) immunostaining in muscle fibers. All patients responded to immunosuppressive agents. Seven others cases were identified in the literature. It is important to recognize this atypical presentation as it seems to respond to immunosuppressive agents. Publication Types: Research Support, Non-U.S. Gov't PMID: 18534849 [PubMed - indexed for MEDLINE]

78: J Clin Neuromuscul Dis. 2008 Jun;9(4):397-401. Hypogonadism is common in men with myopathies. Al-Harbi TM, Bainbridge LJ, McQueen MJ, Tarnopolsky MA. Division of Neurology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. BACKGROUND: Hypogonadism has been described in patients with myotonic muscular dystrophy type 1 but has not been evaluated in other myopathies. METHODS: We measured total and free serum testosterone levels in 59 men with myotonic muscular dystrophy type 1 (N = 12), facioscapulohumeral muscular dystrophy (N = 11), dystrophinopathy (N = 12), metabolic myopathy (N = 7), and inclusion body myositis (N = 17) and compared these with the normal reference interval. RESULTS: Thirty-two of the 59 (54%) participants had low total testosterone, 23 (39%) had low total and free values, and 5 (8%) had low free with normal total levels. There were no significant differences in the prevalence of hypogonadism between those with myotonic muscular dystrophy type 1 and the other groups even after considering age as a confounder. CONCLUSIONS: Hypogonadism is common in men with myopathies, and with the importance of testosterone in the maintenance of muscle mass, treatment of hypogonadism should be considered. Publication Types: Comparative Study PMID: 18525423 [PubMed - indexed for MEDLINE]

79: J Neuropathol Exp Neurol. 2008 Jun;67(6):624-32. The kinesin superfamily motor protein KIF4 is associated with immune cell activation in idiopathic inflammatory myopathies. Bernasconi P, Cappelletti C, Navone F, Nessi V, Baggi F, Vernos I, Romaggi S, Confalonieri P, Mora M, Morandi L, Mantegazza R. Neurology IV, Foundation Neurological Institute Carlo Besta, Department of Medical Pharmacology, Milan, Italy. pbernasconi@instituto-besta.it The idiopathic inflammatory myopathies (IIMs) dermatomyositis, polymyositis, and inclusion body myositis are characterized by myofiber degeneration and inflammation. The triggering factors of muscle autoaggression in these disorders are unknown, but infiltrating T cells may be activated locally and proliferate in situ. T-cell polarization involving reorientation of cytoskeleton and microtubule-organizing centers mediated by motor proteins may occur within inflammatory cells in the muscle. We therefore analyzed ubiquitous and neuronal kinesin superfamily (KIF) members KIF-5, dynein, and KIF4 in IIM muscle biopsies and in activated peripheral blood lymphocytes from healthy donors. Only KIF-4 was altered. Transcript levels were significantly higher in IIM muscle than in controls, and KIF4 inflammatory cells were found in IIM muscles. In polymyositis and inclusion body myositis, KIF4 cells were mainly located around individual muscle fibers, whereas in dermatomyositis, they were also near blood vessels. KIF4 cells were not specific to any immune lineage, and some were Ki67. In peripheral blood lymphocytes stimulated with mitogens, interleukin 2 or anti-CD3/CD28 antibodies, KIF4 expression was upregulated, and the protein was localized in the cytoplasm in association with lysosome-associated membrane protein 1 and perforin lysosomal vesicles. These results imply that KIF4 is associated with activated T cells, irrespective of their functional phenotype, and that it is likely involved in cytoskeletal modifications associated with in situ T-cell activation in IIM. Publication Types: Research Support, Non-U.S. Gov't PMID: 18520780 [PubMed - indexed for MEDLINE]

80: Pathol Res Pract. 2008;204(9):609-23. Epub 2008 Jun 2. Myopathology of non-infectious inflammatory myopathies - the current status. Hewer E, Goebel HH. Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland. ekkehard.hewer@usz.ch Besides the classical inflammatory myopathies (IM), dermatomyositis (DM), polymyositis, and inclusion body myositis, the much larger spectrum of IM includes focal and nodular myositis, granulomatous myositis, macrophagic myofasciitis, graft vs. host myositis, eosinophilic myositis, and other immune-associated conditions, some of them only recently described. In addition, paraneoplastic, statin-induced and critical illness myopathies have been considered immune-associated IM. Infectious, i.e., bacterial, viral, and parasitic IM are much less frequent in the northern hemisphere. In IM, muscle biopsy is an essential diagnostic procedure to initiate therapy. The myopathological spectrum encompasses disease-specific histopathological features, such as perifascicular atrophy in DM, non-necrotizing granulomas in sarcoid myopathy, autophagic vacuoles with tubulofilamentous inclusions in inclusion body myositis, rarely electron microscopic criteria, such as undulating tubules in endothelial cells of DM specimens, and, foremost, immunohistochemical findings. These latter features concern inflammatory infiltrates, the muscle parenchyma, the interstitial compartment, and the vasculature with varying involvement of each component in the different IM. Differences in immunohistochemical parameters among the IM, such as major histocompatibility complexes I and II, cytokines, cell adhesion molecules, different types of inflammatory cells, metalloproteinases, and complement factors procure a large gamut of data, the individual patterns of which characterize the myopathology of individual IM. Publication Types: Review PMID: 18514433 [PubMed - indexed for MEDLINE]

81: Brain. 2008 May;131(Pt 5):1228-40. Epub 2008 Apr 17. Comment in: Brain. 2009 Apr;132(Pt 4):e106; author reply e107. Interrelation of inflammation and APP in sIBM: IL-1 beta induces accumulation of beta-amyloid in skeletal muscle. Schmidt J, Barthel K, Wrede A, Salajegheh M, Bähr M, Dalakas MC. Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. j.schmidt@gmx.org Distinct interrelationships between inflammation and beta-amyloid-associated degeneration, the two major hallmarks of the skeletal muscle pathology in sporadic inclusion body myositis (sIBM), have remained elusive. Expression of markers relevant for these pathomechanisms were analysed in biopsies of sIBM, polymyositis (PM), dermatomyositis (DM), dystrophic and non-myopathic muscle as controls, and cultured human myotubes. By quantitative PCR, a higher upregulation was noted for the mRNA-expression of CXCL-9, CCL-3, CCL-4, IFN-gamma, TNF-alpha and IL-1 beta in sIBM muscle compared to PM, DM and controls. All inflammatory myopathies displayed overexpression of degeneration-associated markers, yet only in sIBM, expression of the mRNA of amyloid precursor protein (APP) significantly and consistently correlated with inflammation in the muscle and mRNA-levels of chemokines and IFN-gamma. Only in sIBM, immunohistochemical analysis revealed that inflammatory mediators including IL-1 beta co-localized to beta-amyloid depositions within myofibres. In human myotubes, exposure to IL-1 beta caused upregulation of APP with subsequent intracellular aggregation of beta-amyloid. Our data suggest that, in sIBM muscle, production of high amounts of pro-inflammatory mediators specifically induces beta-amyloid-associated degeneration. The observations may help to design targeted treatment strategies for chronic inflammatory disorders of the skeletal muscle. Publication Types: Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't PMID: 18420712 [PubMed - indexed for MEDLINE]

82: Arch Biochem Biophys. 2008 Jun 1;474(1):15-21. Epub 2008 Mar 26. Amyloid toxicity in skeletal myoblasts: Implications for inclusion-body myositis. Jayaraman M, Kannayiram G, Rajadas J. Bioorganic and Neurochemistry Laboratory, Central Leather Research Institute, Adyar, Chennai 600 020, India. Skeletal muscle disorder, inclusion-body myositis (IBM) has been known for accumulation of amyloid characteristic proteins in muscle. To understand the biophysical basis of IBM, the interaction of amyloid fibrils with skeletal myoblast cells (SMC) has been studied in vitro. Synthetic insulin fibrils and Abeta(25-35) fibrils were used for this investigation. From the saturation binding analysis, the calculated dissociation constant (K(d)) for insulin fibril and Abeta(25-35) fibrils were 69.37+/-11.17nM and 115.60+/-12.17nM, respectively. The fibrillar insulin comparatively has higher affinity binding to SMC than Abeta fibrils. The competitive binding studies with native insulin showed that the amount of bound insulin fibril was significantly decreased due to displacement of native insulin. However, the presence of native insulin is not altered the binding of beta-amyloid fibril. The cytotoxicity of insulin amyloid intermediates was measured. The pre-fibrillar intermediates of insulin showed significant toxicity (35%) as compared to matured fibrils. Myoblast treated with beta-amyloid fibrils showed more oxidative damage than the insulin fibril. Cell differentiating action of amyloidic insulin was assayed by creatine kinase activity. The insulin fibril treated cells differentiated more slowly compared to native insulin. However, beta-amyloid fibrils do not show cell differentiation property. These findings reinforce the hypothesis that accumulation of amyloid related proteins is significant for the pathological events that could lead to muscle degeneration and weakness in IBM. Publication Types: Research Support, Non-U.S. Gov't PMID: 18397759 [PubMed - indexed for MEDLINE]

83: Genet Test. 2008 Mar;12(1):101-9. Validation of GNE:p.M712T identification by melting curve analysis. Valles-Ayoub Y, Saechao C, Haghighatgoo A, Neshat MS, Esfandiarifard S, Pietruszka M, Darvish D. HIBM Research Group, Encino, California, USA. Hereditary inclusion body myopathy/distal myopathy with rimmed vacuoles is an adult onset autosomal recessive muscle-wasting disease common in people of Iranian-Jewish descent, due to the founder allelic variant GNE:p.M712T. High correlation of disease susceptibility with GNE:p.M712T allows its use as a molecular marker for diagnosis. In this study, we applied and validated the use of melting curve analysis using SimpleProbe technology for detection of this mutation using specimens obtained by mouthwash, buccal swab, and whole blood. The assay was then applied to 43 clinical specimens, and results were validated by additional methods. A probe spanning this mutation in exon 12 accurately discerns two Tm corresponding to its hybridization to wild-type and M712T-derived amplicons. A 10 degrees C divergence in Tm allowed rapid single-tube genotyping of reference and patient samples with 100% accuracy. Distal myopathy constitutes a large heterogeneous group of pathologies with similar physiological manifestations and little molecular markers for distinguishing subtypes. Application of SimpleProbes for detection of GNE:p.M712T on genomic DNA obtained from buccal epithelial cells allows accurate, rapid, and cost-effective identification of this allele in individuals at risk. This procedure is amenable to automated high-throughput applications and can be extended to both clinical and research applications. Publication Types: Research Support, Non-U.S. Gov't Validation Studies PMID: 18373408 [PubMed - indexed for MEDLINE]

