.
Search for "inclusion body myositis" English only.
[There is always overlap in these lists but they should be inclusive as a result]
1: Ann Rheum Dis. 2007 Feb 8; [Epub ahead of print]
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, Esbjornsson M,
Lindvall B, Lundberg IE.
Rheumatology Unit, Karolinska Institutet, Sweden.
OBJECTIVES: To achieve an improved understanding of the molecular mechanisms
of
high-dose intravenous immune globulin (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 2g/kg of IVIg, 3 times with
a
monthly interval. Functional Index in Myositis, serum creatinine kinase
(CK)-levels and muscle biopsies were performed before treatment and after the
third IVIg infusion. Immunological molecules were also studied in biopsies taken
24-48hrs after first infusion. RESULTS: Improved muscle function was observed
in
three patients (1PM, 1DM, 1IBM) and CK-levels decreased in five. T cells,
macrophages, MHC class I antigen on muscle fibres, ICAM-1 and VCAM-1 expression
and 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 with 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 the role of IVIG as an immune modulating therapy in
patients with inflammatory myopathies.
PMID: 17277004 [PubMed - as supplied by publisher]
2: Exp Neurol. 2006 Dec 23; [Epub ahead of print]
Endoplasmic reticulum stress induces myostatin precursor protein and NF-kappaB
in cultured human muscle fibers: Relevance to inclusion body myositis.
Nogalska A, Wojcik S, King Engel W, McFerrin J, 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, USA.
Sporadic-inclusion body myositis (s-IBM) is the most common progressive muscle
disease of older persons. It leads to pronounced muscle fiber atrophy and
weakness, and there is no successful treatment. We have previously shown that
myostatin precursor protein (MstnPP) and myostatin (Mstn) dimer are increased
in
biopsied s-IBM muscle fibers, and proposed that MstnPP/Mstn increase may
contribute to muscle fiber atrophy and weakness in s-IBM patients. Mstn is known
to be a negative regulator of muscle fiber mass. It is synthesized as MstnPP,
which undergoes posttranslational processing in the muscle fiber to produce
mature, active Mstn. To explore possible mechanisms involved in Mstn
abnormalities in s-IBM, in the present study we utilized primary cultures of
normal human muscle fibers and experimentally modified the intracellular
micro-environment to induce endoplasmic-reticulum (ER)-stress, thereby mimicking
an important aspect of the s-IBM muscle fiber milieu. ER stress was induced
by
treating well-differentiated cultured muscle fibers with either tunicamycin
or
thapsigargin, both well-established ER stress inducers. Our results indicate
for
the first time that the ER stress significantly increased MstnPP mRNA and
protein. The results also suggest that in our system ER stress activates
NF-kappaB, and we suggest that MstnPP increase occurred through the
ER-stress-activated NF-kappaB. We therefore propose a novel mechanism leading
to
the Mstn increase in s-IBM. Accordingly, interfering with pathways inducing
ER
stress, NF-kappaB activation or its action on the MstnPP gene promoter might
prevent Mstn increase and provide a new therapeutic approach for s-IBM and,
possibly, for muscle atrophy in other neuromuscular diseases.
PMID: 17261282 [PubMed - as supplied by publisher]
3: Neuromuscul Disord. 2007 Jan 22; [Epub ahead of print]
Distribution of glucocorticoid receptor alpha and beta subtypes in the
idiopathic inflammatory myopathies.
De Bleecker JL, Paepe BD, Vervaet VL, Arys B, Creus KK, Werbrouck BF, Martin JJ.
Department of Neurology, Ghent University Hospital, De Pintelaan 185, B-9000
Gent, Belgium.
In contrast with dermatomyositis and polymyositis, inclusion body myositis
is
unresponsive to glucocorticoid treatment. Glucocorticoid action is mediated
through an active glucocorticoid receptor-alpha and negatively regulated by
another glucocorticoid receptor isoform. In several autoimmune diseases
glucocorticoid receptor-beta up-regulation is involved in glucocorticoid
resistance. We studied glucocorticoid receptor distribution in normal and
inflammatory myopathy muscle and investigated whether differences in
glucocorticoid receptor-alpha and glucocorticoid receptor-beta protein
expression are involved in the differential glucocorticoid sensitivity in
inclusion body myositis versus polymyositis. Multistep immunofluorescence and
Western blotting on fractionated cytoplasmic or nuclear muscle samples were
used. Glucocorticoid receptor-alpha was the predominant receptor subtype in
muscle and occurred abundantly in myonuclei of control and diseased muscle
alike. Glucocorticoid receptor-beta was constitutively expressed on a subset
of
endothelial cells. No differences between dermatomyositis and the other
idiopathic inflammatory myopathies were observed. Increased nuclear
glucocorticoid receptor that has dissociated from heat shock protein 90 was
found in glucocorticoid treated subjects. Glucocorticoid receptor-alpha and
-beta isoform levels were unaltered in muscle tissues from control subjects
that
had received glucocorticoid treatment prior to biopsy. No differences in
relative glucocorticoid receptor-alpha and glucocorticoid receptor-beta protein
expression were seen in inclusion body myositis versus polymyositis specimens.
Our study indicates that the different glucocorticoid sensitivity in the
idiopathic inflammatory myopathies is not related to up- or down-regulation
of a
given glucocorticoid receptor isoform at the protein level.
PMID: 17251024 [PubMed - as supplied by publisher]
4: J Immunol. 2007 Feb 1;178(3):1523-33.
BTNL2, a Butyrophilin/B7-Like Molecule, Is a Negative Costimulatory Molecule
Modulated in Intestinal Inflammation.
Arnett HA, Escobar SS, Gonzalez-Suarez E, Budelsky AL, Steffen LA, Boiani N,
Zhang M, Siu G, Brewer AW, Viney JL.
Inflammation.
Butyrophilin-like 2 (BTNL2) is a butyrophilin family member with homology to
the
B7 costimulatory molecules, polymorphisms of which have been recently associated
through genetic analyses to sporadic inclusion body myositis and sarcoidosis.
We
have characterized the full structure, expression, and function of BTNL2.
Structural analysis of BTNL2 shows a molecule with an extracellular region
containing two sets of two Ig domains, a transmembrane region, and a previously
unreported cytoplasmic tail. Unlike most other butyrophilin members, BTNL2 lacks
the prototypical B30.2 ring domain. TaqMan and Northern blot analysis indicate
BTNL2 is predominantly expressed in digestive tract tissues, in particular small
intestine and Peyer's patches. Immunohistochemistry with BTNL2-specific Abs
further localizes BTNL2 to epithelial and dendritic cells within these tissues.
Despite its homology to the B7 family, BTNL2 does not bind any of the known
B7
family receptors such as CD28, CTLA-4, PD-1, ICOS, or B and T lymphocyte
attenuator. Because of its localization in the gut and potential role in the
immune system, BTNL2 expression was analyzed in a mouse model of inflammatory
bowel disease. BTNL2 is overexpressed during both the asymptomatic and
symptomatic phase of the Mdr1a knockout model of spontaneous colitis. In
functional assays, soluble BTNL2-Fc protein inhibits the proliferation of murine
CD4(+) T cells from the spleen, mesenteric lymph node, and Peyer's patch. In
addition, BTNL2-Fc reduces proliferation and cytokine production from T cells
activated by anti-CD3 and B7-related protein 1. These data suggest a role for
BTNL2 as a negative costimulatory molecule with implications for inflammatory
disease.
PMID: 17237401 [PubMed - in process]
5: Drug News Perspect. 2006 Nov;19(9):549-57.
Potential therapeutic targets for idiopathic inflammatory myopathies.
De Bleecker JL, Creus KK, De Paepe B.
Department of Neurology, Ghent University Hospital, Ghent, Belgium.
jan.debleecker@Ugent.be
The inflammatory myopathies essentially comprise three diseases with different
immunopathologic features. Dermatomyositis (DM) is a complement-mediated
microangiopathy. The immune response in polymyositis (PM) and sporadic inclusion
body myositis (IBM) is a CD8+ T-cell-mediated cellular reaction against an
unknown muscle fiber antigen. The multiple immune factors that guide
inflammatory cell diapedesis and trafficking have been elucidated over the past
two decades. Many of these molecules can now be targeted by monoclonal
antibodies and other pharmacologic approaches. Randomized controlled trials
are
being started on a number of new agents to find out whether more specific immune
interventions than the currently used glucocorticosteroids can treat DM and
PM
patients with fewer side effects, and may represent a first treatment modality
for IBM, an entity unresponsive to all currently available pharmacological
treatments. Copyright 2006 Prous Science. All rights reserved.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17220960 [PubMed - in process]
6: Neurobiol Dis. 2007 Jan 2; [Epub ahead of print]
The cell-specific expression of metalloproteinase-disintegrins (ADAMs) in
inflammatory myopathies.
Dehmel T, Janke A, Hartung HP, Goebel HH, Wiendl H, Kieseier BC.
Department of Neurology, Heinrich-Heine University, Moorenstrasse 5, 40225
Duesseldorf, Germany.
Inflammatory cell invasion and cytokine activation are important steps in the
pathogenesis of immune-mediated diseases of muscle.
Metalloproteinase-disintegrins (ADAMs) are considered to play a critical role
in
leukocyte migration by promoting cellular adhesion, cleavage of molecules of
the
extracellular matrix and shedding of membrane bound cytokines. Here, we report
the expression patterns of ADAM8, ADAM9, ADAM10, ADAM12, ADAM17 and ADAM19 in
cultured human myoblasts and peripheral blood mononuclear cells (PBMCs) in
vitro, as well as in biopsies from patients suffering from polymyositis (PM),
dermatomyositis (DM), inclusion body myositis (IBM) and non-inflammatory
controls. We observed an in vitro downregulation of the RNAs of ADAM10, ADAM17
and ADAM19 in myoblasts after stimulation with various pro- and
anti-inflammatory mediators, whereas in PBMCs an RNA upregulation of ADAM9,
ADAM10, ADAM17 and ADAM19 was detectable under identical conditions. In human
muscle biopsies, invading CD3+ T lymphocytes expressed ADAM17 and ADAM19,
whereas macrophages co-localized to ADAM8, as detected by immunohistochemistry.
Transfection of PBMCs with ADAM19 single interfering RNA and incubation with
a
metalloproteinase inhibitor suggest proteolytic activity of ADAM19 and
involvement in the shedding of tumor necrosis factor-alpha. No differences in
the cellular expression profiles between PM, DM and IBM were found, whereas
the
sections from non-inflammatory controls did not reveal any positive
immunoreactivity for ADAMs, except for ADAM10, which is localized exclusively
to
muscle fibres. Our results suggest that certain ADAMs are expressed by specific
cell populations during the genesis of immune-mediated diseases of human muscle.
PMID: 17207628 [PubMed - as supplied by publisher]
7: Arthritis Rheum. 2007 Jan;56(1):372-83.