84: Arch Biochem Biophys. 2008 May 15;473(2):172-82. Epub 2008 Mar 10. Erratum in: Arch Biochem Biophys. 2008 Nov 1;479(1):104. Genetics and aetiology of Pagetic disorders of bone. Helfrich MH, Hocking LJ. Bone and Musculoskeletal Research Programme, University of Aberdeen, Institute of Medical Sciences, School of Medicine and Dentistry, Foresterhill, Aberdeen AB25 2ZD, UK. m.helfrich@abdn.ac.uk Paget's disease of bone (PDB) is a late-onset disorder characterised by focal areas of increased bone turnover containing enlarged hyperactive osteoclasts. The disease has a strong genetic predisposition and mutations in SQSTM1 have been associated with familial and sporadic disease in up to 40% of cases. Additional genetic loci have been associated in other cases, but genes are yet to be identified. Earlier-onset conditions with similar bone pathology (familial expansile osteolysis, expansile skeletal hyperphosphatasia and early-onset PDB) are caused by mutations in TNFRSF11A (RANK). The syndrome of inclusion body myositis, Paget's disease and frontotemporal dementia is caused by mutations in VCP. Despite the increased knowledge about genes involved in PDB and related disorders, the etiology of the diseases remains puzzling. Presence of inclusion bodies appears to link Pagetic diseases mechanistically to diseases associated with presence of misfolded proteins or abnormalities in the ubiquitin-proteasomal, or autophagy pathways. Juvenile PDB, caused by osteoprotegerin deficiency, appears mechanistically distinct from the other Pagetic diseases. This review will discuss evidence from recent studies, including new animal models for Pagetic diseases. Publication Types: Research Support, Non-U.S. Gov't Review PMID: 18359282 [PubMed - indexed for MEDLINE]

85: Semin Neurol. 2008 Apr;28(2):241-9. Inflammatory myopathies: evaluation and management. Greenberg SA. Department of Neurology, Brigham and Women's Hospital, Department of Neurology, Division of Neuromuscular Disease, Brigham and Women'sHospital, and Harvard Medical School, Boston, MA 02115, USA. sagreenberg@partners.org The inflammatory myopathies, including dermatomyositis, inclusion body myositis, and polymyositis, are poorly understood autoimmune diseases affecting skeletal muscle. Dermatomyositis is a disease mainly of skin and muscle, but may affect lung and other tissues. Proximal or generalized weakness or skin rash are the typical presenting features. Inclusion body myositis has a specific clinical pattern of weakness that generally distinguishes it from other inflammatory myopathies, with prominent involvement of wrist and finger flexors, and quadriceps. Polymyositis generally presents with proximal or generalized weakness. Typical dermatomyositis muscle pathology is quite distinct, with perivascular inflammatory cells that include plasmacytoid dendritic cells, and abnormal capillaries and perimysial perifascicular myofibers. Both inclusion body myositis and polymyositis usually have infiltration into muscle of large numbers of inflammatory cells, typically surrounding and displacing, and sometimes invading, myofibers. Inclusion body myositis is refractory to corticosteroids and to several immunomodulating therapies that have been used. Dermatomyositis and polymyositis are treated with corticosteroids and a variety of agents. Osteoporosis and opportunistic infections pose a significant risk during treatment of patients. This review discusses the clinical manifestations, pathology, and treatment approaches for the inflammatory myopathies. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review PMID: 18351525 [PubMed - indexed for MEDLINE]

86: Clin Genet. 2008 Jul;74(1):54-60. Epub 2008 Mar 12. Inclusion body myopathy, Paget's disease of the bone and frontotemporal dementia: recurrence of the VCP R155H mutation in an Italian family and implications for genetic counselling. Viassolo V, Previtali SC, Schiatti E, Magnani G, Minetti C, Zara F, Grasso M, Dagna-Bricarelli F, Di Maria E. Department of Neuroscience, Ophthalmology and Genetics, University of Genova, Genova, Italy, and Laboratory of Genetics, Galliera Hospital, Genova, Italy. The acronym IBMPFD denotes a syndrome including inclusion body myopathy, Paget's disease of the bone (PDB) and frontotemporal dementia (FTD) as cardinal features, which is caused by missense mutations in the VCP gene. We studied the clinical characteristics and the histopathological features in two siblings and their mother who presented with adult-onset myopathy and presenile, rapidly progressive FTD. One sibling also showed PDB. Light and electron microscopy performed on muscle biopsies demonstrated degenerative changes with inclusion bodies and abnormal aggregates. Mutation analysis of the VCP gene on affected siblings revealed a heterozygous missense mutation (R155H) in a hot spot. This is the first Italian family with multiple individuals diagnosed as having IBMPFD and carrying the recurrent R155H mutation. The implications for genetic counselling were also discussed, with regard to the procedures that may be offered to families suffering from a multisystem disorder with high risk of cognitive decline. Publication Types: Research Support, Non-U.S. Gov't PMID: 18341608 [PubMed - indexed for MEDLINE]

87: Best Pract Res Clin Rheumatol. 2008 Mar;22(1):101-11. Juvenile Paget's disease, familial expansile osteolysis and other genetic osteolytic disorders. Ralston SH. Rheumatic Diseases Unit, Molecular Medicine Centre, University of Edinburgh, Edinburgh, UK. stuart.ralston@ed.ac.uk Several rare inherited osteolytic disorders have been described that show phenotypic overlap with Paget's disease of bone (PDB). Familial expansile osteolysis, early-onset familial PDB and expansile skeletal hyperphosphatasia are related disorders caused by mutations affecting the TNFRSF11A gene, which encodes the receptor activator of NFkappaB (RANK). The mutations result in failure of normal processing of RANK and osteoclast activation. Inactivating mutations in the TNFRSF11B gene, which encodes osteoprotegerin, cause idiopathic hyperphosphatasia which is a severe disorder that shares phenotypic similarities with PDB. The syndrome of hereditary inclusion body myopathy, PDB and frontotemporal dementia is caused by mutations in the gene encoding for valosin-containing protein which is involved in regulating degradation of ubiquitinated proteins. Anecdotal reports indicate that osteoclast inhibitors such as bisphosphonates are effective for suppressing bone turnover and improving symptoms in these disorders, although the long-term effects on clinical outcomes are unclear. Publication Types: Research Support, Non-U.S. Gov't Review PMID: 18328984 [PubMed - indexed for MEDLINE]

88: Ann Neurol. 2008 Jul;64(1):15-24. Comment in: Ann Neurol. 2008 Jul;64(1):1-3. Inflammation induces tau pathology in inclusion body myositis model via glycogen synthase kinase-3beta. Kitazawa M, Trinh DN, LaFerla FM. Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697-4545, USA. OBJECTIVE: Inclusion body myositis (IBM) is an inflammatory muscle disease, although the role of inflammation remains to be elucidated. Here, we address the mechanisms by which inflammation modulates Abeta and tau, two hallmark features of this disease. METHODS: A transgenic mouse model of IBM was utilized in which acute and chronic inflammation was induced via lipopolysaccharide. The effects of inflammation were assessed by analyzing the myopathological and the behavioral phenotype. Human IBM skeletal muscle biopsies were investigated to determine concordance with data from the animal model. RESULTS: Both acute and chronic lipopolysaccharide exposure augmented infiltration by CD8(+) cytotoxic T cells and increased amyloid precursor protein steady-state levels in skeletal muscle, whereas increased Abeta generation was observed only in chronically treated mice. Both acute and chronic inflammation enhanced tau phosphorylation in skeletal muscle. The mechanism underlying this effect was mediated by the tau kinase, glycogen synthase kinase-3beta (GSK-3beta). Suppression of GSK-3beta activity using either a specific inhibitor or lithium chloride significantly reduced tau phosphorylation and partially rescued motor impairment. In human IBM muscle, GSK-3beta and phospho-tau were colocalized, further supporting the pathogenic role of GSK-3beta in this disease. Using C2C12 myoblast cultures, we found that GSK-3beta was activated by proinflammatory cytokines (interleukin-1beta, interleukin-6, tumor necrosis factor-alpha), leading to enhanced tau phosphorylation. INTERPRETATION: Our results identify a molecular mechanism by which proinflammatory stimuli affect tau pathology via the GSK-3beta signaling pathway in skeletal muscle. Publication Types: Research Support, N.I.H., Extramural PMID: 18318434 [PubMed - indexed for MEDLINE]

89: Ann Rheum Dis. 2008 Dec;67(12):1670-7. Epub 2008 Feb 13. A high incidence of disease flares in an open pilot study of infliximab in patients with refractory inflammatory myopathies. Dastmalchi M, Grundtman C, Alexanderson H, Mavragani CP, Einarsdottir H, Helmers SB, Elvin K, Crow MK, Nennesmo I, Lundberg IE. Rheumatology, Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Solna, SE-171 76 Stockholm, Sweden. maryam.dastmalchi@karolinska.se OBJECTIVE: To investigate the effect of the tumour necrosis factor (TNF) blocking agent infliximab in patients with treatment-resistant inflammatory myopathies. METHODS: A total of 13 patients with refractory polymyositis (PM), dermatomyositis (DM), or inclusion body myositis (IBM) were treated with 4 infliximab infusions (5 mg/kg body weight) over 14 weeks. Outcome measures included myositis disease activity score with improvement defined according to The International Myositis Assessment and Clinical Studies Group (IMACS), and MRI. Repeated muscles biopsies were investigated for cellular infiltrates, major histocompatibility complex (MHC) class I and II, TNF, interleukin (IL)1alpha, IL6, high mobility group box chromosomal protein 1 (HMGB-1), interferon gamma (IFNgamma), myxovirus resistance protein A (MxA) and membrane attack complex (MAC) expression. Type I IFN activity was analysed in sera. RESULTS: Nine patients completed the study. Three patients discontinued due to adverse events and one due to a discovered malignancy. Three of the completers improved by >or=20% in three or more variables of the disease activity core set, four were unchanged and two worsened >or=30%. No patient improved in muscle strength by manual muscle test. At baseline, two completers had signs of muscle inflammation by MRI, and five at follow-up. T lymphocytes, macrophages, cytokine expression and MAC deposition in muscle biopsies were still evident after treatment. Type I IFN activity was increased after treatment. CONCLUSIONS: Infliximab treatment was not effective in refractory inflammatory myopathies. In view of radiological and clinical worsening, and activation of the type I IFN system in several cases, infliximab is not an alternative treatment in patients with treatment-resistant myositis. Publication Types: Clinical Trial Research Support, Non-U.S. Gov't PMID: 18272672 [PubMed - indexed for MEDLINE]

90: PLoS One. 2008 Feb 13;3(2):e1609. The ER-bound RING finger protein 5 (RNF5/RMA1) causes degenerative myopathy in transgenic mice and is deregulated in inclusion body myositis. Delaunay A, Bromberg KD, Hayashi Y, Mirabella M, Burch D, Kirkwood B, Serra C, Malicdan MC, Mizisin AP, Morosetti R, Broccolini A, Guo LT, Jones SN, Lira SA, Puri PL, Shelton GD, Ronai Z. Signal Transduction, The Burnham Institute for Medical Research, La Jolla, California, USA. Growing evidence supports the importance of ubiquitin ligases in the pathogenesis of muscular disorders, although underlying mechanisms remain largely elusive. Here we show that the expression of RNF5 (aka RMA1), an ER-anchored RING finger E3 ligase implicated in muscle organization and in recognition and processing of malfolded proteins, is elevated and mislocalized to cytoplasmic aggregates in biopsies from patients suffering from sporadic-Inclusion Body Myositis (sIBM). Consistent with these findings, an animal model for hereditary IBM (hIBM), but not their control littermates, revealed deregulated expression of RNF5. Further studies for the role of RNF5 in the pathogenesis of s-IBM and more generally in muscle physiology were performed using RNF5 transgenic and KO animals. Transgenic mice carrying inducible expression of RNF5, under control of beta-actin or muscle specific promoter, exhibit an early onset of muscle wasting, muscle degeneration and extensive fiber regeneration. Prolonged expression of RNF5 in the muscle also results in the formation of fibers containing congophilic material, blue-rimmed vacuoles and inclusion bodies. These phenotypes were associated with altered expression and activity of ER chaperones, characteristic of myodegenerative diseases such as s-IBM. Conversely, muscle regeneration and induction of ER stress markers were delayed in RNF5 KO mice subjected to cardiotoxin treatment. While supporting a role for RNF5 Tg mice as model for s-IBM, our study also establishes the importance of RNF5 in muscle physiology and its deregulation in ER stress associated muscular disorders. Publication Types: Research Support, N.I.H., Extramural PMID: 18270596 [PubMed - indexed for MEDLINE]

91: J Neurol Neurosurg Psychiatry. 2008 Jun;79(6):731-3. Epub 2008 Feb 12. Oculopharyngeal myopathy with inflammation and calcinosis: an unusual phenotype. Jenkins T, Al-Sarraj S, Rose M. Department of Neurology, Kings College Hospital, Denmark Hill, London SE5 9RS, UK. The case is reported of a patient with progressive proximal and distal weakness, dysphagia, respiratory weakness, calcifications, ptosis and ophthalmoparesis with inflammation, rimmed vacuoles and positive amyloid and ubiquitin on muscle biopsy. The histopathological features fit best with inclusion body myositis, but ophthalmoparesis and ptosis have not previously been described. The clinical phenotype fits best with hereditary inclusion body myopathy or distal-oculopharyngeal muscular dystrophy, but the degree of inflammation seen is unusual. None of these are associated with calcinosis. Publication Types: Case Reports PMID: 18270238 [PubMed - indexed for MEDLINE]

92: J Neurol Neurosurg Psychiatry. 2008 Sep;79(9):1056-60. Epub 2008 Feb 7. Sporadic inclusion body myositis: phenotypic variability and influence of HLA-DR3 in a cohort of 57 Australian cases. Needham M, James I, Corbett A, Day T, Christiansen F, Phillips B, Mastaglia FL. Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australian Neuromuscular Research Institute (ANRI), Queen Elizabeth II Medical Centre, Nedlands, Perth 6009, WA, Australia. needhm01@student.uwa.edu.au BACKGROUND AND AIMS: There have been few studies of the variability in the clinical phenotype in sporadic inclusion body myositis (sIBM) and it is not known whether the human leucocyte antigen (HLA) haplotype influences the phenotype and course of the disease. We studied a large cohort of patients with sIBM in order to determine the degree of phenotypic variability and different modes of presentation, as well as the influence of HLA haplotypes. METHOD: A cross-sectional study of 57 biopsy-proven sIBM cases from three Australian centres was performed. Patients were interviewed and examined by a single investigator, and had HLA typing and autoantibody studies. RESULTS: Although the initial symptoms in the majority of cases were attributable to quadriceps weakness (79%), a proportion of patients presented due to finger weakness (12%), foot drop (7%) or dysphagia (1.8%). Although the majority had the classic combination of quadriceps and forearm muscle involvement, some patients had predominantly forearm weakness with sparing of the quadriceps, or severe involvement of the anterior tibial muscles. Asymmetrical involvement was common (82%), particularly of the forearm muscles, with the non-dominant side being more severely affected in most cases. Carriage of the HLA-DRB1*0301 (DR3) allele was associated with lower quadriceps muscle strength and a more rapid decline in strength. CONCLUSIONS: The findings emphasise the variability in the mode of presentation, patterns of muscle involvement and clinical course of sIBM in this population, and indicate that the HLA-DRB1*0301 (DR3) allele may influence the rate of progression as well as susceptibility to the disease. Publication Types: Research Support, Non-U.S. Gov't PMID: 18258695 [PubMed - indexed for MEDLINE]

93: J Clin Neurosci. 2008 Apr;15(4):440-4. Epub 2008 Feb 6. Two-dimensional gel electrophoresis in inclusion body myositis. Hutchinson DO, Jongbloed B. Department of Neurology, Auckland Hospital, Auckland, New Zealand. dhutch@adhb.govt.nz Inclusion body myositis (IBM) is an acquired inflammatory myopathy in which a wide range of proteins is deposited within the cytoplasm of muscle fibres. To explore the possibility that this deposition occurs due to uncontrolled protein production arising from a defect at the nuclear level, we studied muscle samples from IBM and control subjects using two-dimensional gel electrophoresis. Twenty-seven gels from five controls and 24 gels from six patients with IBM were exhaustively compared using image analysis software and visual inspection. We found significant intra- and inter-subject variability in the number of protein spots on the gels. From 2272 to 4522 spots were found in different control gels, and from 2821 to 4153 spots in the IBM gels. No unique spots were identified in the IBM gels. When viewed with other work, the results of this study suggest that widespread, uncontrolled activation of genes is unlikely to be a component of the pathogenesis in IBM. PMID: 18258434 [PubMed - indexed for MEDLINE]

94: Arch Pathol Lab Med. 2008 Feb;132(2):232-8. Multiplex immunoassay analysis of cytokines in idiopathic inflammatory myopathy. Baird GS, Montine TJ. Department of Pathology, University of Washington, Harborview Medical Center, Box 359645, Seattle, WA 98104-2499, USA. geoffsbaird@gmail.com CONTEXT: Idiopathic inflammatory myopathies (IIMs), including dermatomyositis, polymyositis, and inclusion-body myositis, can be difficult to diagnose. OBJECTIVE: To determine if a multiplex immunoassay for markers of inflammation in muscle homogenates correlates with a diagnosis of IIM. DESIGN: Frozen archived muscle biopsy specimens from 30 patients with IIM and 34 patients without IIM were homogenized and analyzed for cytokine content with a multiplex microbead-based immunoassay system. Analyte concentrations were normalized to total lysate protein concentration prior to comparison. RESULTS: Two cytokines, interleukin 1ra and monocyte chemoattractant protein 1, and 1 soluble adhesion molecule, intracellular adhesion molecule 1, were found at significantly greater concentrations in muscle samples from patients with IIM. Intracellular adhesion molecule 1 levels alone were 83% sensitive and 91% specific for IIM at a cutoff of 1240 pg/mg muscle protein. CONCLUSIONS: Immunoassays for selected inflammatory markers can serve in conjunction with histopathologic analysis as sensitive and specific tools for the diagnosis of IIM. Publication Types: Research Support, Non-U.S. Gov't PMID: 18251582 [PubMed - indexed for MEDLINE]

95: Neurology. 2008 Feb 5;70(6):414-5. Comment on: Neurology. 2008 Feb 5;70(6):418-24. Polymyositis: not a unicorn or mythological beast...but maybe a duck? Kissel JT. Publication Types: Comment Editorial PMID: 18250286 [PubMed - indexed for MEDLINE]

96: Muscle Nerve. 2008 Apr;37(4):473-6. Inclusion body myositis functional rating scale: a reliable and valid measure of disease severity. Jackson CE, Barohn RJ, Gronseth G, Pandya S, Herbelin L; Muscle Study Group. Collaborators: Tawil R, Griggs R, Thornton C, Kissel J, Mendell J, Genge A, Karpati G, Jackson C, Rose M, Amato A, Barohn R, Saperstein D, McDermott MP, Pandya S, Wahlen D, King W, Venturini A, Myers D, Prisley S, Tagerman M, O'Brien M, Herbelin L, Cos L, Downing K, Plesiak R, Barefield F, Morrison C, Briemberg H, Holloway R, Peterson D, Janciuras J, Martens W, Blood C. University of Texas Health Science Center, San Antonio, TX, USA. jacksonce@uthscsa.edu We developed a disease-specific, 10-point functional rating scale for patients with inclusion body myositis (IBMFRS). The IBMFRS was utilized as a secondary outcome measure in a multicenter pilot trial of the clinical safety and tolerability of high-dose beta interferon-1a. In this trial, 28 IBM patients completed the IBMFRS at baseline and monthly for 6 months. The IBMFRS showed statistically significant correlations ( p less than 0.001) with maximal voluntary isometric contraction, manual muscle testing, handgrip dynamometry, and the amyotrophic lateral sclerosis (ALS) functional rating scale (ALSPRS). Compared to these other outcome measures, the IBMFRS was also the most sensitive measure of change over the course of the study. Publication Types: Multicenter Study Randomized Controlled Trial Validation Studies PMID: 18236463 [PubMed - indexed for MEDLINE]

97: Am J Physiol Regul Integr Comp Physiol. 2008 Mar;294(3):R829-35. Epub 2008 Jan 23. Rabbits fed cholesterol-enriched diets exhibit pathological features of inclusion body myositis. Chen X, Ghribi O, Geiger JD. Department of Pharmacology, Physiology, and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, 501 N. Columbia Road, Grand Forks, North Dakota 58203, USA. Sporadic inclusion body myositis (IBM) is the most common age-related muscle disease in humans; however, its etiology is unknown, there are few animal models for this disease, and effective treatments have not been identified. Similarities between pathological findings in Alzheimer's disease brain and IBM skeletal muscle include increased levels of amyloid precursor protein (APP) and amyloid beta-protein (Abeta). Moreover, there have been suggestions that elevated levels of free cholesterol might participate in the pathogenesis of Alzheimer's disease and IBM due, in part, to its role in Abeta generation. Here, we tested the hypothesis that rabbits fed cholesterol-enriched diets might faithfully exhibit human-like IBM pathological features. In skeletal muscle of one-third of the female rabbits fed cholesterol-enriched diet but not control diet, we found features of IBM, including vacuolated muscle fibers, increased numbers of mononuclear inflammatory cells, increased intramuscular deposition of Abeta, hyperphosphorylated tau, and increased numbers of muscle fibers immunopositive for ubiquitin. The cholesterol-enriched diet increased mRNA and protein levels of APP, increased the protein levels of betaAPP cleaving enzyme, and shifted APP processing in favor of Abeta production. Our study has demonstrated that increased ingestion of high levels of dietary cholesterol can result in pathological features that resemble IBM closely and thus may serve as an important new model with which to study this debilitating disorder. Publication Types: Research Support, N.I.H., Extramural PMID: 18216139 [PubMed - indexed for MEDLINE]

98: J Rheumatol. 2008 Mar;35(3):445-7. Epub 2008 Jan 15. Epidemiology of sporadic inclusion body myositis and polymyositis in Olmsted County, Minnesota. Wilson FC, Ytterberg SR, St Sauver JL, Reed AM. Division of Rheumatology, Mayo Clinic, College of Medicine, Rochester, Minnesota 55905, USA. wilson.floranne@mayo.edu OBJECTIVE: To determine the incidence and prevalence of sporadic inclusion body myositis (sIBM) and polymyositis (PM) in a population-based study. METHODS: Charts of patients with myositis in Olmsted County, Minnesota, USA, from 1981 to 2000 were reviewed. RESULTS: For sIBM, the age- and sex-adjusted incidence rates per 100,000 were 0.79 (95% confidence interval = 0.24-1.35), and for PM, 0.41 (95% CI 0.08-0.73). The age- and sex-adjusted prevalence rates per 100,000 were 7.06 (95% CI 0.87-13.24) for sIBM and 3.45 (95% CI 0.00-7.35) for PM. CONCLUSION: The incidence and prevalence rates for sIBM are higher than previously reported. PMID: 18203321 [PubMed - indexed for MEDLINE]