Restricted T cell receptor BV gene usage in the lungs and muscles of patients
with idiopathic inflammatory myopathies.
Englund P, Wahlstrom J, Fathi M, Rasmussen E, Grunewald J, Tornling G, Lundberg
IE.
Karolinska University Hospital at Solna, and Karolinska Institutet, Stockholm,
Sweden.
OBJECTIVE: To investigate T cell receptor (TCR) expression in 3 different
compartments that could be involved in patients with myositis: muscle, lung,
and
peripheral blood. METHODS: Nine patients with polymyositis (PM),
dermatomyositis, or inclusion body myositis underwent bronchoscopy and
bronchoalveolar lavage (BAL) as well as muscle biopsy and blood sampling. A
panel of 19 monoclonal antibodies specific for TCR V(beta) (BV) and V(alpha)
(AV) were used to characterize the TCR profile in CD4(+) and CD8(+) T cell
populations in BAL fluid and peripheral blood by flow cytometry. Muscle biopsy
tissues were analyzed by immunohistochemistry. Patients were also typed for
HLA-DRB1 and DRB3 alleles. RESULTS: A total of 17 T cell expansions were
detected in BAL fluid, 6 in the CD4(+) T cell population and 11 in the CD8(+)
T
cell population. Four T cell expansions were detected in peripheral blood. A
selective TCR V usage was found in muscle. Two PM patients, both of whom had
BAL
fluid BV3(+) T cell expansions in the CD4 population and in whom BV3 was also
a
prominent TCR V segment in muscle tissue, shared the HLA-DRB1*03 allele. These
2
patients were the only ones who were positive for anti-Jo-1 antibody.
CONCLUSION: We found a restricted accumulation of T lymphocytes expressing
selected TCR V-gene segments in the target organ compartments (i.e., lung and
muscle). The occurrence of shared TCR gene segment usage in muscle and lungs
could suggest common target antigens in these organs.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17195241 [PubMed - in process]
8: J Immunol. 2007 Jan 1;178(1):547-56.
A local antigen-driven humoral response is present in the inflammatory
myopathies.
Bradshaw EM, Orihuela A, McArdel SL, Salajegheh M, Amato AA, Hafler DA,
Greenberg SA, O'Connor KC.
Department of Neurology, Laboratory of Molecular Immunology, Center for
Neurologic Diseases and Brigham and Women's Hospital, Harvard Medical School,
Boston, MA 02115, USA.
The inflammatory myopathies are putative autoimmune disorders characterized
by
muscle weakness and the presence of intramuscular inflammatory infiltrates.
Although inclusion body myositis and polymyositis have been characterized as
cytotoxic CD8(+) T cell-mediated diseases, we recently demonstrated high
frequencies of CD138(+) plasma cells in the inflamed muscle tissue of patients
with these diseases. To gain a deeper understanding of the role these B cell
family members play in the disease pathology, we examined the molecular
characteristics of the H chain portion of the Ag receptor. Biopsies of muscle
tissue were sectioned and tissue regions and individual cells were isolated
through laser capture microdissection. Ig H chain gene transcripts isolated
from
the sections, regions, and cells were used to determine the variable region
gene
sequences. Analysis of these sequences revealed clear evidence of affinity
maturation in that significant somatic mutation, isotype switching, receptor
revision, codon insertion/deletion, and oligoclonal expansion had occurred
within the B and plasma cell populations. Moreover, analysis of tissue regions
isolated by laser capture microdissection revealed both clonal expansion and
variation, suggesting that local B cell maturation occurs within muscle. In
contrast, sequences from control muscle tissues and peripheral blood revealed
none of these characteristics found in inflammatory myopathy muscle tissue.
Collectively, these data demonstrate that Ag drives a B cell Ag-specific
response in muscle in patients with dermatomyositis, inclusion body myositis,
and polymyositis. These findings highlight the need for a revision of the
current paradigm of exclusively T cell-mediated intramuscular Ag-specific
autoimmunity in inclusion body myositis and polymyositis.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 17182595 [PubMed - in process]
9: Muscle Nerve. 2006 Dec 1; [Epub ahead of print]
Myopathy associated with gluten sensitivity.
Hadjivassiliou M, Chattopadhyay AK, Grunewald RA, Jarratt JA, Kandler RH, Rao
DG, Sanders DS, Wharton SB, Davies-Jones GA.
Department of Neurology, The Royal Hallamshire Hospital, Glossop Road, Sheffield
S10 2JF, UK.
Ataxia and peripheral neuropathy are the most common neurological manifestations
of gluten sensitivity. Myopathy is a less common and poorly characterized
additional neurological manifestation of gluten sensitivity. We present our
experience with 13 patients who presented with symptoms and signs suggestive
of
a myopathy and in whom investigation led to the diagnosis of gluten sensitivity.
Three of these patients had a neuropathy with or without ataxia in addition
to
the myopathy. The mean age at onset of the myopathic symptoms was 54 years.
Ten
patients had neurophysiological evidence of myopathy. Inflammatory myopathy
was
the most common finding on neuropathological examination. One patient had
basophilic rimmed vacuoles suggestive of inclusion-body myositis. Six patients
received immunosuppressive treatment in addition to starting on a gluten-free
diet; five improved and one remained unchanged. Among seven patients not on
immunosuppressive treatment, four showed clinical improvement of the myopathy
with a gluten-free diet. The improvement was also associated with reduction
or
normalization of serum creatine kinase level. The myopathy progressed in one
patient who refused the gluten-free diet. Myopathy may be another manifestation
of gluten sensitivity and is likely to have an immune-mediated pathogenesis.
A
gluten-free diet may be a useful therapeutic intervention. Muscle Nerve, 2006.
PMID: 17143894 [PubMed - as supplied by publisher]
10: Muscle Nerve. 2007 Feb;35(2):266-7.
Synaptic dysfunction does not contribute to muscle weakness in inclusion-body
myositis.
Badrising UA, Verschuuren JJ, Wintzen AR, van Dijk JG.
Department of Neurology and Clinical Neurophysiology Leiden University Medical
Center Leiden, The Netherlands.
PMID: 17143892 [PubMed - in process]
11: Clin Rheumatol. 2006 Nov 22; [Epub ahead of print]
(99m)Technetium pyrophosphate scintigraphy in the detection of skeletal muscle
disease.
Walker UA, Garve K, Brink I, Miehle N, Peter HH, Kelly T.
Department of Rheumatology and Clinical Immunology, Albert-Ludwigs University
Medical School, Hugstetterstr. 55, 79106, Freiburg, Germany,
ulrich.walker@klinikum.uni-freiburg.de.
We aimed to assess the specificity and sensitivity of (99m)technetium
pyrophosphate muscle scintigraphy in the diagnostic workup of patients with
suspected myopathy. We reviewed the charts of 166 patients; 52% of the subjects
had myalgias, 36% had muscle weakness, 45% had an elevated serum creatine kinase
(CK), and 49% had an increased C reactive protein (CRP). Scintigraphy was
positive in 34 patients (20%). The test was more sensitive in the presence of
muscle weakness, elevated CK, or increased CRP. The presence of myalgias did
not
influence the odds. Sensitivity was 60% in patients with the final diagnosis
of
polymyositis, dermatomyositis, or inclusion body myositis, and 70% in
noninflammatory myopathies. Eight percent had false positive scintigrams. In
individuals with biopsy-proven myopathy (51 subjects), the diagnostic
sensitivity was 43%, and its specificity was 60%. Low positive and high negative
likelihood ratios (5.0 and 0.65, respectively) document an only limited
diagnostic efficiency of (99m)Tc-PYP scintigraphy in the evaluation of
inflammatory and noninflammatory myopathies and suggest that the test is not
helpful in the routine diagnostic workup of muscle complaints, even after a
priori selection of patients for CK plus CRP abnormalities.
PMID: 17119862 [PubMed - as supplied by publisher]
12: Joint Bone Spine. 2006 Dec;73(6):646-54. Epub 2006 Oct 10.
Contribution of autoantibodies to the diagnosis and nosology of inflammatory
muscle disease.
Sordet C, Goetz J, Sibilia J.
Rheumatology Department and Immunology Laboratory, Strasbourg Teaching Hospital,
Louis Pasteur University, EA 3432 Strasbourg, France.
The myositides are systemic autoimmune conditions of which the most important
are polymyositis, dermatomyositis, and inclusion body myositis. In addition
to
the classic clinical diagnostic criteria, myositis-specific autoantibodies were
identified about 15 years ago. Among the dozen or so myositis-specific
autoantibodies reported to date, the most characteristic are directed against
cytoplasmic antigens, such as tRNA synthetase (Jo-1 or PL-1, PL-7, PL-12, EJ,
OJ, JS, and KS), signal-recognition particle (SRP), Mas, KJ, Fer (eEF1), and
Wa.
Antibodies to nuclear antigens include anti-Mi-2, anti-PMS (PMS1, and PMS2),
and
related antibodies (MLH1, DNA protein kinase catalytic subunit (DNA PKCS)...),
and anti-56 kDa. Myositis-associated antibodies are not specific but may be
found in patients with myositis. They are directed to nuclear or nucleolar
antigens such as PM-Scl, Ku, RNP (U1-RNP and U2-RNP, U4/U6-RNP, and U5-RNP),
Ro
52 kDa and, more rarely, Ro 60 kDa and La. Myositis-specific antibodies have
proved useful on two fronts. They have improved the diagnosis of myositis by
leading to the identification of characteristic clinical patterns, such as
anti-synthetase syndrome. The place of autoantibodies alongside classic clinical
and laboratory criteria remains to be determined, however. First, standardized
assays will have to be developed to replace current detection methods, which
use
widely variable techniques and antigen preparations. Myositis-specific
antibodies have also shed light on the pathogenesis of myositis. For instance,
the development of antibodies to tRNA synthetases constitutes an original
autoimmunity model that shows how muscle damage, probably of a nonspecific
nature, can lead to the production of autoantibodies that perpetuate and
aggravate the muscle lesions.
Publication Types:
Review
PMID: 17110150 [PubMed - indexed for MEDLINE]
13: Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16995-7000. Epub 2006 Oct 31.
MyoD expression restores defective myogenic differentiation of human
mesoangioblasts from inclusion-body myositis muscle.
Morosetti R, Mirabella M, Gliubizzi C, Broccolini A, De Angelis L, Tagliafico
E,
Sampaolesi M, Gidaro T, Papacci M, Roncaglia E, Rutella S, Ferrari S, Tonali
PA,
Ricci E, Cossu G.
Department of Neurosciences and Interdisciplinary Laboratory for Stem Cell
Research and Cellular Therapy, Catholic University, Largo A. Gemelli 8, 00168
Rome, Italy.
Inflammatory myopathies (IM) are acquired diseases of skeletal muscle comprising
dermatomyositis (DM), polymyositis (PM), and inclusion-body myositis (IBM).
Immunosuppressive therapies, usually beneficial for DM and PM, are poorly
effective in IBM. We report the isolation and characterization of
mesoangioblasts, vessel-associated stem cells, from diagnostic muscle biopsies
of IM. The number of cells isolated, proliferation rate and lifespan, markers
expression, and ability to differentiate into smooth muscle do not differ among
normal and IM mesoangioblasts. At variance with normal, DM and PM
mesoangioblasts, cells isolated from IBM, fail to differentiate into skeletal
myotubes. These data correlate with lack in connective tissue of IBM muscle
of
alkaline phosphatase (ALP)-positive cells, conversely dramatically increased
in
PM and DM. A myogenic inhibitory basic helix-loop-helix factor B3 is highly
expressed in IBM mesoangioblasts. Indeed, silencing this gene or overexpressing
MyoD rescues the myogenic defect of IBM mesoangioblasts, opening novel
cell-based therapeutic strategies for this crippling disorder.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17077152 [PubMed - indexed for MEDLINE]
14: Am J Clin Pathol. 2006 Dec;126(6):843-8.
Diagnostic yield associated with multiple simultaneous skeletal muscle biopsies.
Prayson RA.
Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH
44195, USA.
Certain skeletal muscle disorders, such as inflammatory myopathies, may show
regional variability, prompting consideration of simultaneous biopsy of more
than 1 muscle to increase the likelihood of diagnosis. There are few data in
the
literature to support this approach. This study is a retrospective 8-year review
of 99 cases (52 men; mean age, 61.8 years) who had multiple muscles biopsied
simultaneously. The most common clinical symptoms prompting biopsy included
weakness in 83 cases and myalgia in 15. The most common diagnoses were as
follows: neurogenic atrophy, 48; inflammatory myopathy, excluding inclusion
body
myositis, 29; and type II muscle fiber atrophy, 24. Diagnoses were the same
in
both biopsied muscles in 54 cases (55%). In 17 cases, a diagnosis was made from
only 1 biopsy. Of 29 inflammatory myopathies and vasculitis (excluding inclusion
body myositis), a diagnosis could be made from only 1 of the 2 biopsies in 10
cases (34%). In a significant subset of cases, a potentially treatable
inflammatory myopathic condition might have been missed if only 1 site had been
biopsied, justifying biopsy of 2 sites in suspected cases of inflammatory
myopathy.
PMID: 17074688 [PubMed - indexed for MEDLINE]
15: Neuromuscul Disord. 2006 Dec;16(12):839-44. Epub 2006 Oct 23.
AbetaPP-overexpression and proteasome inhibition increase alphaB-crystallin
in
cultured human muscle: relevance to inclusion-body myositis.
Wojcik S, Engel WK, McFerrin J, Paciello O, Askanas V.
USC Neuromuscular Center, Department of Neurology, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA
90017-1912, USA.
Amyloid-beta precursor protein (AbetaPP) and its fragment amyloid-beta (Abeta)
are increased in s-IBM muscle fibers and appear to play an important role in
the
pathogenic cascade. alphaB-Crystallin (alphaBC) was shown immunohistochemically
to be accumulated in s-IBM muscle fibers, but the stressor(s) influencing
alphaBC accumulation was not identified. We now demonstrate, using our
experimental IBM model based on genetic overexpression of AbetaPP into cultured
normal human muscle fibers, that: (1) AbetaPP overexpression increased alphaBC
3.7-fold (p=0.025); (2) additional inhibition of proteasome with epoxomicin
increased alphaBC 7-fold (p=0.002); and (3) alphaBC physically associated with
AbetaPP and Abeta oligomers. We also show that in biopsied s-IBM muscle fibers,
alphaBC was similarly increased 3-fold (p=0.025) and physically associated with
AbetaPP and Abeta oligomers. We propose that increased AbetaPP is a stressor
increasing alphaBC expression in s-IBM muscle fibers. Determining the
consequences of alphaBC association with Abeta oligomers could have clinical
therapeutic relevance.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 17056255 [PubMed - in process]
16: Biochem Soc Trans. 2006 Nov;34(Pt 5):738-42.
Molecular misreading: the occurrence of frameshift proteins in different
diseases.
van Leeuwen FW, Kros JM, Kamphorst W, van Schravendijk C, de Vos RA.
Netherlands Institute for Neuroscience, Meibergdreef 47, 1105 BA Amsterdam,
The
Netherlands. f.van.leeuwen@nin.knaw.nl
Neuronal homoeostasis requires a constant balance between biosynthetic and
catabolic processes. Eukaryotic cells primarily use two distinct mechanisms
for
degradation: the proteasome and autophagy of aggregates by the lysosomes. We
focused on the UPS (ubiquitin-proteasome system). As a result of molecular
misreading, misframed UBB (ubiquitin B) (UBB+1) is generated. UBB+1 accumulates
in the neuritic plaques and neurofibrillary tangles in all patients with AD
(Alzheimer's disease) and in the neuronal and glial hallmarks of other
tauopathies and in polyglutamine diseases such as Huntington's disease. UBB+1
is
not present in synucleinopathies such as Parkinson's disease. We showed that
UBB+1 causes UPS dysfunction, aggregation and apoptotic cell death. UBB+1 is
also present in non-neurological cells, hepatocytes of the diseased liver and
in
muscles during inclusion body myositis. Other frequently occurring (age-related)
diseases such as Type 2 (non-insulin-dependent) diabetes mellitus are currently
under investigation. These findings point to the importance of the UPS in
diseases and open new avenues for target identification of the main players
of
the UPS. Treatment of these diseases with tools (e.g. viral RNA interference
constructs) to intervene with specific targets is the next step.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17052186 [PubMed - indexed for MEDLINE]
17: Acta Myol. 2006 Jun;25(1):13-22.
Parkin and its association with alpha-synuclein and AbetaPP in inclusion-body
myositis and AbetaPP-overexpressing cultured human muscle fibers.
Paciello O, Wojcik S, Engel WK, McFerrin J, Askanas V.
USC Neuromuscular Center, Department of Neurology, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, Los Angeles
90017-1912, USA.
Parkin, an E3-ubiquitin ligase in the ubiquitin-proteasome system, facilitates
degradation of alpha-synuclein and other proteins. Since ubiquitinated
multiprotein-aggregates containing amyloid-beta (Abeta), alpha-synuclein, and
other proteins, are characteristic of sporadic inclusion-body myositis (s-IBM)
muscle fibers, we asked whether parkin might have a role in s-IBM pathogenesis.
We studied the association of parkin with alpha-synuclein and Abeta-precursor
protein (AbetaPP) in s-IBM muscle biopsies and in our IBM model based on
overexpression of AbetaPP into cultured human muscle fibers. We report the
following in s-IBM muscle fibers: a) parkin was increased 2.7 fold and
accumulated in aggregates also containing Abeta and alpha-synuclein; b)
alpha-synuclein was increased 6.3 fold; c) parkin physically associated with
alpha-synuclein and AbetaPP; d) alpha-synuclein and AbetaPP were ubiquitinated.
In the IBM model: a) parkin was increased 2.7 fold, b) it associated with
alpha-synuclein and AbetaPP. CONCLUSION: 1. This is the first demonstration
that
in a human muscle disease alpha-synuclein associates with parkin, and might
be
ubiquitinated by it. 2. The small increase of parkin relative to the much larger
increase of alpha-synuclein might be insufficient to secure complete
ubiquitination and consequent degradation of alpha-syn. 3. AbetaPP might be
a
novel substrate of parkin.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 17039976 [PubMed - indexed for MEDLINE]
18: J Neurol. 2006 Sep;253(Supplement 5):v64-v65.
Therapeutic options in autoimmune inflammatory myopathies (dermatomyositis,
polymyositis, inclusion body myositis).
Pongratz D.
Friedrich-Baur-Institut, Medizinischen Fakultat, Neurologischen Klinik und
Poliklinik, Ludwig Maximilians Universitat Munchen, Ziemssenstrasse 1, 80336,
Munchen, Germany.
Polymyositis, dermatomyositis, and inclusion body myositis are idiopathic
inflammatory myopathies of unknown etiology with autoimmune pathogenesis. For
choosing an individual and efficient therapy, diagnostic assignment is an
important factor. Therapeutic options in dermatomyositis and polymyositis
include corticosteroids and immunosuppressives. Intravenous immunoglobulins
are
only needed in special cases. In inclusion body myositis, corticosteroids and
immunosuppressives are not successful. At the moment intravenous immunoglobulins
are the only therapeutic possibility.
PMID: 16998756 [PubMed - as supplied by publisher]
19: J Neurol. 2006 Sep;253(Supplement 5):v2-v8.
Epidemiology of neuroimmunological diseases.
Flachenecker P.
Neurological Rehabilitation Center "Quellenhof", Kuranlagenallee
2, 75323, Bad
Wildbad, Germany, flachenecker@quellenhof.de.
This review gives an overview of various neuroimmunological diseases in terms
of
incidence and prevalence rates, age and sex distribution, and the frequency
of
subtypes, if applicable. The disorders selected for review are inflammatory
muscle disorders (polymyositis, dermatomyositis and inclusion body myositis),
myasthenia gravis, immune-mediated polyneuropathies (Guillain-Barre syndrome,
chronic polyneuritis and vasculitic neuropathies), and multiple sclerosis.
PMID: 16998750 [PubMed - as supplied by publisher]
20: Hum Pathol. 2006 Oct;37(10):1367-8; author reply 1368.
Comment on:
Hum Pathol. 2005 Aug;36(8):917-21.
Is myocardial damage truly absent in inclusion body myositis with elevated
troponin T level?
Finsterer J, Stollberger C.
Publication Types:
Comment
Letter
PMID: 16996378 [PubMed - indexed for MEDLINE]
21: J Neurol Neurosurg Psychiatry. 2006 Oct;77(10):1187-90.
Comment in:
J Neurol Neurosurg Psychiatry. 2006 Oct;77(10):1104-5.
Expression of granulysin in polymyositis and inclusion-body myositis.
Ikezoe K, Ohshima S, Osoegawa M, Tanaka M, Ogawa K, Nagata K, Kira JI.
Department of Neurology, Neurological Institute, Graduate School of Medical
Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582,
Japan.
BACKGROUND: Granulysin, a recently defined cytolytic molecule, is expressed
in
cytotoxic T cells and natural killer cells in a similar way to perforin, which
is reported to have a major role in the pathogenesis of polymyositis and
inclusion-body myositis (IBM). OBJECTIVE: To clarify the role of granulysin
in
polymyositis and IBM. METHODS: The expression of granulysin and perforin was
examined by double staining with CD8, CD4 and CD56 in endomysial infiltrating
cells and autoinvasive cells in muscle biopsy specimens of 17 patients with
polymyositis (6 steroid resistant and 11 steroid responsive) and of 7 patients
with IBM. RESULTS: Similar to perforin, granulysin was expressed in CD8, CD4
or
CD56 cells in patients with polymyositis and IBM. The ratio of cells double
positive for granulysin and CD8 to all CD8 cells at endomysial sites was notably
higher in steroid-resistant polymyositis than in steroid-responsive polymyositis
and IBM. CONCLUSION: Granulysin expression in CD8 cells seems to be correlated
with steroid resistance in polymyositis.