99: Neurosci Lett. 2008 Jan 31;431(2):141-5. Epub 2007 Dec 15. Casein kinase 1 alpha associates with the tau-bearing lesions of inclusion body myositis. Kannanayakal TJ, Mendell JR, Kuret J. Center for Molecular Neurobiology, Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, 1060 Carmack Road, Columbus, OH 43210, United States. Inclusion body myositis and Alzheimer's disease are age-related disorders characterized in part by the appearance of intracellular lesions composed of filamentous aggregates of the microtubule-associated protein tau. Abnormal tau phosphorylation accompanies tau aggregation and may be an upstream pathological event in both diseases. Enzymes implicated in tau hyperphosphorylation in Alzheimer's disease include members of the casein kinase 1 family of phosphotransferases, a group of structurally related protein kinases that frequently function in tandem with the ubiquitin modification system. To determine whether casein kinase 1 isoforms associate with degenerating muscle fibers of inclusion body myositis, muscle biopsy sections isolated from sporadic disease cases were subjected to double-label fluorescence immunohistochemistry using selective anti-casein kinase 1 and anti-phospho-tau antibodies. Results showed that the alpha isoform of casein kinase 1, but not the delta or epsilon isoforms, stained degenerating muscle fibers in all eight inclusion body myositis cases examined. Staining was almost exclusively localized to phospho-tau-bearing inclusions. These findings, which extend the molecular similarities between inclusion body myositis muscle and Alzheimer's disease brain, implicate casein kinase 1 alpha as one of the phosphotransferases potentially involved in tau hyperphosphorylation. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PMID: 18191026 [PubMed - indexed for MEDLINE]

100: J Neurochem. 2008 May;105(3):971-81. Epub 2007 Dec 24. Hyposialylation of neprilysin possibly affects its expression and enzymatic activity in hereditary inclusion-body myopathy muscle. Broccolini A, Gidaro T, De Cristofaro R, Morosetti R, Gliubizzi C, Ricci E, Tonali PA, Mirabella M. Department of Neuroscience, Catholic University, School of Medicine, Rome, Italy. a.broccolini@rm.unicatt.it Autosomal recessive hereditary inclusion-body myopathy (h-IBM) is caused by mutations of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene, a rate-limiting enzyme in the sialic acid metabolic pathway. Previous studies have demonstrated an abnormal sialylation of glycoproteins in h-IBM. h-IBM muscle shows the abnormal accumulation of proteins including amyloid-beta (Abeta). Neprilysin (NEP), a metallopeptidase that cleaves Abeta, is characterized by the presence of several N-glycosylation sites, and changes in these sugar moieties affect its stability and enzymatic activity. In the present study, we found that NEP is hyposialylated and its expression and enzymatic activity reduced in all h-IBM muscles analyzed. In vitro, the experimental removal of sialic acid by Vibrio Cholerae neuraminidase in cultured myotubes resulted in reduced expression of NEP. This was most likely because of a post-translational modification consisting in an abnormal sialylation of the protein that leads to its reduced stability. Moreover, treatment with Vibrio Cholerae neuraminidase was associated with an increased immunoreactivity for Abeta mainly in the form of distinct cytoplasmic foci within myotubes. We hypothesize that, in h-IBM muscle, hyposialylated NEP has a role in hampering the cellular Abeta clearing system, thus contributing to its abnormal accumulation within vulnerable fibers and possibly promoting muscle degeneration. Publication Types: Research Support, Non-U.S. Gov't PMID: 18182043 [PubMed - indexed for MEDLINE]

101: Neuromuscul Disord. 2008 Jan;18(1):6-16. Epub 2007 Dec 21. Sporadic inclusion body myositis: a continuing puzzle. Needham M, Mastaglia FL. Centre for Neuromuscular and Neurological disorders, Level 4, A Block, Australian Neuromuscular Research Institute, Queen Elizabeth II Medical Centre, University of Western Australia, Perth, WA 6009, Australia. There is now compelling evidence that sporadic inclusion body myositis (sIBM) is a muscle-specific autoimmune disease in which both T and B-cells play a part and in which both cytotoxic muscle fibre necrosis and degeneration occur. However the factors responsible for breakdown of immune tolerance and the nature of the target antigens expressed by muscle fibres remain unknown. Genetic factors are known to contribute to susceptibility, in particular MHC haplotyes which may influence antigenic presentation, and could also operate through genetic variations in muscle fibre constituents or immune effector mechanisms. Viral infection may act as a trigger mechanism, as in cases of HIV-associated sIBM. Our understanding of the mechanisms leading to the degenerative changes in muscle fibres is still incomplete. Protein misfolding and proteasomal dysfunction rather than defective transcriptional control is likely to underlie the abnormal accumulation of multiple proteins in the muscle fibre inclusions. However, aberrant transcription is thought to be the basis for the accumulation of potentially toxic mutant protein forms (e.g. UBB(+1)). The origin of the multiple clonally expanded somatic mtDNA mutations in COX-negative segments of muscle fibres remains uncertain but may be linked to the effects of oxidative stress. It is proposed that the disproportionate involvement of certain muscles in sIBM may be due to the existence of muscle group-specific transcriptomes which are differentially affected by the disease process and that the male predominance of the disease may indicate the influence of genes preferentially expressed in males. There is a need to develop better animal models of sIBM in which the relationship between the inflammatory and degenerative components of the disease as well as the gender difference in susceptibility and differential vulnerability of different muscle groups can be more critically investigated. Publication Types: Research Support, Non-U.S. Gov't Review PMID: 18160291 [PubMed - indexed for MEDLINE]

102: J Neuropathol Exp Neurol. 2008 Jan;67(1):41-9. Inclusion body myositis associated with human T-lymphotropic virus-type I infection: eleven patients from an endemic area in Japan. Matsuura E, Umehara F, Nose H, Higuchi I, Matsuoka E, Izumi K, Kubota R, Saito M, Izumo S, Arimura K, Osame M. Department of Neurology and Geriatrics, Center for Chronic Viral Diseases, Graduate School of Kagoshima University, Kagoshima, Japan. The objective of this study was to investigate the association of human T-lymphotropic virus-type I (HTLV-I) infection with sporadic inclusion body myositis in 11 patients from an endemic area in Japan. The clinical features were consistent with sporadic inclusion body myositis, and anti-HTLV-I antibodies were present in the sera of all patients. Their muscle biopsies showed the diagnostic features of inclusion body myositis, including endomysial T-cell infiltration, rimmed vacuoles, deposits of phosphorylated tau, and abnormal filaments in the nuclei and cytoplasm of the myofibers. The fibers expressed major histocompatibility complex class I antigens and were invaded by CD8 and CD4 cells. In a single human leukocyte antigen-A2-positive patient, in situ human leukocyte antigen-A*0201 / Tax11-19-pentamer staining showed pentamer-positive cells surrounding the muscle fibers. Double-immunogold silver staining and polymerase chain reaction in situ hybridization revealed that HTLV-I proviral DNA was localized on helper-inducer T cells, but not on muscle fibers. Human T-lymphotropic virus-type I proviral loads in peripheral blood mononuclear cells from each patient were similar to those in HTLV-I-associated myelopathy/tropical spastic paraparesis. This study suggests that HTLV-I infection may be one of the causes of sporadic inclusion body myositis, as has been reported in human immunodeficiency virus type-1 infection. Publication Types: Research Support, Non-U.S. Gov't PMID: 18091562 [PubMed - indexed for MEDLINE]

103: Best Pract Res Clin Rheumatol. 2007 Dec;21(6):1051-70. Diagnostic uncertainty in the inflammatory myopathies. Verity MA. David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA. mverity@mednet.ucla.edu A group of case histories with appropriate muscle biopsy findings is presented to demonstrate some atypical presentations of the inflammatory myopathies. Differential diagnostic possibilities are considered in presentations of idiopathic polymyositis, statin myotoxicity, the inflammatory component with the dysferlinopathies, treated dermatomyositis, a necrotizing myopathy with pipe-stem microvascular change, an inflammatory myopathy with abundant macrophages, inclusion-body myositis, and the differential diagnosis of problems with eosinophilic infiltration in the muscle biopsy. Attention is given to the role of membrane attack complex deposition in the microvasculature and the role of major histiocompatibility complex-1-expressing muscle fibers indicating activation of the endoplasmic reticulum stress response. Publication Types: Case Reports PMID: 18068861 [PubMed - indexed for MEDLINE]

104: Nephrol Dial Transplant. 2008 Mar;23(3):813-5. Epub 2007 Dec 8. A spoonful of sugar helps the proteinuria go down? Topham P, Barratt J, Feehally J. Department of Infection, Immunity and Inflammation, John Walls Renal Unit, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, UK. peter.topham@uhl-tr.nhs.uk Publication Types: Review PMID: 18065797 [PubMed - indexed for MEDLINE]

105: Neuromuscul Disord. 2008 Feb;18(2):150-2. Epub 2007 Dec 3. Apolipoprotein epsilon alleles in sporadic inclusion body myositis: a reappraisal. Needham M, Hooper A, James I, van Bockxmeer F, Corbett A, Day T, Garlepp MJ, Mastaglia FL. Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Queen Elizabeth II Medical Centre, Perth, Australia. Needhm01@student.uwa.edu.au Previous studies have differed as to whether APOE epsilon4 is a susceptibility factor for developing sporadic inclusion body myositis (sIBM), with a positive association being found only in an Australian cohort of cases. We have now re-examined this in a larger cohort of 57 sIBM cases and have also carried out a meta-analysis of all the published studies looking for evidence of a risk association or effect of APOE alleles on disease expression. Our findings argue against a specific role for any APOE alleles in conferring susceptibility to sIBM but have demonstrated a non-significant trend towards an earlier age-of-onset in patients with the epsilon2 allele. Publication Types: Case Reports Meta-Analysis Research Support, Non-U.S. Gov't PMID: 18060780 [PubMed - indexed for MEDLINE]

106: Acta Neurol Scand. 2008 Jun;117(6):393-8. Epub 2007 Nov 14. Expression of transglutaminase 2 does not differentiate focal myositis from generalized inflammatory myopathies. Macaione V, Aguennouz M, Mazzeo A, De Pasquale MG, Russo M, Toscano A, De Luca G, Di Giorgio RM, Vita G, Rodolico C. Department of Biochemical, Physiological and Nutritional Sciences, University of Messina, Messina, Italy. vmacaione@unime.it OBJECTIVES: Idiopathic inflammatory myopathies (IIM), including dermatomyositis (DM), polymyositis (PM), sporadic inclusion-body myositis (s-IBM) and focal myositis (FM) are a heterogeneous group of autoimmune disorders of skeletal muscle. An increased transglutaminase 2 (TG2) expression has been found in DM, PM and s-IBM. The aim of our study was to investigate TG2 expression in FM in comparison with other IIM. MATERIALS AND METHODS: We re-examined tissue material we have gathered in the course of our previous studies on IIM, investigating muscle expression of TG2 in patients with FM in comparison with DM, PM and s-IBM using immunocytochemistry and real-time RT-PCR. RESULTS: Immunocytochemistry revealed an increased TG2 signal in endomysial vessels, in atrophic and degenerating/regenerating muscle fibres in PM, DM, s-IBM and FM; in s-IBM, some vacuoles were immunostained too. Real-time RT-PCR study confirmed a significantly increased expression of TG2 in all IIM muscles examined. CONCLUSIONS: Our study demonstrates the presence of TG2 in FM muscles. The study suggests that TG2 expression does not represent a distinctive marker to differentiate FM from generalized IIM. TG2 over-expression in inflamed skeletal muscle does not seem have a pathogenetic role in such a disease, but it could represent a way to contain the inflammatory process. PMID: 18005224 [PubMed - indexed for MEDLINE]