PMID: 16980658 [PubMed - indexed for MEDLINE]
22: Muscle Nerve. 2007 Jan;35(1):17-23.
Myeloid dendritic cells in inclusion-body myositis and polymyositis.
Greenberg SA, Pinkus GS, Amato AA, Pinkus JL.
Department of Neurology, Division of Neuromuscular Disease, Brigham and Women's
Hospital, 75 Francis Street, and Harvard Medical School, Boston, Massachusetts
02115, USA. sgreenberg@partners.org
Dendritic cells (DCs), immune system cells central to the development of
immunity, have not previously been reported in muscle in inclusion-body myositis
(IBM). We performed immunohistochemical studies on muscle biopsy specimens from
50 patients using monoclonal antibodies that distinguish two classes of DCs,
myeloid DC and plasmacytoid DC. In 17 of 20 IBM and 9 of 10 polymyositis (PM)
specimens, myeloid DCs were present in substantial numbers, frequently
surrounded and sometimes invading otherwise intact myofibers, and were part
of
dense collections of cells that included T cells. Dermatomyositis muscle had
more plasmacytoid DCs than myeloid DCs, whereas IBM and PM had greater numbers
of myeloid DCs. The stellate morphology of myeloid DCs in dense collections
of
cells that included T cells suggests local intramuscular antigen presentation
in
IBM and PM.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16969836 [PubMed - in process]
23: Muscle Nerve. 2007 Jan;35(1):49-54.
Celiac disease and antibodies associated with celiac disease in patients with
inflammatory myopathy.
Selva-O'Callaghan A, Casellas F, de Torres I, Palou E, Grau-Junyent JM,
Vilardell-Tarres M.
Internal Medicine Department, Vall D'Hebron General Hospital, Universitat
Autonoma Barcelona, C/Siracusa No. 12 Bis A, Barcelona, Spain.
aselva@vhebron.net
Celiac disease is usually associated with autoimmune disorders and has
occasionally been reported in patients with inflammatory myopathies. Our aim
was
to determine the presence of celiac disease and antibodies associated with
celiac disease in patients with inflammatory myopathies and to investigate their
relationship. Serum antigliadin, anti-tissue transglutaminase, and
antiendomysial antibodies were determined in 51 patients with inflammatory
myopathies. HLA-DQ2 and -DQ8 alleles were studied to assess their complementary
diagnostic value. Jejunal biopsy was performed in patients with moderate to
high
levels of antigliadin antibodies. Patients with jejunal histology consistent
with celiac disease initiated a gluten-free diet. Seventeen patients (31%) were
positive for antigliadin antibodies, which were significantly more frequent
in
patients with inclusion-body myositis than dermatomyositis (P < 0.001). Positive
status to HLA-DQ2 and/or -DQ8 did not differ between antigliadin-positive (75%
and 12.5%) or -negative (60% and 15%) patients. Three of five jejunal biopsies
were diagnostic for celiac disease with histological normalization after a
gluten-free diet. Thus, celiac disease is more prevalent in patients with
inflammatory myopathies than in the general population. Positive status to
HLA-DQ2 allele, which is known to be more frequent in patients with inflammatory
myopathies, could explain the high prevalence of antigliadin antibodies in this
population. The diagnostic value of HLA-DQ2 or -DQ8 haplotypes to detect celiac
disease in patients with inflammatory myopathy is limited.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16967485 [PubMed - in process]
24: Phys Med Biol. 2006 Sep 21;51(18):4719-33. Epub 2006 Sep 4.
Mean time-of-flight of photons in transillumination measurements of optically
anisotropic tissue with an inclusion.
Dudko OK, Weiss GH, Chernomordik V.
Mathematical and Statistical Computing Laboratory, Division of Computational
Bioscience, Center for Information Technology, National Institutes of Health,
Bethesda, MD 20892, USA.
We study the effect of optical anisotropy on the mean time-of-flight of photons
in a slab of turbid medium containing an inclusion whose optical properties
differ from those of the bulk. For this analysis the difference in the mean
time
for a photon introduced into the slab to reach a specified target point with
and
without the inclusion is calculated. This difference is defined to be a measure
of the contrast. The theoretical model is based on a continuous-time random
walk
on a lattice, which can be solved exactly and furnishes an exact expression
for
the contrast. Qualitative and quantitative characteristics of the contrast are
analysed as functions of the geometric configuration of the system components
(locations of the source, the inclusion and the detector), parameters that
specify the optical anisotropy of the medium, and either the scattering
properties of the inclusion or the lifetime of the small fluorophore in the
case
of the time-resolved fluorescence experimental configuration.
Publication Types:
Research Support, N.I.H., Intramural
PMID: 16953052 [PubMed - indexed for MEDLINE]
25: FASEB J. 2006 Oct;20(12):2165-7. Epub 2006 Aug 29.
Transgenic expression of beta-APP in fast-twitch skeletal muscle leads to
calcium dyshomeostasis and IBM-like pathology.
Moussa CE, Fu Q, Kumar P, Shtifman A, Lopez JR, Allen PD, LaFerla F, Weinberg
D,
Magrane J, Aprahamian T, Walsh K, Rosen KM, Querfurth HW.
Department of Neurology, Caritas St. Elizabeth's Medical Center of Boston,
Tufts
University School of Medicine, 736 Cambridge St., Boston, MA, USA.
Intracellular deposition of the beta-amyloid (Abeta) peptide is an increasingly
recognized pathological hallmark associated with neurodegeneration and muscle
wasting in Alzheimer's disease (AD) and inclusion body myositis (IBM),
respectively. Previous reports have implicated dysregulation of beta-amyloid
precursor protein (betaAPP) expression in IBM. Accumulation of full-length
betaAPP, its various proteolytic derivatives including Abeta, and phospho-tau
into vacuolated inclusions is an early pathogenic event. We previously reported
on a statistical tendency favoring fast twitch fiber involvement in IBM,
reminiscent of the tissue specific patterns of misfolded protein deposition
seen
in neurodegenerative diseases. To test this principle, we generated an animal
model in which human wild-type (WT) betaAPP expression was limited to postnatal
type II skeletal muscle. Hemizygous transgenic mice harboring increased levels
of holo betaAPP751 and Abeta in skeletal muscle fibers became significantly
weaker with age compared with nontransgenic littermates and exhibited typical
myopathic features. A subpopulation of dissociated muscle fibers from transgenic
mice exhibited a 2-fold increase in resting calcium and membrane depolarization
compared with nontransgenic littermates. Taken together, these data indicate
that overexpression of human betaAPP in fast twitch skeletal muscle of
transgenic mice is sufficient for the development of some features
characteristic of IBM, including abnormal tau histochemistry. The increase in
resting calcium and depolarization are novel findings, suggesting both a
mechanism for the weakness and an avenue for therapeutic intervention in IBM.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16940437 [PubMed - indexed for MEDLINE]
26: Neuromuscul Disord. 2006 Nov;16(11):754-8. Epub 2006 Aug 28.
Familial inclusion body myositis in a mother and son with different ancestral
MHC haplotypes.
Mastaglia F, Price P, Walters S, Fabian V, Miller J, Zilko P.
Centre for Neuromuscular and Neurological Disorders, University of Western
Australia, 4th Floor, A Block, Queen Elizabeth II Medical Centre, Nedlands WA
6009, Australia. flmast@cyllene.uwa.edu.au
An Ashkenazi Jewish family in which the mother and a son both have inclusion
body myositis (IBM) is reported. The condition developed at an earlier age and
was more rapidly progressive and less responsive to treatment in the son than
in
the mother or other IBM patients in our clinic. Genetic analysis showed that
the
mother carried alleles of the 8.1 MHC ancestral haplotype (AH; HLA-B8,
DRB1*0301), which is found in 85% of IBM patients in Western Australia. The
son
did not inherit this haplotype, but carried alleles characteristic of the 52.1AH
(HLA-B5, DRB1*1502) of paternal origin. The findings indicate that in this
family either the 8.1AH or 52.1AH may carry susceptibility for IBM and that
the
52.1AH is associated with a more severe and treatment-resistant form of the
disease.
Publication Types:
Case Reports
PMID: 16934978 [PubMed - indexed for MEDLINE]
27: Nat Clin Pract Rheumatol. 2006 May;2(5):270-7.
Mechanisms of disease: genetics of Paget's disease of bone and related
disorders.
Daroszewska A, Ralston SH.
University of Edinburgh, UK.
Paget's disease of bone (PDB) is a common disorder in which focal abnormalities
of increased bone turnover lead to complications such as bone pain, deformity,
pathological fractures, and deafness. PDB has a strong genetic component and
several susceptibility loci for the disease have been identified by genome-wide
scans. Mutations that predispose individuals to PDB and related disorders have
been identified in four genes. The rare PDB-like syndromes of familial expansile
osteolysis, early-onset familial PDB, and expansile skeletal hyperphosphatasia
are caused by insertion mutations in TNFRSF11A, which encodes receptor activator
of nuclear factor (NF)kappaB (RANK)-a critical regulator of osteoclast function.
Inactivating mutations in TNFRSF11B, which encodes osteoprotegerin (a decoy
receptor for RANK ligand) cause idiopathic hyperphosphatasia, and polymorphisms
in this gene seem to increase the risk for classical PDB. Mutations of the
sequestosome 1 gene (SQSTM1), which encodes an important scaffold protein in
the
NFkappaB pathway, are a common cause of classical PDB. The rare syndrome of
hereditary inclusion body myopathy, PDB, and fronto-temporal dementia is caused
by mutations in the valosin-containing protein (VCP) gene. This gene encodes
VCP, which has a role in targeting the inhibitor of NFkappaB for degradation
by
the proteasome. Several additional genes for PDB remain to be discovered, and
it
seems likely that they will also involve the RANK-NFkappaB signaling pathway
or
components of the proteasomal processing of this pathway, underscoring the
critical importance of this signaling pathway in bone metabolism and bone
disease.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16932700 [PubMed - indexed for MEDLINE]
28: Nat Clin Pract Rheumatol. 2006 Apr;2(4):219-27.
Erratum in:
Nat Clin Pract Rheumatol. 2006 Jul;2(7):398.
Mechanisms of disease: signaling pathways and immunobiology of inflammatory
myopathies.
Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Bethesda, MD 20892-1382, USA.
dalakasm@ninds.nih.gov
The signaling pathways involved in the immunobiology of polymyositis,
dermatomyositis, and inclusion-body myositis are outlined in this Review, which
is based on research performed during the past 10 years. In dermatomyositis,
the
complement cascade is activated and the expression of cytokines and chemokines
is upregulated. In polymyositis and inclusion-body myositis, autoinvasive CD8+
T
cells are clonally expanded. This T-cell subset possesses conserved amino-acid
sequences in complementarity-determining region 3 of the T-cell receptor and,
via the perforin pathway, exerts a myotoxic effect on muscle fibers that express
major histocompatibility complex (MHC) class I molecules. In all inflammatory
myopathies, molecules associated with T-cell transmigration and cytokine
signaling, as well as chemokines and their receptors, are strongly expressed
by
endothelial and inflammatory cells. Early in the pathogenesis of polymyositis
and inclusion-body myositis, expression of MHC class I molecules on muscle
fibers is upregulated, even in the absence of autoinvasive CD8+ T cells.
Emerging data indicate that such continuous upregulation of the expression of
MHC class I molecules on muscle fibers leads to an endoplasmic reticulum stress
response, intracellular accumulation of misfolded glycoproteins, and activation
of nuclear factor kappaB pathways, which can further stimulate formation of
MHC
class I-CD8 complexes, resulting in a self-sustaining inflammatory response.
Advances in our understanding of the signaling pathways involved in the
pathogenesis of these inflammatory myopathies are expected to result in the
identification of novel therapeutic targets for these diseases.
Publication Types:
Research Support, N.I.H., Intramural
Review
PMID: 16932688 [PubMed - indexed for MEDLINE]
29: Nat Clin Pract Neurol. 2006 Aug;2(8):437-47.
Sporadic inclusion body myositis--diagnosis, pathogenesis and therapeutic
strategies.
Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Bethesda, MD 20892-1382, USA.
dalakasm@ninds.nih.gov
Sporadic inclusion body myositis (sIBM) presents with a characteristic clinical
phenotype of slow-onset weakness and atrophy, affecting proximal and distal
limb
muscles and facial and pharyngeal muscles. Histologically, sIBM is characterized
by chronic myopathic features, lymphocytic infiltrates invading non-vacuolated
fibers, vacuolar degeneration, and accumulation of amyloid-related proteins.
The
cause of sIBM is unclear, but two processes-one autoimmune and the other
degenerative-appear to occur in parallel. In contrast to dystrophies, in sIBM
the autoinvasive CD8(+) T cells are cytotoxic and antigen-driven, invading
muscle fibers expressing major histocompatibility complex class I antigen and
costimulatory molecules. The concurrent degenerative features include
vacuolization, filamentous inclusions and intracellular accumulations of
amyloid-beta-related molecules. Although viruses have not been amplified from
the muscle fibers, at least 12 cases of sIBM have been seen in association with
retroviral infections, indicating that a chronic persistent viral infection
might be a potential triggering factor. Emerging data imply that continuous
upregulation of cytokines and major histocompatibility complex class I on the
muscle fibers causes an endoplasmic reticulum stress response, resulting in
intracellular accumulation of misfolded glycoproteins and activation of the
transcription factor NFkappaB, leading to further cytokine activation. In spite
of the brisk, antigen-driven T-cell infiltrates, sIBM does not respond to
immunotherapies. New therapies using monoclonal antibodies against lymphocyte
signaling pathways might prove helpful in arresting disease progression.
Publication Types:
Research Support, N.I.H., Intramural
Review
PMID: 16932602 [PubMed - indexed for MEDLINE]
30: Neurology. 2006 Aug 22;67(4):560-1.
Comment on:
Neurology. 2006 Aug 22;67(4):644-51.
Frontotemporal dementia: the post-tau era.
Ghetti B, Goebel HH.
Publication Types:
Comment
Editorial
PMID: 16924003 [PubMed - indexed for MEDLINE]
31: Neuromuscul Disord. 2006 Aug;16(8):495-7. Epub 2006 Aug 22.
Raised troponin T in inclusion body myositis is common and serum levels are
persistent over time.
Lindberg C, Klintberg L, Oldfors A.
Neuromuscular Centre, Department of Neurology, Sahlgrenska University Hospital,
Sweden. christopher.lindberg@vgregion.se
Cardiac Troponin T (cTnT), creatine kinase (CK) and creatine kinase isoenzyme
MB
(CKMB) were measured in 42 consecutive patients with sporadic inclusion body
myositis (s-IBM). 26 patients (62%) had a cTnT level >0.05 microg/L, the
cut off
used in the diagnosis of myocardial infarction. The cTnT levels correlated
somewhat more closely to CKMB (rho=0.83, p<0.0001) than to CK (rho=0.60,
p<0.0001). Patients on immunosuppressive treatment had lower cTnT levels
than
untreated, while there were no significant differences according to age, disease
duration or gender. Repeated samples in 26 patients showed that the cTnT levels
were essentially unchanged over time up to 17 months. None of the patients had
signs of myocardial damage or renal failure at time of sampling. It may be of
value to analyse cTnT at some occasion(s) in s-IBM patients.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16920359 [PubMed - indexed for MEDLINE]
32: Curr Rheumatol Rep. 2006 Jun;8(3):178-87.
Differential diagnosis of idiopathic inflammatory myopathies.
Baer AN.
Department of Medicine, Division of Allergy, Immunology, and Rheumatology,
School of Medicine and Biomedical Sciences, State University of New York at
Buffalo, Erie County Medical Center, 462 Grider Street, Buffalo, NY 14215, USA.
alanbaer@buffalo.edu
Symmetric proximal muscle weakness has many potential etiologies. An onset
over
weeks to months and elevated serum levels of muscle enzymes point to the
diagnosis of an idiopathic inflammatory myopathy, including dermatomyositis,
polymyositis, and inclusion body myositis. However, there is a broad
differential diagnosis, including certain muscular dystrophies, metabolic
myopathies, drug- or toxin-induced myotoxicity, neuropathies, and infectious
myositides. The differentiation is critical for defining appropriate treatment.
In addition, an alternative diagnosis may explain the lack of response to
immunosuppressive treatment for some patients with polymyositis. Careful
clinical evaluation and choice of available diagnostic tests are required to
establish the correct diagnosis.
Publication Types:
Review
PMID: 16901075 [PubMed - indexed for MEDLINE]
33: J Neuropathol Exp Neurol. 2006 Aug;65(8):826-33.
Proteomic analysis of inclusion body myositis.
Li J, Yin C, Okamoto H, Jaffe H, Oldfield EH, Zhuang Z, Vortmeyer AO, Rushing
EJ.
Surgical Neurology Branch, National Institutes of Neurological Disorders and
Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Sporadic inclusion body myositis (IBM) is the most frequently acquired
inflammatory myopathy of late adult life, yet its diagnostic criteria and
pathogenesis remain poorly defined. Because effective treatment is lacking,
research efforts have intensified to identify specific markers for this
debilitating disorder. In this study, proteomic analysis of 4 cases of sporadic
IBM was compared with 5 cases of inflammatory myopathy without clinicopathologic
features of IBM to distinguish the IBM-specific proteome. Proteins were
separated by 2-dimensional polyacrylamide gel electrophoresis and profiled by
mass spectrometric sequencing. Expression of most proteins remained unchanged;
however, 16 proteins were upregulated and 6 proteins were downregulated in IBM
compared with cases of non-IBM inflammatory myopathy. These IBM-specific
proteins included apolipoprotein A-I, amyloid beta precursor protein, and
transthyretin, which have been associated with amyloidosis; superoxide
dismutase, enolase, and various molecular chaperones indicate perturbations
in
detoxification, energy metabolism, and protein folding, respectively. The
IBM-downregulated proteins mainly serve as carriers for muscle contraction and
other normal muscle functions. We further applied Western blot and
immunohistochemistry to verify the proteomic findings. This study validates
proteomics as a powerful tool in the study of muscle disease and indicates a
unique pattern of protein expression in IBM.
Publication Types:
Comparative Study
PMID: 16896316 [PubMed - indexed for MEDLINE]
34: J Rheumatol. 2006 Aug;33(8):1623-30.
Platelet-endothelial cell adhesion molecule-1 and CD146: soluble levels and
in
situ expression of cellular adhesion molecules implicated in the cohesion of
endothelial cells in idiopathic inflammatory myopathies.
Figarella-Branger D, Schleinitz N, Boutiere-Albanese B, Camoin L, Bardin N,
Guis
S, Pouget J, Cognet C, Pellissier JF, Dignat-George F.
Laboratoire de Biopathologie de l'Adhesion et de la Signalisation, EA 3281,
Faculte de Medecine Timone, Universite de la Mediterranee, Marseille, France.
Dominique.Figarella-Branger@medecine.univ-mrs.fr
OBJECTIVE: Idiopathic inflammatory myopathies (IIM) are a heterogeneous group
of
diseases characterized by chronic inflammation of muscles. We investigated the
role of cellular adhesion molecules implicated in the cohesion of endothelial
cells in IIM. METHODS: In 22 patients with IIM we investigated plasma
concentrations of soluble junctional adhesion molecules [platelet-endothelial
cell adhesion molecule (sPECAM-1) and sCD146] and cellular adhesion molecules
[sP-selectin, sE-selectin, intercellular adhesion molecule (sICAM-1), and
vascular cell adhesion molecule (sVCAM-1)] implicated in leukocyte/endothelial
cell interactions. Results were compared to a control group. Muscle biopsy
samples from 8 out of 22 IIM patients were studied by immunohistochemistry for
tissue expression of these molecules and compared to normal muscle samples.
PECAM-1 and CD146 expression was also studied using immunoblots from muscle
biopsies from 5 patients and 2 controls. RESULTS: We observed distinct patterns
of soluble levels and in situ expression between dermatomyositis (DM),
polymyositis (PM), and sporadic inclusion body myositis (s-IBM). PM samples
showed significantly increased levels of sCD146, sPECAM-1, and s-ICAM1 and
increased expression of CD146, CD31, and ICAM-1 in endothelial cells, whereas
CD146 and ICAM-1 were also recorded in some muscle fibers. In DM, sE-selectin,
sP-selectin, and sPECAM-1 were significantly increased, with abnormal expression
of ICAM-1 in endothelial cells and perifascicular muscle fibers. In the small
group of s-IBM samples, results were similar to PM, but the only significant
increase was the level of sPECAM-1. Immunoblots confirmed increased expression
of PECAM-1 and CD146 in all IIM muscles in comparison to controls, with the
highest expression in PM and IBM samples. CONCLUSION: We observed abnormal
increases of soluble levels of adhesion molecules implicated in endothelial
cell
junctions in PM (sCD146, sPECAM-1) and to a lesser extent in DM and s-IBM
(sPECAM-1). We conclude that the distinctly different profiles between PM/s-IBM
and DM reflect differences in the pathophysiological background of these
diseases.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16881117 [PubMed - indexed for MEDLINE]
35: Clin Neuropathol. 2006 Jul-Aug;25(4):172-9.
Pediatric macrophagic myofasciitis associated with motor delay.
Gruis KL, Teener JW, Blaivas M.