107: Front Biosci. 2008 Jan 1;13:2548-77. Chemokines in idiopathic inflammatory myopathies. De Paepe B, Creus KK, De Bleecker JL. Department of Neurology, Ghent University Hospital, Ghent, Belgium. The idiopathic inflammatory myopathies (IIM) represent a heterogeneous group of acquired muscle diseases. The three best-studied subgroups: dermatomyositis (DM), polymyositis (PM), and sporadic inclusion body myositis (IBM), differ considerably both clinically and pathophysiologically. DM is a chiefly humoral endotheliopathy often associated with characteristic skin manifestations. In PM and IBM nonnecrotic muscle fibers are invaded by auto-aggressive cytotoxic T-cells and macrophages. IBM presents with additional structural abnormalities of myofibers, including rimmed vacuoles and depositions of ectopic proteins. Data accumulates implicating the chemokines in the immunopathogenesis of the different IIM. This review bundles current knowledge of the chemokine and chemokine receptor expression in the skeletal muscle of DM, PM and IBM patients. The IIM are characterized by a general increase of specific chemokines, while the chemokine distribution reflects the two different immune responses represented within these muscle diseases: (I) The endotheliopathy of DM is characterized by increased levels of CXCL12 and CCL2 in the affected blood vessels, (II) In the myocytotoxic immune response of PM and IBM, active invasion of nonnecrotic myofibers by inflammatory cells is associated with CXCL10 and CCL2 upregulation. The ever accumulating data illustrates the important role of the chemokine system in IIM, indicating the therapeutic potential of interfering agents. This raises hopes for future treatments for DM and PM with fewer side effects, and the possible establishment of a therapy suited for IBM, a myopathy which has proven unresponsive to all available immuno-modulating interventions up till now. Publication Types: Review PMID: 17981734 [PubMed - indexed for MEDLINE]

108: Arthritis Rheum. 2007 Nov;56(11):3784-92. Type I interferon-inducible gene expression in blood is present and reflects disease activity in dermatomyositis and polymyositis. Walsh RJ, Kong SW, Yao Y, Jallal B, Kiener PA, Pinkus JL, Beggs AH, Amato AA, Greenberg SA. Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. OBJECTIVE: To apply gene expression profiling to the study of peripheral blood mononuclear cells from patients with inflammatory myopathies, in order to provide insight into disease pathogenesis and identify potential biomarkers associated with disease activity. METHODS: We used Affymetrix whole-genome microarrays to measure the expression of approximately 38,500 genes in 65 blood and 15 muscle samples from 44 patients with dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM), myasthenia gravis, or genetically determined myopathies and from 12 healthy volunteers. In 9 patients, 2 samples were obtained at different time points, when disease was either active or improving, and these paired blood samples were also compared. Bioinformatics techniques were used to identify genes with significant differential expression among diagnostic categories and in relation to disease activity. We corroborated the microarray data with quantitative real-time reverse transcriptase-polymerase chain reaction. RESULTS: Most patients with active DM or PM, but not patients with IBM, had significant and high up-regulation of the type I interferon-alpha/beta (IFNalpha/beta)-inducible genes in blood. Furthermore, the up-regulation of these genes correlated with disease activity in DM and PM, with down-regulation occurring when disease was controlled with treatment. CONCLUSION: DM and PM are diseases characterized by the systemic overexpression of IFNalpha/beta-inducible genes. The magnitude of the overexpression of these genes is higher in DM and correlates with disease activity in both disorders. Although PM and IBM have been modeled as having similar immunologic processes occurring within muscle, there are substantial differences in the expression of IFNalpha/beta-inducible genes in blood in these diseases. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PMID: 17968926 [PubMed - indexed for MEDLINE]

109: Skeletal Radiol. 2008 Jan;37(1):43-8. Epub 2007 Oct 26. Muscle sonography in six patients with hereditary inclusion body myopathy. Adler RS, Garolfalo G, Paget S, Kagen L. Division of Ultrasound and Body Imaging, Hospital for Special Surgery, Weill Medical College of Cornell University, 535 East 70th Street, New York, NY 10021, USA. adlerr@hss.edu OBJECTIVE: To evaluate the morphological changes of muscle with sonography in six patients affected by hereditary inclusion body myopathy (HIBM). MATERIALS AND METHODS: We studied a group of six Persian Jews diagnosed with HIBM. All were homozygous for the GNE mutation M712T. Ultrasonographic examinations of the quadriceps femoris and hamstring muscle groups were performed. A follow-up ultrasound examination was performed, after an interval of 3 years, in four of these patients. Muscles were assessed subjectively as to echogenicity, determined by gray-scale assessment, and loss of normal muscle morphology. Power Doppler sonography (PDS) was used to assess vascularity. RESULTS: A sonographic finding of central atrophy and peripheral sparing resulting in a target-like appearance was noted in the hamstring compartment of all six patients. The quadriceps compartment also showed involvement of the rectus femoris of all patients, which, in some cases, was the only muscle involved in the quadriceps. Vascularity was markedly reduced in the affected areas, with blood flow demonstrated in the peripherally spared areas. The severity of atrophy increased with disease duration. CONCLUSION: In this case series, we describe a new sonographic finding as well as document progression of HIBM disease, which has generally been described as quadriceps sparing. The myopathic target lesion, as well as isolated rectus femoris atrophy, may provide a useful adjunct to disease diagnosis. PMID: 17962939 [PubMed - indexed for MEDLINE]

110: Neurology. 2007 Oct 23;69(17):1672-9. T cell receptor profiling in muscle and blood lymphocytes in sporadic inclusion body myositis. Salajegheh M, Rakocevic G, Raju R, Shatunov A, Goldfarb LG, Dalakas MC. Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. BACKGROUND: Sporadic IBM (sIBM) is characterized by invasion of non-necrotic MHC-I class-expressing muscle fibers by clonally expanded CD8+ cells. Whether the endomysial cells expand in situ or are recruited from the circulation is unclear. METHODS: We used CDR3 spectratyping of the T cell receptor (TCR) V beta chains to determine clonal expansion of T cells in simultaneously obtained muscle and peripheral blood lymphocytes (PBL) from 12 patients with sIBM, and compared the difference between the two compartments. To determine whether the identified clones belonged to autoinvasive T cells, we performed immunohistochemistry on the same muscle specimens. Spectratyping was repeated in four muscle biopsies 1 year after the first. RESULTS: In control PBL, all 24 TCR V beta subfamilies had a polyclonal or Gaussian distribution. In sIBM PBL, 5% of the V beta subfamilies demonstrated a single and 16% up to three peaks. In contrast, in their corresponding muscles, 27% (p = 0.0003) of the V beta subfamilies demonstrated a single and 71% ( p less than 0.0001) up to three peaks. Among the amplified subfamilies, V beta 9, 10, 11, 16, 18, 23, and 24 showed the highest degree of restriction within muscle. Immunohistochemistry demonstrated that the clonally expanded CD8+ cells were autoinvasive. In follow-up biopsies the clonality persisted with an unchanged degree of restriction, but not always of the same subfamilies, suggesting epitope spreading. CONCLUSION: In sporadic inclusion body myositis, the endomysial T cells are specifically recruited to the muscle or expand in situ. The restriction of multiple V beta subfamilies and their change over time suggests recognition of various local antigens and epitope spreading. Publication Types: Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't PMID: 17954782 [PubMed - indexed for MEDLINE]

111: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17016-21. Epub 2007 Oct 17. Erratum in: Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):399. Distinctive patterns of microRNA expression in primary muscular disorders. Eisenberg I, Eran A, Nishino I, Moggio M, Lamperti C, Amato AA, Lidov HG, Kang PB, North KN, Mitrani-Rosenbaum S, Flanigan KM, Neely LA, Whitney D, Beggs AH, Kohane IS, Kunkel LM. Howard Hughes Medical Institute, Program in Genomics, Division of Genetics, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. The primary muscle disorders are a diverse group of diseases caused by various defective structural proteins, abnormal signaling molecules, enzymes and proteins involved in posttranslational modifications, and other mechanisms. Although there is increasing clarification of the primary aberrant cellular processes responsible for these conditions, the decisive factors involved in the secondary pathogenic cascades are still mainly obscure. Given the emerging roles of microRNAs (miRNAs) in modulation of cellular phenotypes, we searched for miRNAs regulated during the degenerative process of muscle to gain insight into the specific regulation of genes that are disrupted in pathological muscle conditions. We describe 185 miRNAs that are up- or down-regulated in 10 major muscular disorders in humans [Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophies types 2A and 2B, Miyoshi myopathy, nemaline myopathy, polymyositis, dermatomyositis, and inclusion body myositis]. Although five miRNAs were found to be consistently regulated in almost all samples analyzed, pointing to possible involvement of a common regulatory mechanism, others were dysregulated only in one disease and not at all in the other disorders. Functional correlation between the predicted targets of these miRNAs and mRNA expression demonstrated tight posttranscriptional regulation at the mRNA level in DMD and Miyoshi myopathy. Together with direct mRNA-miRNA predicted interactions demonstrated in DMD, some of which are involved in known secondary response functions and others that are involved in muscle regeneration, these findings suggest an important role of miRNAs in specific physiological pathways underlying the disease pathology. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PMID: 17942673 [PubMed - indexed for MEDLINE]

112: Clin Genet. 2007 Nov;72(5):420-6. Novel VCP mutations in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia. Watts GD, Thomasova D, Ramdeen SK, Fulchiero EC, Mehta SG, Drachman DA, Weihl CC, Jamrozik Z, Kwiecinski H, Kaminska A, Kimonis VE. Division of Genetics, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD, OMIM 167320) has recently been attributed to eight missense mutations in valosin-containing protein (VCP). We report novel VCP mutations N387H and L198W in six individuals from two families who presented with proximal muscle weakness at a mean age of diagnosis of 40 years, most losing the ability to walk within a few years of onset. Electromyographic studies in four individuals were suggestive of 'myopathic' changes, and neuropathic pattern was identified in one individual in family 1. Muscle biopsy in four individuals showed myopathic changes characterized by variable fiber size, two individuals showing rimmed vacuoles and IBM-type cytoplasmic inclusions in muscle fibers, and electron microscopy in one individual revealing abundant intranuclear inclusions. Frontotemporal dementia associated with characteristic behavioral changes including short-term memory loss, language difficulty, and antisocial behavior was observed in three individuals at a mean age of 47 years. Detailed brain pathology in one individual showed cortical degenerative changes, most severe in the temporal lobe and hippocampus. Abundant ubiquitin-positive tau-, alpha-synuclein-, polyglutamine repeat-negative neuronal intranuclear inclusions and only rare intracytoplasmic VCP positive inclusions were seen. These new mutations may cause structural changes in VCP and provide some insight into the functional effects of pathogenic mutations. Publication Types: Case Reports Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PMID: 17935506 [PubMed - indexed for MEDLINE]