Department of Neurology, University of Michigan Health System, Ann Arbor, MI,
USA. kgruis@umich.edu
BACKGROUND: Macrophagic myofasciitis (MMF) is a rare inflammatory myopathy
characterized by accumulation of perifascicular macrophages without muscle fiber
necrosis. Few sporadic pediatric cases have been described, and MMF is
recognized as a possible reaction to intramuscular injections of
aluminum-containing vaccines. The association of MMF and motor delay is unclear
in the pediatric population. We report the clinical evaluation and follow-up
of
4 young children with MMF and review of 4 cases previously reported of sporadic,
pediatric MMF to better determine the possible association of sporadic MMF in
children presenting with motor delay. PATIENTS AND METHODS: Described our 4
case
reports in which we observed children presenting for evaluation of motor delay
with unrevealing clinical and laboratory evaluations for common causes of motor
delay and histopathological evaluations consistent with macrophagic
myofasciitis. Muscle data was obtained by quadriceps muscle biopsy. RESULTS:
Clinical presentations were similar in all children and were characterized by
motor delay, hypotonia, and failure to thrive with an unrevealing evaluation
for
central nervous system disease, congenital, and mitochondrial myopathies.
CONCLUSIONS: Our cases and those previously reported in the literature
demonstrate MMF should be considered in the evaluation of children with failure
to thrive, hypotonia, and muscle weakness, as clinical outcome appears to be
favorable.
Publication Types:
Case Reports
Review
PMID: 16866298 [PubMed - indexed for MEDLINE]
36: Acta Neuropathol (Berl). 2006 Sep;112(3):325-32. Epub 2006 Jul 22.
The inflammatory reaction pattern distinguishes primary dysferlinopathies from
idiopathic inflammatory myopathies: an important role for the membrane attack
complex.
Brunn A, Schroder R, Deckert M.
Department of Neuropathology, University of Cologne, Kerpener Strasse 62, 50924
Koln, Germany. anna.brunn@uni-koeln.de
Degenerative muscle changes in dysferlinopathies are often accompanied by
inflammatory infiltrates and may even mimic primary idiopathic inflammatory
myopathies. In the present study, the inflammatory reaction pattern with respect
to the cellular composition of the infiltrates and the expression of potent
cytokines was characterized in dysferlinopathies and in idiopathic inflammatory
myopathies. Cellular infiltrates in dysferlinopathies mainly consisted of
CD4+CD25- T cells and macrophages. We noted a prominent expression of
interferon-gamma which may contribute to the marked upregulation of MHC class
I
antigen observed on the vast majority of muscle fibres. Furthermore, membrane
attack complex positive deposits were found on intact as well as necrotic muscle
fibres. Collectively, our study indicates that the inflammatory reaction pattern
in dysferlinopathies is distinct from the one in idiopathic inflammatory
myopathies. In particular, membrane attack complex deposits and a
pro-inflammatory milieu in the absence of interleukin-10 expression may
contribute to progressive muscle damage in dysferlinopathies.
PMID: 16862423 [PubMed - indexed for MEDLINE]
37: Muscle Nerve. 2006 Oct;34(4):444-50.
Elevated levels of amyloid precursor protein in muscle of patients with
amyotrophic lateral sclerosis and a mouse model of the disease.
Koistinen H, Prinjha R, Soden P, Harper A, Banner SJ, Pradat PF, Loeffler JP,
Dingwall C.
Neurodegeneration Research Department, GlaxoSmithKline Research & Development
Ltd., New Frontiers Science Park, Third Avenue, Harlow, Essex, UK.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease
defined by motor neuron loss. Transgenic mouse models show features that closely
mimic those seen in the clinical situation, reflected in the molecular changes
observed in mouse models and in tissues from patients. We report a dramatic
increase in the expression of amyloid precursor protein (APP) in the hindlimb
muscles, but not the spinal cord of the G93A transgenic mouse model,
significantly before the appearance of clinical abnormalities. APP levels were
unchanged in nontransgenic mice and in mice overexpressing human wild-type
Cu/Zn-dependent superoxide dismutase 1 (SOD1). Preliminary results indicate
a
similar change in APP expression in human deltoid muscle samples from ALS
patients compared with age-matched controls. The inhibitory role of APP in
innervation at the neuromuscular junction and increased expression in
inclusion-body myositis suggest that presymptomatic upregulation of APP may
be
consistent with a potential role for APP in ALS pathology.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16856153 [PubMed - indexed for MEDLINE]
38: Muscle Nerve. 2006 Oct;34(4):406-16.
Nuclear membrane proteins are present within rimmed vacuoles in inclusion-body
myositis.
Greenberg SA, Pinkus JL, Amato AA.
Department of Neurology, Division of Neuromuscular Disease, Brigham and Women's
Hospital, Boston, Massachusetts 02115, USA. sagreenberg@partners.org
The rimmed vacuoles within muscle in inclusion-body myositis (IBM) are
structures of uncertain origin. Two hypotheses have been proposed for their
formation: that they develop as a consequence of abnormal lysosomal function
or
in association with the breakdown of myonuclei. We tested the latter hypothesis
by studying muscle samples from 14 patients with IBM and 18 controls using
immunohistochemistry for nuclear membrane proteins, examining semithin sections,
and performing electron microscopy. We found that in IBM muscle vacuoles were
immunoreactive for the inner nuclear membrane proteins emerin and lamin A/C.
Myonuclei with fragmented or focally absent nuclear membranes were present in
immunohistochemical and electron microscopy studies. The association of nuclear
membrane proteins with rimmed vacuoles confirms the hypotheses that rimmed
vacuoles in IBM form in association with myonuclear pathology and that IBM
differs from other inflammatory myopathies in that abnormalities of myonuclei
are more prominent.
Publication Types:
Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16823856 [PubMed - indexed for MEDLINE]
39: Neurology. 2006 Jun 27;66(12):1959; author reply 1959.
Comment on:
Neurology. 2006 Jan 24;66(2 Suppl 1):S110-3.
Treatment and prevention of the amyloidoses: can the lessons learned be applied
to sporadic inclusion-body myositis?
Konstantopoulos K, Vaiopoulos G, Mailis A.
Publication Types:
Comment
Letter
PMID: 16801679 [PubMed - indexed for MEDLINE]
40: Neurology. 2006 Aug 22;67(4):644-51. Epub 2006 Jun 21.
Comment in:
Neurology. 2006 Aug 22;67(4):560-1.
Valosin-containing protein gene mutations: clinical and neuropathologic
features.
Guyant-Marechal L, Laquerriere A, Duyckaerts C, Dumanchin C, Bou J, Dugny F,
Le
Ber I, Frebourg T, Hannequin D, Campion D.
Department of Neurology, Rouen University Hospital, France.
BACKGROUND: Hereditary inclusion body myopathy (IBMPFD) with Paget disease
of
bone (PDB) and frontotemporal dementia (FTD) is a rare multisystem disorder
with
autosomal dominant inheritance. Recently, missense mutations in the gene
encoding valosin-containing protein (VCP) have been found in individuals with
IBMPFD. VCP/P97, which exerts a variety of cellular functions, plays a key role
in the ubiquitin-proteasome dependent degradation of cytosolic proteins and
in
the retrotranslocation of misfolded proteins from the endoplasmic reticulum
into
the cytoplasm. METHODS: The authors describe the clinical features of two
kindreds in which VCP R93C and R155C missense mutations segregate and perform
a
histopathologic examination of brain, muscle, bone, and liver of three subjects
harboring the R155C mutation. RESULTS: Frontotemporal dementia was present in
100% of affected subjects in Family F1 and 70% in Family F2, as compared with
an
average of 30% in previously described IBMPFD families. In contrast, PDB was
a
more inconstant clinical feature. Biochemical and histopathologic data are
consistent with the hypothesis that VCP R155C mutation disrupts normal VCP
function, leading to diffuse accumulation of ubiquitinated proteins within the
cells. CONCLUSIONS: VCP mutations are present in two families in which FTD is
the most prominent symptom. The histopathologic study performed in patients
harboring the R155C mutation supports the hypothesis that this mutation disrupts
normal VCP function, leading to diffuse accumulation of ubiquitinated proteins
within the cells. IBMPFD belongs to a class of genetic diseases associated with
an alteration of the ubiquitin-proteasome system.
PMID: 16790606 [PubMed - indexed for MEDLINE]
41: Acta Neuropathol (Berl). 2006 Aug;112(2):185-93. Epub 2006 Jun 21.
Rimmed vacuoles with beta-amyloid and tau protein deposits in the muscle of
children with hereditary myopathy.
Fidzianska A, Glinka Z.
Neuromuscular Unit MRC, Polish Academy of Science, Pawinskiego 5, 02-106,
Warsaw, Poland. neurmyol@cmdik.pan.pl
We investigated whether beta-amyloid and tau protein are involved in the
formation of inclusion body myositis (IBM)-like inclusions found in children
with rimmed vacuoles and congenitally affected muscles. We immunostained muscle
biopsy specimens from four children and one 18-year-old boy with congenital
myopathy containing rimmed vacuoles and IBM-like inclusions with antibodies
against beta-amyloid, tau protein and ubiquitin. Focal accumulations of both
beta-amyloid and phosphorylated tau coexisted with tubulofilamentous structures
in all cases. Our studies demonstrate for the first time that the full
morphological phenotype of IBM including beta-amyloid and tau protein deposits
may also develop in children, and that congenital, probably genetic, muscle
defects may lead to abnormal protein aggregation in IBM-like inclusions.
Publication Types:
Case Reports
Research Support, Non-U.S. Gov't
PMID: 16788822 [PubMed - indexed for MEDLINE]
42: J Neuropathol Exp Neurol. 2006 Jun;65(6):571-81.
Novel ubiquitin neuropathology in frontotemporal dementia with
valosin-containing protein gene mutations.
Forman MS, Mackenzie IR, Cairns NJ, Swanson E, Boyer PJ, Drachman DA, Jhaveri
BS, Karlawish JH, Pestronk A, Smith TW, Tu PH, Watts GD, Markesbery WR, Smith
CD, Kimonis VE.
Department of Pathology, University of Pennsylvania School of Medicine,
Philadelphia, 19104, USA. formanm@mail.med.upenn.edu
Frontotemporal dementia (FTD) with inclusion body myopathy and Paget disease
of
bone (IBMPFD) is a rare, autosomal-dominant disorder caused by mutations in
the
valosin-containing protein (VCP) gene, a member of the AAA-ATPase gene
superfamily. The neuropathology associated with sporadic FTD is heterogeneous
and includes tauopathies and frontotemporal lobar degeneration with
ubiquitin-positive inclusions (FTLD-U). However, there is limited information
on
the neuropathology in IBMPFD. We performed a detailed, systematic analysis of
the neuropathologic changes in 8 patients with VCP mutations. A novel pattern
of
ubiquitin pathology was identified in IBMPFD that was distinct from sporadic
and
familial FTLD-U without VCP gene mutations. This was characterized by
ubiquitin-positive neuronal intranuclear inclusions and dystrophic neurites.
In
contrast to FTLD-U, only rare intracytoplasmic inclusions were identified. The
ubiquitin pathology was abundant in the neocortex, less robust in limbic and
subcortical nuclei, and absent in the dentate gyrus. Only rare inclusions were
detected with antibodies to VCP and there was no biochemical alteration in the
VCP protein. VCP is associated with a variety of cellular activities, including
regulation of the ubiquitin-proteasome system. Our findings are consistent with
the hypothesis that the pathology associated with VCP gene mutations is the
result of impairment of ubiquitin-based degradation pathways.
Publication Types:
Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16783167 [PubMed - indexed for MEDLINE]
43: Eur Neurol. 2006;55(4):204-8. Epub 2006 Jun 13.
Serum levels of matrix metalloproteinases-2 and -9 and their tissue inhibitors
in inflammatory neuromuscular disorders.
Hurnaus S, Mueller-Felber W, Pongratz D, Schoser BG.
Friedrich Baur Institute, Department of Neurology, Ludwig Maximilian University
Munich, Munich, Germany.
We monitored serum levels of matrix metalloproteinases (MMPs) and their tissue
inhibitors (TIMPs) before and during intravenously applied immunoglobulin (IVIG)
therapy in 33 patients with chronic immune-mediated neuropathies and myopathies
and 15 controls. Baseline MMP-2 and TIMP-2 serum levels were lower and MMP-9
and
TIMP-1 serum levels higher in all patients compared to age-matched controls.
Eight days after IVIG treatment, MMP-2, TIMP-2, and TIMP-1 serum levels
increased, while MMP-9 serum levels decreased, indicating tissue repair. After
60 days, MMP-9 levels increased, MMP-2 approached normal levels, while TIMP-1
and TIMP-2 serum levels were below day 8 levels, indicating relapsing tissue
damage. Comparing the MMP/TIMP results with the clinical courses, IVIG treatment
tended to change MMP/TIMP levels in a way that paralleled clinical improvement
and relapse. In sum, during a distinct time period, IVIG therapy seems to be
able to modulate MMP-mediated tissue repair.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16772717 [PubMed - indexed for MEDLINE]
44: Eur Neurol. 2006;55(4):183-8. Epub 2006 Jun 13.
Needle electromyographic findings in 98 patients with myositis.
Blijham PJ, Hengstman GJ, Hama-Amin AD, van Engelen BG, Zwarts MJ.
Department of Clinical Neurophysiology, Institute of Neurology, Institute of
Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The
Netherlands.
BACKGROUND/AIMS: Little is known about the distribution of electromyographic
(EMG) abnormalities in myositis even though this is relevant in daily practice.
METHODS: A retrospective semiquantitative analysis of needle EMG findings was
performed in a group of 98 patients with myositis. The frequency, type, and
distribution of abnormalities were studied. The influence of the use of
corticosteroids and the stage of the disease were evaluated. RESULTS: In most
patients, a myopathic pattern with spontaneous activity was found, although
several clinically relevant exceptions were noted. Long-duration motor unit
potentials were found in all three diagnostic groups and were not associated
with disease duration. In the lower extremity a distal to proximal gradient
was
present, adding to the diagnostic confusion with neurogenic diseases, and
spontaneous activity was absent in a relatively large group although none of
the
patients in the acute stage of the disease had a normal EMG. The use of
corticosteroids reduced the number of abnormal findings in dermatomyositis and
polymyositis, but not in inclusion body myositis. CONCLUSION: A myopathic
pattern with spontaneous activity was most frequently found, although several
clinically relevant exceptions were noted. These results illustrate the spectrum
of EMG findings in myositis, and may aid the clinician in the interpretation
of
the EMG in these patients.
PMID: 16772711 [PubMed - indexed for MEDLINE]
45: Autoimmunity. 2006 May;39(3):161-70.
Update on idiopathic inflammatory myopathies.
Briani C, Doria A, Sarzi-Puttini P, Dalakas MC.
University of Padova, Department of Neurosciences, Padova, Italy.
chiara.briani@unipd.it
The inflammatory myopathies are a group of acquired diseases, characterized
by
an inflammatory infiltrate of the skeletal muscle. On the basis of clinical,
immuno-pathological and demographic features, three major diseases can be
identified: dermatomyositis (DM); polymyositis (PM); and inclusion body myositis
(IBM). New diagnostic criteria have recently been introduced, which are crucial
for discriminating between the three different subsets of inflammatory
myopathies and for excluding other disorders. DM is a complement-mediated
microangiopathy affecting skin and muscle. PM and IBM are T cell-mediated
disorders, where CD8-positive cytotoxic T cells invade muscle fibres expressing
MHC class I antigens, thus leading to fibre necrosis. In IBM, vacuolar formation
with amyloid deposits are also present. This article summarizes the main
clinical, laboratory, electrophysiological, immunological and histologic
features as well as the therapeutic options of the inflammatory myopathies.
Publication Types:
Review
PMID: 16769649 [PubMed - indexed for MEDLINE]
46: Mol Genet Metab. 2006 Aug;88(4):389-90. Epub 2006 Jun 9.
Normal sialylation of serum N-linked and O-GalNAc-linked glycans in hereditary
inclusion-body myopathy.
Savelkoul PJ, Manoli I, Sparks SE, Ciccone C, Gahl WA, Krasnewich DM, Huizing M.
Publication Types:
Letter
PMID: 16762577 [PubMed - indexed for MEDLINE]
47: Clin Rheumatol. 2006 May 31; [Epub ahead of print]
Treatment of early and refractory dermatomyositis with infliximab: a report
of
two cases.
Dold S, Justiniano ME, Marquez J, Espinoza LR.
Section of Rheumatology, Department of Medicine, Louisiana State University
School of Medicine, LSU Medical Center, 1542 Tulane Avenue, New Orleans, LA,
70112, USA, luisrolan@msn.com.
The idiopathic inflammatory myopathies embody the largest group of acquired
and
potentially treatable causes of skeletal muscle weakness. The three major groups
of this disorder are polymyositis (PM), dermatomyositis (DM), and inclusion
body
myositis. Corticosteroids continue to be the mainstay of initial treatment in
the majority of cases of PM/DM. The treatment of refractory disease can be
challenging despite the utilization of the medications currently available.
We
report two patients with refractory DM who were treated with infliximab. We
describe their presentation, clinical course, treatment, and outcomes.
PMID: 16736125 [PubMed - as supplied by publisher]
48: Am J Pathol. 2006 Jun;168(6):1986-97.
Genetically augmenting Abeta42 levels in skeletal muscle exacerbates inclusion
body myositis-like pathology and motor deficits in transgenic mice.
Kitazawa M, Green KN, Caccamo A, LaFerla FM.
Department of Neurobiology and Behavior, 1109 Gillespie Neuroscience Facility,
University of California, Irvine, Irvine, CA 92697-4545, USA.
The pathogenic basis of inclusion body myositis (IBM), the leading muscle
degenerative disease afflicting the elderly, is unknown, although the
histopathological features are remarkably similar to those observed in
Alzheimer's disease. One leading hypothesis is that the buildup of amyloid-beta
(Abeta) peptide within selective skeletal muscle fibers contributes to the
degenerative phenotype. Abeta is a small peptide derived via endoproteolysis
of
the amyloid precursor protein (APP). To determine the pathogenic effect of
augmenting Abeta42 levels in skeletal muscle, we used a genetic approach to
replace the endogenous wild-type presenilin-1 (PS1) allele with the PS1(M146V)
allele in MCK-APP mice. Although APP transgene expression was unaltered, Abeta
levels, particularly Abeta42, were elevated in skeletal muscle of the double
transgenic (MCK-APP/PS1) mice compared to the parental MCK-APP line. Elevated
phospho-tau accumulation was found in the MCK-APP/PS1 mice, and the greater
activation of GSK-3beta and cdk5 were observed. Other IBM-like pathological
features, such as inclusion bodies and inflammatory infiltrates, were more
severe and prominent in the MCK-APP/PS1 mice. Motor coordination and balance
were more adversely affected and manifested at an earlier age in the MCK-APP/PS1
mice. The data presented here provide experimental evidence that Abeta42 plays
a
proximal and critical role in the muscle degenerative process.
Publication Types:
Research Support, N.I.H., Extramural
PMID: 16723713 [PubMed - indexed for MEDLINE]
49: Neuromuscul Disord. 2006 Jun;16(6):361-7. Epub 2006 May 8.
Different early pathogenesis in myotilinopathy compared to primary desminopathy.
Fischer D, Clemen CS, Olive M, Ferrer I, Goudeau B, Roth U, Badorf P, Wattjes
MP, Lutterbey G, Kral T, van der Ven PF, Furst DO, Vicart P, Goldfarb LG, Moza
M, Carpen O, Reichelt J, Schroder R.
Muskellabor, Department of Neurology, University of Bonn, Bonn, Germany.
dirk.fischer@ukb.uni-bonn.de
Mutations in the human myotilin gene may cause limb-girdle muscular dystrophy
1A
and myofibrillar myopathy. Here, we describe a German patient with the
clinically distinct disease phenotype of late adult onset distal anterior leg
myopathy caused by a heterozygous S55F myotilin mutation. In addition to a
thorough morphological and clinical analysis, we performed for the first time
a
protein chemical analysis and transient transfections. Morphological analysis
revealed an inclusion body myopathy with myotilin- and desmin-positive
aggregates. The clinical and pathological phenotype considerably overlaps with
late onset distal anterior leg myopathy of the Markesbery-Griggs type.
Interestingly, all three analyzed myotilin missense mutations (S55F, S60F and
S60C) do not lead to gross changes in the total amount of myotilin or to
aberrant posttranslational modifications in diseased muscle, as observed in
a
number of muscular dystrophies. Transiently transfected wild-type and S55F
mutant myotilin similarly colocalised with actin-containing stress fibers in
BHK-21 cells. Like the wild-type protein, mutated myotilin did not disrupt the
endogenous desmin cytoskeleton or lead to pathological protein aggregation in
these cells. This lack of an obvious dominant negative effect sharply contrasts
to transfections with, for instance, the disease-causing A357P desmin mutant.
In
conclusion our data indicate that the disorganization of the extrasarcomeric
cytoskeleton and the presence of desmin-positive aggregates are in fact late
secondary events in the pathogenesis of primary myotilinopathies, rather than
directly related. These findings suggest that unrelated molecular pathways may
result in seemingly similar disease phenotypes at late disease stages.
Publication Types:
Case Reports
Comparative Study
Research Support, Non-U.S. Gov't
PMID: 16684602 [PubMed - indexed for MEDLINE]
50: Clin Occup Environ Med. 2006;5(2):333-52, viii.
Compression neuropathies of the upper extremity.