113: Neurology. 2007 Nov 20;69(21):2008-19. Epub 2007 Oct 10. Comment in: Neurology. 2007 Nov 20;69(21):1966-7. Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications. Greenberg SA. Department of Neurology, Brigham and Womens Hospital, Harvard Medical School, Boston, MA 02115, USA. sagreenberg@partners.org Several immune system cell types and processes have been recently identified in muscle in inclusion body myositis, dermatomyositis, and polymyositis. Plasmacytoid dendritic cells, the immune system's professional producer of the type 1 interferons alpha and beta, are present in dermatomyositis muscle and skin. These tissues also show high expression of transcripts and proteins from genes that are induced by interferon alpha and beta. Myeloid dendritic cells, which contribute to an immunologic synapse responsible for activation of the adaptive immune system, are abundant within muscle in inclusion body myositis and polymyositis. B cells and plasma cells, effector cells of the humoral immune system, have been stimulated by antigen to transcribe immunoglobulins and produce antibodies in muscle in all three of these diseases. The presence of these immune cells and processes suggests revisions in models of the pathogenesis of the inflammatory myopathies and provides rationales for future therapeutic approaches. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PMID: 17928577 [PubMed - indexed for MEDLINE]

114: Curr Opin Rheumatol. 2007 Nov;19(6):550-9. Inclusion-body myositis, a multifactorial muscle disease associated with aging: current concepts of pathogenesis. Askanas V, Engel WK. USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, California 90017-1912, USA. askanas@usc.edu PURPOSE OF REVIEW: Sporadic inclusion-body myositis, the most common muscle disease of older persons, has no known cause or persistently beneficial treatment. The unfolding pathogenesis could lead to new treatment strategies and it is now of growing interest among clinicians and basic scientists. About 100 papers related to the subject were published in 2006 and the first part of 2007 (we cite only articles most relevant to this review). RECENT FINDINGS: This review focuses on the current concepts of the pathogenesis of sporadic inclusion-body myositis. Both degeneration and mononuclear-cell inflammation are components of the pathology, but how each relates to the pathogenesis remains unclear. We suggest that an intramuscle fiber degenerative component is primary, leading to muscle-fiber destruction, while the lymphocytic inflammatory component may only slightly contribute to sporadic inclusion-body myositis muscle-fiber damage. Intracellular accumulation of amyloid-beta precursor protein, amyloid-beta, and amyloid-beta oligomers in an aging muscle-fiber cellular milieu, and other abnormalities, appear to be key pathogenic factors. We summarize intracellular molecular events and their consequences, and correlate findings in sporadic inclusion-body myositis muscle biopsies with inclusion-body myositis experimental models in tissue culture and in transgenic mice. SUMMARY: Treatment of sporadic inclusion-body myositis remains a challenge. Antiinflammatory approaches used so far are without major or enduring benefit. Possible new treatment avenues are suggested. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review PMID: 17917534 [PubMed - indexed for MEDLINE]

115: Curr Opin Rheumatol. 2007 Nov;19(6):536-41. A gene expression approach to study perturbed pathways in myositis. Greenberg SA. Division of Neuromuscular Disease, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. sagreenberg@partners.org PURPOSE OF REVIEW: To review new insights into the disease mechanisms of dermatomyositis, inclusion body myositis, and polymyositis gained from large-scale microarray gene expression studies of patient tissue samples. RECENT FINDINGS: The detection of unexpected gene transcripts using microarrays in inflammatory myopathy tissue has led to the discovery of new types and roles of immune system cells present in muscle in these diseases. Plasmacytoid dendritic cells, the immune system's professional producer of the type 1 interferons alpha and beta, are prominent in dermatomyositis muscle. Plasma cells and myeloid dendritic cells are abundant in polymyositis and inclusion body myositis muscle. Type 1 interferon induction is the single most upregulated pathological pathway genome-wide in dermatomyositis muscle and blood. In individual patients with dermatomyositis and some with polymyositis, a blood type 1 interferon-signature correlates with disease activity. SUMMARY: The identification of new cells and pathways in inflammatory myopathies has led to deeper mechanistic understanding of these diseases and potential therapeutic approaches. Through insights gained in gene expression studies, a strong scientific rationale has developed for blockade of the type 1 interferon pathway for treatment of dermatomyositis. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review PMID: 17917532 [PubMed - indexed for MEDLINE]

116: Ann N Y Acad Sci. 2007 Sep;1110:285-96. Treatment of autoimmune disease with rabbit anti-T lymphocyte globulin: clinical efficacy and potential mechanisms of action. Lytton SD, Denton CP, Nutzenberger AM. SeraDiaLogistics, Hertlingstr 1, 81545 München, Germany. simon.lytton@t-online.de The rabbit anti-T lymphocyte globulins (rATGs) are immune-suppressive anti-T cell agents with beneficial effects in solid organ and hematological transplantation. The present review evaluates the potential mechanisms of rATGs and their impact on pilot and exploratory studies of diffuse cutaneous systemic sclerosis (scleroderma-SSc), inclusion body myositis (IBM), vasculitis, and type 1 diabetes mellitus (T1DM). The rATGs are associated with improvements in well-defined parameters of clinical autoimmunity: insulin usage, tissue inflammation, and systemic organ functions. Meta-analysis of a retrospective database of SSc, N = 196 and two prospective randomized pilot studies; IBM, N = 11 and T1DM, N = 17 shows a two- to ninefold increase in the relative response to treatments with intravenous infusions of rATG. The rATGs deplete T cells and are associated with increases in the percentage of CD25+ T cell subsets. This may underlie the apparent long-lasting immunomodulation associated with these agents. The future optimization of rATG adjunct therapy requires statistically powered-controlled prospective trials of rATG dose-finding and timing of administration. The potential mechanisms of rATGs:depletion of autoreactive T cells, generation CDCD25+Foxp3+ regulatory T cells (Tregs), and the acquisition of regulatory immune cell functions, need to be examined in patients prior to rATG infusion and at time intervals following rATG treatment to identify those mechanisms relevant to the improvement of their clinical outcome. PMID: 17911443 [PubMed - indexed for MEDLINE]

117: Clin Neuropathol. 2007 Sep-Oct;26(5):232-40. Brain imaging and neuropsychology in late-onset dementia due to a novel mutation (R93C) of valosin-containing protein. Krause S, Göhringer T, Walter MC, Schoser BG, Reilich P, Linn J, Pöpperl GE, Frölich L, Hentschel F, Lochmüller H, Danek A. Neurologische Klinik, Ludwig-Maximilians-Universität München, Germany. Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD, MIM 167320) is a recently identified autosomal dominant disorder due to mutations in the valosin-containing protein (VCP) that affects muscle, bone and brain. Brain involvement and neuropsychological findings of IBMPFD have not been described in detail. A patient carried a novel heterozygous base pair change, 47832C>T, in the VCP gene that resulted in substitution of an arginine residue by cysteine at position 93 (R93C). He presented first with myopathy while bone involvement remained subclinical. The patient developed behavioral abnormalities in his 60s and showed frank personality change with fluent empty speech at the age of 74 years. This syndrome was best classified as semantic dementia. Magnetic resonance imaging disclosed slight but progressive cerebral atrophy with prominent callosal and frontal white matter loss. Positron emission tomography demonstrated glucose hypometabolism of the frontal and temporal lobes disproportionate to their structural involvement. This first comprehensive clinical and neuroimaging study in IBMPFD may raise the awareness among clinicians as well as basic scientists for this exemplary genetic model of dementia. Publication Types: Case Reports Research Support, Non-U.S. Gov't PMID: 17907600 [PubMed - indexed for MEDLINE]

118: Neurobiol Aging. 2009 May;30(5):752-8. Epub 2007 Sep 24. Inclusion body myopathy and frontotemporal dementia caused by a novel VCP mutation. Bersano A, Del Bo R, Lamperti C, Ghezzi S, Fagiolari G, Fortunato F, Ballabio E, Moggio M, Candelise L, Galimberti D, Virgilio R, Lanfranconi S, Torrente Y, Carpo M, Bresolin N, Comi GP, Corti S. Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Via F. Sforza 35, 20122 Milan, Italy. Hereditary inclusion body myopathy (IBM) with Paget's disease of the bone (PDB) and frontotemporal dementia (FTD) is a rare autosomal dominant disease caused by mutations in the valosin-containing protein (VCP) gene. We report a novel heterozygous VCP gene mutation (R159C) in a 69-year-old Italian patient presenting with slowly progressive muscle weakness of the distal upper and proximal lower limbs since the age of 50 years, 18 years later FTD supervened. No dementia or myopathies were revealed in the family history covering two generations. Degenerative changes and rimmed vacuoles together with VCP- and ubiquitin-positive cytoplasmic and nuclear aggregates were observed at the muscle biopsy. Several elements support the pathogenic role of the R159C VCP gene mutation: the occurrence at the same codon of a different, previously identified pathogenic mutation within a VCP gene mutational hot-spot, the histopathological and biochemical evidence of muscle VCP accumulation and the combined clinical presentation of IBM and FTD. These findings suggest VCP gene investigation even in apparently sporadic cases. Publication Types: Case Reports Research Support, Non-U.S. Gov't PMID: 17889967 [PubMed - indexed for MEDLINE]

119: Neuromuscul Disord. 2008 Jan;18(1):27-33. Epub 2007 Sep 20. Histone H1 is released from myonuclei and present in rimmed vacuoles with DNA in inclusion body myositis. Nakano S, Shinde A, Fujita K, Ito H, Kusaka H. Department of Neurology, Kansai Medical University, Moriguchi 570-8507, Japan. nakanos@takii.kmu.ac.jp To investigate myonuclear alterations in sporadic inclusion body myositis (s-IBM), we immuno-localized histones in muscles in 11 patients. The examination showed that vacuolar rims were frequently positive for histone H1. In triple-color fluorescence study, the H1-positive products were found on the inner side of an emerin-positive circle with DNA. Moreover, H1-positive materials appeared to be released into the cytoplasm in some vacuoles and myonuclei. The localization of H1 was different from phosphorylated Elk-1, which is a nuclear protein, but abnormally accumulated in the cytoplasm in s-IBM. The results strongly support the hypothesis that rimmed vacuoles are derived from the nucleus. The cytoplasmic H1-release suggests dysfunction of nuclear membranes in an early phase of the nuclear disintegration. We hypothesize that, in s-IBM muscles, compromised nuclear envelope may permit release of some nuclear components such as histone H1 and cannot facilitate the incorporation of others to the nucleus as in pElk-1. Publication Types: Research Support, Non-U.S. Gov't PMID: 17888663 [PubMed - indexed for MEDLINE]

120: J Cardiovasc Med (Hagerstown). 2007 Oct;8(10):859-63. Apical ballooning (Takotsubo syndrome) in mitochondrial disorder during mechanical ventilation. Finsterer J, Stöllberger C, Sehnal E, Valentin A, Huber J, Schmiedel J. Krankenanstalt Rudolfstiftung, Vienna, Austria. duarte@aonmail.at Takotsubo syndrome may be associated with neuromuscular disorders, but has never been described in a patient with mitochondrial disorder. A 75-year-old woman developed muscle cramps, ptosis, fasciculations and slowly progressive weakness and wasting of all four limbs, starting 2.5 years earlier. After exclusion of various differential diagnoses, including non-specific granulomatous myositis, inclusion body myositis, and motor neuron disease, mitochondrial disorder was assumed. Muscle weakness progressed to respiratory insufficiency, requiring mechanical ventilation. Five days after intubation, she developed hypotension, torsades de pointes, ST-segment elevation, and negative T waves. Echocardiography revealed apical ballooning with akinesia of the left ventricular anteroseptal, apical, apicolateral and inferior segments. Coronary angiography was normal, and ventriculography confirmed apical hypokinesia and ballooning. Takotsubo syndrome was diagnosed, resolving completely within 7 weeks under bisoprolol.This case shows that Takotsubo syndrome occurs also in mitochondrial disorder and under mechanical ventilation, and may be triggered by stress from respiratory insufficiency, intubation, pain from tracheostomy, stress from mechanical ventilation, medication, or from the uncertain prognosis. Publication Types: Case Reports PMID: 17885529 [PubMed - indexed for MEDLINE]

121: Neurology. 2008 Feb 5;70(6):418-24. Epub 2007 Sep 19. Comment in: Neurology. 2008 Feb 5;70(6):414-5. Correlation of muscle biopsy, clinical course, and outcome in PM and sporadic IBM. Chahin N, Engel AG. Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA. OBJECTIVE: To correlate muscle biopsy findings with prebiopsy and postbiopsy clinical course and response to therapy in polymyositis (PM) and sporadic inclusion body myositis (IBM). BACKGROUND: Existence of pure PM has recently been questioned; subsequently, the definition and criteria for diagnosing PM were debated. METHODS: Patient records, follow-up information, and muscle biopsies were analyzed in 107 patients whose biopsies were initially read as PM and IBM. RESULTS: The patients fell into three groups by combined biopsy and clinical criteria: PM, 27 patients; IBM, 64 patients; PM/IBM, 16 patients with biopsy diagnosis of PM but clinical features of IBM. For the three groups, the respective mean periods from disease onset to end of follow-up were 5.9, 8.5, and 9.6 years. Another autoimmune disease was present in 4 of 27 PM, 8 of 64 IBM, and 1 of 16 PM/IBM cases. An autoimmune serologic marker occurred in one-third of each group. Nineteen PM patients had no associated autoimmune disease or marker. Nonnecrotic fiber invasion by mononuclear cells appeared in all IBM, 17 of 27 PM, and 13 of 16 PM/IBM patients. The density of both invaded fibers and cytochrome-c oxidase-negative fibers was higher in IBM and PM/IBM than in PM. Immunotherapy improved 22 of 27 PM patients but had only transient beneficial effects in 2 of 32 IBM and 1 of 14 PM/IBM patients. CONCLUSIONS: 1) Sixteen of 43 patients (37%) with biopsy features of polymyositis (PM) had clinical features of inclusion body myositis (IBM). 2) Absence of canonical biopsy features of IBM from clinically affected muscles of IBM patients challenges biopsy criteria for IBM, or the IBM markers appear late in some patients, or their distribution in muscle is patchy and restricted compared with that of the inflammatory exudate. 3) The muscle biopsy is a reliable instrument in the diagnosis of PM and IBM in close to 85% of the patients. Errors of diagnosis in the remaining 15% can be avoided or reduced by combined evaluation of the clinical and pathologic findings. PMID: 17881720 [PubMed - indexed for MEDLINE]

122: J Immunol. 2007 Oct 1;179(7):4939-44. Autoantibodies in canine masticatory muscle myositis recognize a novel myosin binding protein-C family member. Wu X, Li ZF, Brooks R, Komives EA, Torpey JW, Engvall E, Gonias SL, Shelton GD. Department of Pathology, University of California, San Diego 92101, USA. Inflammatory myopathies are a group of autoimmune diseases that affect muscles. In humans, the most common inflammatory myopathies are polymyositis, dermatomyositis, and inclusion body myositis. Autoantibodies may be found in humans with inflammatory myopathies, and these play an important role in diagnosis and disease classification. However, these Abs are typically not muscle specific. Spontaneously occurring canine inflammatory myopathies may be good parallel disorders and provide insights into human myositis. In dogs with inflammatory myopathy, muscle-specific autoantibodies have been found, especially in masticatory muscle myositis. We have identified the major Ag recognized by the autoantibodies in canine masticatory muscle myositis. This Ag is a novel member of the myosin binding protein-C family, which we call masticatory myosin binding protein-C (mMyBP-C). mMyBP-C is localized not only within the masticatory muscle fibers, but also at or near their cell surface, perhaps making it accessible as an immunogen. The gene for mMyBP-C also exists in humans, and mMyBP-C could potentially play a role in certain human inflammatory myopathies. Understanding the role of mMyBP-C in this canine inflammatory myopathy may advance our knowledge of mechanisms of autoimmune inflammatory muscle diseases, not only in dogs, but also in humans. PMID: 17878394 [PubMed - indexed for MEDLINE]

123: J Neurol Sci. 2008 Jan 15;264(1-2):77-86. Epub 2007 Sep 12. Non-pathogenic protein aggregates in skeletal muscle in MLF1 transgenic mice. Li ZF, Wu X, Jiang Y, Liu J, Wu C, Inagaki M, Izawa I, Mizisin AP, Engvall E, Shelton GD. Burnham Institute for Medical Research, La Jolla, CA 92037, United States. Protein aggregate formation in muscle is thought to be pathogenic and associated with clinical weakness. Over-expression of either wild type or a mutant form of myeloid leukemia factor 1 (MLF1) in transgenic mouse skeletal muscle and in cultured cells resulted in aggregate formation. Aggregates were detected in MLF1 transgenic mice at 6 weeks of age, and increased in size with age. However, histological examination of skeletal muscles of MLF1 transgenic mice revealed no pathological changes other than the aggregates, and RotaRod testing did not detect functional deficits. MLF1 has recently been identified as a protein that could neutralize the toxicity of intracellular protein aggregates in a Drosophila model of Huntington's disease (HD). We also demonstrate that MLF1 interacts with MRJ, a heat shock protein, which can independently neutralize the toxicity of intracellular protein aggregates in the Drosophila HD model. Our data suggest that over-expression of MLF1 has no significant impact on skeletal muscle function in mice; that progressive formation of protein aggregates in muscle are not necessarily pathogenic; and that MLF1 and MRJ may function together to ameliorate the toxic effects of polyglutamine or mutant proteins in myodegenerative diseases such as inclusion body myositis and oculopharyngeal muscular dystrophy, as well as neurodegenerative disease. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PMID: 17854834 [PubMed - indexed for MEDLINE]

124: Ann N Y Acad Sci. 2007 Aug;1109:441-53. Chemokine profile of different inflammatory myopathies reflects humoral versus cytotoxic immune responses. De Paepe B, Creus KK, De Bleecker JL. Department of Neurology, Ghent University Hospital, Belgium. The idiopathic inflammatory myopathies (IM) are subdivided into dermatomyositis (DM), polymyositis (PM), and sporadic inclusion body myositis (IBM). These autoimmune muscle diseases represent different immunopathological entities. DM is a humoral endotheliopathy initiated by complement deposition in intramuscular blood vessels, and characterized by perimysial inflammation and muscle fiber atrophy in perifascicular regions. In PM and IBM, nonnecrotic muscle fibers are actively invaded by autoaggressive macrophages and cytotoxic T cells. Chemokines are key mediators of inflammatory disease as they regulate leukocyte recruitment to tissue target sites. We studied a large selection of alpha/beta-chemokines and receptors in normal controls and in the IM using immunohistochemistry, immunofluorescence, in situ hybridization, and Western blotting. We showed that the chemokine array of normal myocytes was limited, while the blood vessels in normal skeletal muscle tissue displayed a broad chemokine profile. The IM were characterized by a general increase of specific chemokines and chemokine receptors, while chemokine distribution reflected the two different immune responses represented within these muscle diseases. In DM, endothelial expression of CCL2 and CXCL12beta was highly increased. In PM and IBM, macrophages and cytotoxic T cells actively invading nonnecrotic muscle fibers expressed highest levels of CXCL10 and CCL2. Some chemokines were selectively expressed by different IM infiltrates: CCL4 was present only in the perimysial inflammatory foci of a subset of DM biopsies, while CXCL1, CXCL2, CXCL3, and CCL7-positive cells were exclusively detected in endomysial infiltrates of a number of PM and IBM samples. The chemokine receptor profile of the IM indicated the predominance of Th1-mediated immune responses in all three IM. Our studies identified three ligand-receptor pairs, namely CXCL10/CXCR3, CXCL12/CXCR4, and CCL2/CCR2, as potential targets for chemokine-based therapy in IM. Publication Types: Research Support, Non-U.S. Gov't PMID: 17785333 [PubMed - indexed for MEDLINE]

125: Acta Neuropathol. 2007 Nov;114(5):517-26. Epub 2007 Aug 31. NOGO is increased and binds to BACE1 in sporadic inclusion-body myositis and in A beta PP-overexpressing cultured human muscle fibers. Wojcik S, Engel WK, Yan R, McFerrin J, Askanas V. USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, 637 S. Lucas Ave, Los Angeles, CA 90017-1912, USA. Increased amyloid-beta precursor protein (A beta PP) and amyloid-beta (A beta) accumulation appear to be upstream steps in the pathogenesis of sporadic inclusion-body myositis (s-IBM). BACE1, participating in A beta production is also increased in s-IBM muscle fibers. Nogo-B and Nogo-A belong to a family of integral membrane reticulons, and Nogo-B binding to BACE1 blocks BACE1 access to A beta PP, decreasing A beta production. We studied Nogo-B and Nogo-A in s-IBM muscle and in our IBM muscle culture models, based on A beta PP-overexpression or ER-stress-induction in cultured human muscle fibers (CHMFs). We report that: (1) in biopsied s-IBM fibers, Nogo-B is increased, accumulates in aggregates, is immuno-co-localized with BACE1, and binds to BACE1; Nogo-A is undetectable. (2) In CHMFs, (a) A beta PP overexpression increases Nogo-B, Nogo-A, and BACE1, (b) ER stress increases BACE1 but decreases Nogo-B and Nogo-A, (c) Nogo-B and Nogo-A associate with BACE1. Accordingly, two novel mechanisms, A beta PP overexpression and ER stress, are involved in Nogo-B and Nogo-A expression in human muscle. We propose that in s-IBM muscle the Nogo-B increase may represent an attempt by muscle fiber to decrease A beta production. However, the increase of Nogo-B seems insufficient because A beta continues to accumulate and the disease progresses. We propose that manipulations, which increase Nogo-B in s-IBM muscle might offer a new therapeutic opportunity. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PMID: 17764014 [PubMed - indexed for MEDLINE]

126: Muscle Nerve. 2008 Jan;37(1):111-4. An Italian family with inclusion-body myopathy and frontotemporal dementia due to mutation in the VCP gene. Gidaro T, Modoni A, Sabatelli M, Tasca G, Broccolini A, Mirabella M. Department of Neuroscience, Catholic University, L.go A. Gemelli 8, 00168 Rome, Italy. Mutations of the valosin-containing protein gene (VCP) are responsible for autosomal-dominant hereditary inclusion-body myopathy associated with frontotemporal dementia and Paget's disease of bone. We identified the p.R155C missense mutation in the VCP gene segregating in an Italian family with three affected siblings, two of whom had a progressive myopathy associated with dementia, whereas one exhibited a progressive myopathy and preclinical signs of Paget's disease of bone. Our study demonstrates that VCP mutations are found in patients of Italian background and may lead to a variable clinical phenotype even within the same kinship. Publication Types: Case Reports Research Support, Non-U.S. Gov't PMID: 17763460 [PubMed - indexed for MEDLINE]

127: Arthritis Rheum. 2007 Sep;56(9):3112-24. A possible mechanism for endogenous activation of the type I interferon system in myositis patients with anti-Jo-1 or anti-Ro 52/anti-Ro 60 autoantibodies. Eloranta ML, Barbasso Helmers S, Ulfgren AK, Rönnblom L, Alm GV, Lundberg IE. Uppsala University, Uppsala, Sweden. OBJECTIVE: To investigate type I interferon (IFN) system activation and its correlation with autoantibodies and organ manifestations in polymyositis (PM), dermatomyositis (DM), and inclusion body myositis. METHODS: Sera from 30 patients and 16 healthy controls, or purified IgG, were combined with material released from necrotized cells to stimulate IFNalpha production by peripheral blood mononuclear cells (PBMCs) from healthy blood donors. Muscle biopsy specimens from 25 patients and 7 healthy controls were investigated for blood dendritic cell antigen 2 (BDCA-2)-positive plasmacytoid dendritic cells (PDCs) and IFNalpha/beta-inducible myxovirus resistance 1 (MX-1) protein. RESULTS: Sera from 13 patients who were positive for anti-Jo-1 or anti-Ro 52/anti-Ro 60 autoantibodies induced IFNalpha production in PBMCs when combined with necrotic cell material. In addition, IgG prepared from anti-Jo-1-positive PM sera induced IFNalpha with necrotic material, but not when the latter was treated with RNase. BDCA-2 expression in PDCs in muscle tissue was increased in PM patients with anti-Jo-1 autoantibodies, while MX-1 staining in capillaries was increased in DM patients, compared with healthy individuals. IFNalpha-inducing capacity correlated with interstitial lung disease, while MX-1 expression in the capillaries correlated with DM. CONCLUSION: Immune complexes containing anti-Jo-1 or anti-Ro 52/anti-Ro 60 autoantibodies and RNA may act as endogenous IFNalpha inducers that activate IFNalpha production in PDCs. These PDCs could be of importance for inducing myositis, whereas in DM patients without autoantibodies the presence of MX-1 protein in capillaries suggests another cellular IFNalpha source and induction mechanism. Consequently, the type I IFN system may be of importance in both PM and DM, but via different pathways. Publication Types: Research Support, Non-U.S. Gov't PMID: 17763410 [PubMed - indexed for MEDLINE]

128: Eur J Neurol. 2007 Sep;14(9):e14-5. Hereditary inclusion body myopathy with a novel mutation in the GNE gene associated with proximal leg weakness and necrotizing myopathy. Motozaki Y, Komai K, Hirohata M, Asaka T, Ono K, Yamada M. Publication Types: Case Reports Letter PMID: 17718674 [PubMed - indexed for MEDLINE]

129: Neurology. 2007 Aug 14;69(7):655-9. GNE protein expression and subcellular distribution are unaltered in HIBM. Krause S, Aleo A, Hinderlich S, Merlini L, Tournev I, Walter MC, Argov Z, Mitrani-Rosenbaum S, Lochmüller H. Friedrich Baur Institute and Department of Neurology, Ludwig Maximilians University, Munich, Germany. Mutations in GNE encoding UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) cause hereditary inclusion body myopathy (HIBM). To define the role of GNE mutations in HIBM pathogenesis, GNE protein expression was analyzed. GNE protein is expressed at equal levels in HIBM patients and normal control subjects. Immunofluorescence detection of GNE did not reveal any mislocalization of GNE in skeletal muscle. We conclude that impaired GNE function, not lack of expression, may be the key pathogenic factor in HIBM. For diagnostic purposes, direct genetic analysis of the GNE gene in patients with IBM will remain the mainstay and is not aided by immunohistochemistry or immunoblotting using antibodies against the GNE protein. Publication Types: Research Support, Non-U.S. Gov't PMID: 17698786 [PubMed - indexed for MEDLINE]

130: Cell Death Differ. 2007 Nov;14(11):1916-24. Epub 2007 Aug 3. Characterization of hereditary inclusion body myopathy myoblasts: possible primary impairment of apoptotic events. Amsili S, Shlomai Z, Levitzki R, Krause S, Lochmuller H, Ben-Bassat H, Mitrani-Rosenbaum S. Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel. Hereditary inclusion body myopathy (HIBM) is a unique muscular disorder caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene. GNE encodes a bi-functional enzyme acting in the biosynthetic pathway of sialic acid. Since the underlying myopathological mechanism leading to the disease phenotype is poorly understood, we have established human myoblasts cultures, derived from HIBM satellite cells carrying the homozygous M712T mutation, and identified cellular and molecular characteristics of these cells. HIBM and control myoblasts showed similar heterogeneous patterns of proliferation and differentiation. Upon apoptosis induction, phosphatidylserine externalization was similar in HIBM and controls. In contrast, the active forms of caspase-3 and -9 were strongly enhanced in most HIBM cultures compared to controls, while pAkt, downregulated in controls, remained high in HIBM cells. These results could indicate impaired apoptotic signaling in HIBM cells. Since satellite cells enable partial regeneration of the post-mitotic muscle tissue, these altered processes could contribute to the muscle mass loss seen in patients. The identification of survival defects in HIBM affected muscle cells could disclose new functions for GNE in muscle cells. Publication Types: Research Support, Non-U.S. Gov't PMID: 17673919 [PubMed - indexed for MEDLINE]

131: Muscle Nerve. 2007 Oct;36(4):447-54. Nuclear localization of valosin-containing protein in normal muscle and muscle affected by inclusion-body myositis. Greenberg SA, Watts GD, Kimonis VE, Amato AA, Pinkus JL. Department of Neurology, Division of Neuromuscular Disease, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA. sagreenberg@partners.org Inclusion-body myopathy with Paget's disease and frontotemporal dementia (IBMPFD) is a disease of muscle, bone, and brain that results from mutations in the gene encoding valosin-containing protein (VCP). The mechanism of disease resulting from VCP mutations is unknown. Previous studies of VCP localization in normal human muscle samples have found a capillary and perinuclear distribution, but not a nuclear localization. Here we demonstrate that VCP is present in both myonuclei and endothelial cell nuclei in normal human muscle tissue. The immunodetection of VCP varies with acetone or paraformaldehyde fixation. Within the nucleus, VCP associates with the nucleolar protein fibrillarin and Werner syndrome protein (Wrnp) in normal and IBMPFD muscle. In patients with inclusion-body myositis (IBM), normal nuclear localization is present and some rimmed vacuoles are lined with VCP. These findings suggest that impairment in the nuclear function of VCP might contribute to the muscle pathology occurring in IBMPFD. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PMID: 17626287 [PubMed - indexed for MEDLINE]

132: Muscle Nerve. 2007 Nov;36(5):721-5. Myositis with sensory neuronopathy. França MC Jr, Faria AV, Queiroz LS, Nucci A. Department of Neurology, School of Medical Sciences, Campinas State University, Zeferino Vaz, Campinas, SP 13083-970, Brazil. Inflammatory myopathies (IM) are a heterogeneous group of diseases characterized by immune-mediated damage to skeletal muscle. Sensory abnormalities are rare in patients with IM. We report two patients, one with dermatomyositis and the other with inclusion-body myositis, who presented with unexpected sensory abnormalities due to probable immune-mediated damage to dorsal root ganglia. We emphasize the importance of combined neuroimaging and neurophysiological assessment for proper diagnosis. Publication Types: Case Reports Research Support, Non-U.S. Gov't PMID: 17469107 [PubMed - indexed for MEDLINE]

133: Acta Neuropathol. 2007 Nov;114(5):537-42. Epub 2007 Mar 29. Myopathy with tubulin-reactive inclusions in two cats. Shelton GD, Sturges BK, Lyons LA, Williams DC, Aleman M, Jiang Y, Mizisin AP. Department of Pathology 0709, University of California, San Diego, La Jolla, CA 92093-0709, USA. gshelton@ucsd.edu Many types of inclusions have been described in human myopathies including but not limited to nemaline rod bodies, cylindrical spirals, tubular aggregates, cytoplasmic bodies, reducing bodies, and fingerprint bodies, and hyaline inclusions in myofibrillar myopathy and inclusion body myositis. There are very few reports describing inclusions in spontaneously occurring myopathies in cats, and these reports are limited to nemaline rod myopathy. A myopathy with tubulin-reactive crystalline inclusions has recently been reported in a human patient with a clinical presentation of myalgia and fatigue. Similarly, a myopathy with chronic, slowly progressive muscle weakness has been identified here in two unrelated cats. Inclusions were the only pathological change in skeletal muscle biopsies and, ultrastructurally, groups of crystalline structures were evident that had a subsarcolemmal or central location, rhomboid or rectangular shapes, lacked orientation, and were not membrane bound. The crystalline structures reacted positively with an antibody against tubulin. This feline myopathy may be the equivalent of the human myopathy with tubulin-positive crystalline inclusions. Publication Types: Case Reports PMID: 17393175 [PubMed - indexed for MEDLINE]

134: Ann Rheum Dis. 2007 Oct;66(10):1276-83. Epub 2007 Feb 2. Limited effects of high-dose intravenous immunoglobulin (IVIG) treatment on molecular expression in muscle tissue of patients with inflammatory myopathies. Barbasso Helmers S, Dastmalchi M, Alexanderson H, Nennesmo I, Esbjörnsson M, Lindvall B, Lundberg IE. Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden. Sevim.Barbasso@ki.se OBJECTIVES: The study was conducted with the aim of achieving an improved understanding of the molecular mechanisms of high-dose intravenous immunoglobulin (IVIG) in inflammatory myopathies by investigating the effects on muscle function and immunological molecules in skeletal muscle of polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM) patients. METHODS: Thirteen treatment-resistant patients, 6 PM, 4 DM, 2 IBM and 1 juvenile DM, were treated with 2 g/kg of IVIG, three times at monthly intervals. Functional Index in Myositis and serum creatinine kinase (CK) levels were determined, and muscle biopsies were performed before treatment and after the third IVIG infusion. Immunological molecules were also studied in biopsies taken 24-48 h after the first infusion. RESULTS: Improved muscle function was observed in three patients (1 PM, 1 DM and 1 IBM) and CK levels decreased in five. T cells, macrophages, major histocompatibility complex (MHC) class I antigen on muscle fibres, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression and membranolytic attack complex (MAC) deposits on capillaries were present to an equal degree in biopsies before and after IVIG treatment. No correlation between the clinical response and molecular changes was found. CONCLUSIONS: The clinical effects of high-dose IVIG on muscle function in patients with refractory inflammatory active myositis did not correspond to effects on any of the investigated molecules in our study. T cells, macrophages, phenotypical changes in muscle fibres and endothelial cell activation were still present after treatment. These observations question a role for IVIG as an immune-modulating therapy in patients with inflammatory myopathies. Publication Types: Research Support, Non-U.S. Gov't PMID: 17277004 [PubMed - indexed for MEDLINE]

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