Corwin HM.
Division of Physical Medicine and Rehabilitation, University of Louisville
Health Sciences Center, 3900 Kresge Way, Suite 56, Louisville, KY 40207, USA.
halcorwin@pol.net
Nerve compression syndromes of the upper extremity occur at predicable
locations. The diagnosis of nerve compression or nerve entrapment is based on
the neurologic and electrodiagnostic examinations. The anatomy, neurophysiology,
and electrodiagnosis of nerve compression are discussed. Common and uncommon
compression and entrapment syndromes of the upper extremity are described.
Errors in diagnosis occur when the neurologic or electrodiagnostic examinations
are incomplete or inaccurate.
Publication Types:
Review
PMID: 16647652 [PubMed - indexed for MEDLINE]
51: Neuromuscul Disord. 2006 May;16(5):311-5. Epub 2006 Mar 24.
Sporadic inclusion body myositis in Japanese is associated with the MHC
ancestral haplotype 52.1.
Scott AP, Allcock RJ, Mastaglia F, Nishino I, Nonaka I, Laing N.
School of Surgery and Pathology, M504, UWA, Stirling Highway, Nedlands, WA
6009,
Perth WA, Australia. ascott@cyllene.uwa.edu.au
In Caucasians, sporadic inclusion body myositis has been associated with the
MHC
ancestral haplotypes; HLA-A1, B8, DR3 (8.1AH) and HLA-B35, DR1 (35.2AH). It
is
not known whether these haplotypes carry susceptibility for the disease in other
ethnic groups. We report here the results of HLA-B and -DRB1 typing using a
high-resolution sequence-based technique in a cohort of 31 Japanese patients
with definite sIBM. Patient allele frequencies were 40.3% for HLA-B*5201 (10.7%
in controls: p<0.001) and 37.1% for HLA-DRB1*1502 (10% in controls: p<0.001).
Both alleles were found together as part of a conserved haplotype (52.1AH) at
a
frequency of 37.1% in patients (8.4% in controls: p<0.001). This is the first
description of a haplotypic MHC association with sporadic inclusion body
myositis in Japanese patients. These findings indicate that different MHC
ancestral haplotypes are associated with sIBM in different ethnic groups and
further emphasize the importance of genetic factors in this condition.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16564169 [PubMed - indexed for MEDLINE]
52: Neuromuscul Disord. 2006 Apr;16(4):223-36. Epub 2006 Mar 15.
Therapeutic targets in patients with inflammatory myopathies: present approaches
and a look to the future.
Dalakas MC.
Neuromuscular Diseases Section, NINDS, NIH, Building 10, Room 4N248, 10 Center
Drive MSC 1382, Bethesda, MD 20892-1382, USA. dalakasm@ninds.nih.gov
Publication Types:
Research Support, N.I.H., Intramural
Review
PMID: 16542836 [PubMed - indexed for MEDLINE]
53: Neurology. 2006 Mar 14;66(5):755-8.
NCAM is hyposialylated in hereditary inclusion body myopathy due to GNE
mutations.
Ricci E, Broccolini A, Gidaro T, Morosetti R, Gliubizzi C, Frusciante R, Di
Lella GM, Tonali PA, Mirabella M.
Department of Neuroscience, Catholic University, Rome, Italy.
The authors found that the neural cell adhesion molecule (NCAM) is
hyposialylated in hereditary inclusion body myopathy (HIBM) muscle, as suggested
by its decreased molecular weight by Western blot. This abnormality represented
the only pathologic feature differentiating HIBM due to GNE mutations from other
myopathies with similar clinical and pathologic characteristics. If further
confirmed in larger series of patients, this may be a useful diagnostic marker
of GNE-related HIBM.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16534119 [PubMed - indexed for MEDLINE]
54: J Biol Chem. 2006 May 5;281(18):12809-16. Epub 2006 Mar 3.
Parkin protects against mitochondrial toxins and beta-amyloid accumulation
in
skeletal muscle cells.
Rosen KM, Veereshwarayya V, Moussa CE, Fu Q, Goldberg MS, Schlossmacher MG,
Shen
J, Querfurth HW.
Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts
University School of Medicine, Boston, Massachusetts 02135, USA.
kenneth_rosen@cchcs.org
Mutations in the ubiquitin ligase-encoding Parkin gene have been implicated
in
the pathogenesis of autosomal recessive Parkinson disease. Outside of the
central nervous system, Parkin is prominently expressed in skeletal muscle.
We
have found accumulations of Parkin protein in skeletal muscle biopsies taken
from patients with inclusion body myositis, a degenerative disorder in which
intramyofiber accumulations of the beta-amyloid peptide are pathognomonic. In
comparing primary cultures of skeletal muscle derived from parkin knock-out
and
wild-type mice, we have found the absence of parkin to result in greater
sensitivity to mitochondrial stressors rotenone and carbonyl cyanide
3-chlorophenylhydrazone, without any alteration in sensitivity to calcium
ionophore or hydrogen peroxide. Utilizing viral expression constructs coding
for
the Alzheimer disease and inclusion body myositis-linked beta-amyloid precursor
protein and for its metabolic byproducts A beta42 and C100, we found that parkin
knock-out muscle cells are also more sensitive to the toxic effects of
intracellular A beta. We also constructed a lentiviral system to overexpress
wild-type Parkin and have shown that boosting the levels of parkin expression
in
normal skeletal muscle cultures provides substantial protection against both
mitochondrial toxins and overexpressed beta-amyloid. Correspondingly, exogenous
Parkin significantly lowered A beta levels. These data support the hypothesis
that in myocytes parkin has dual properties in the maintenance of skeletal
muscle mitochondrial homeostasis and in the regulation of A beta levels.
Publication Types:
Research Support, N.I.H., Extramural
PMID: 16517603 [PubMed - indexed for MEDLINE]
55: Biochemistry. 2006 Mar 7;45(9):2968-77.
Influence of UDP-GlcNAc 2-epimerase/ManNAc kinase mutant proteins on hereditary
inclusion body myopathy.
Penner J, Mantey LR, Elgavish S, Ghaderi D, Cirak S, Berger M, Krause S, Lucka
L, Voit T, Mitrani-Rosenbaum S, Hinderlich S.
Charite-Universitatsmedizin Berlin, Campus Benjamin Franklin, Institut fur
Biochemie und Molekularbiologie, Arnimallee 22, 14195 Berlin-Dahlem, Germany.
Hereditary inclusion body myopathy (HIBM), a neuromuscular disorder, is caused
by mutations in UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase
(GNE), the key enzyme of sialic acid biosynthesis. To date, more than 40
different mutations in the GNE gene have been reported to cause the disease.
Ten
of them, representing mutations in both functional domains of GNE, were
recombinantly expressed in insect cells (Sf9). Each of the mutants that was
analyzed displayed a reduction in the two known GNE activities, thus revealing
that mutations may also influence the function of the domain not harboring them.
The extent of reduction strongly differs among the point mutants, ranging from
only 20% reduction found for A631T and A631V to almost 80% reduction of at least
one activity in D378Y and N519S mutants and more than 80% reduction of both
activities of G576E, underlined by structural changes of N519S and G576E, as
observed in CD spectroscopy and gel filtration analysis, respectively. We
therefore generated models of the three-dimensional structures of the epimerase
and the kinase domains of GNE, based on Escherichia coli UDP-N-acetylglucosamine
2-epimerase and glucokinase, respectively, and determined the localization of
the HIBM mutations within these proteins. Whereas in the kinase domain most
of
the mutations are localized inside the enzyme, mutations in the epimerase domain
are mostly located at the protein surface. Otherwise, the different mutations
result in different enzymatic activities but not in different disease phenotypes
and, therefore, do not suggest a direct role of the enzymatic function of GNE
in
the disease mechanism.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16503651 [PubMed - indexed for MEDLINE]
56: Brain. 2006 Apr;129(Pt 4):986-95. Epub 2006 Feb 2.
Shared blood and muscle CD8+ T-cell expansions in inclusion body myositis.
Dimitri D, Benveniste O, Dubourg O, Maisonobe T, Eymard B, Amoura Z, Jean L,
Tiev K, Piette JC, Klatzmann D, Herson S, Boyer O.
Service de medecine interne 1, Hopital Pitie-Salpetriere, Paris, France.
Inclusion body myositis (IBM) is the most frequent inflammatory myopathy over
the age of fifty. Pathological findings suggest that two processes may
contribute to IBM pathogenesis: a primary degenerative process affecting muscle
fibre and/or an autoimmune process mediated by major histocompatibility complex
(MHC) class-I-restricted cytotoxic CD8+ T cells. Previous studies have
demonstrated that muscle-infiltrating CD8+ T cells in IBM display restricted
expression of T-cell receptor (TCR)-BV families or evidenced oligoclonal T-cell
expansions. This study was performed to investigate whether blood T cells
similarly exhibit clonal expansions due to the recirculation of
muscle-infiltrating T cells in the periphery. For this, we studied the T-cell
repertoire of 17 IBM patients by complementarity-determining-region (CDR) 3
length distribution (immunoscope) analysis of TCR-B transcripts. Mean age was
68
years (range 53-88) and mean duration of the disease was 6.5 years (2-20).
Oligoclonal T-cell expansions were observed in the blood of IBM patients. The
quantitative average perturbation D index was significantly increased in IBM
patients [D = 13.7% +/- 1.2%, mean +/- standard error of measurement (SEM)]
as
compared with 17 age-matched controls suffering from connective tissue diseases
not associated with T-cell repertoire perturbation, that is, dermatomyositis
(DM) and systemic sclerosis (9.3 +/- 0.6%, P < 0.005). Nevertheless, there
was
no correlation between the level of blood perturbation and muscle inflammation.
Sorting experiments showed that these perturbations were due to oligoclonal
expansions of CD8+ T cells. In the three IBM patients analysed, we could relate
the blood expansions to T-cell clones also found in muscle. The clonally
expanded blood T cells dramatically responded to interleukin-2 (IL-2) in vitro,
suggesting that they had been primed in vivo, presumably in response to yet
unknown muscle auto-antigens. Together, our results indicate that clonally
expanded muscle-infiltrating CD8+ T cells re-circulate in the blood and support
the concept of a CD8+ T-cell-mediated autoimmune component in IBM, similarly
to
what is observed in polymyositis (PM).
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16455793 [PubMed - indexed for MEDLINE]
57: J Neurochem. 2006 Mar;96(5):1491-9. Epub 2006 Jan 25.
Homocysteine-induced endoplasmic reticulum protein (Herp) is up-regulated in
sporadic inclusion-body myositis and in endoplasmic reticulum stress-induced
cultured human muscle fibers.
Nogalska A, Engel WK, McFerrin J, Kokame K, Komano H, Askanas V.
USC Neuromuscular Center, Department of Neurology, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, Los Angeles,
California 90017-1912, USA.
Herp is a stress-response protein localized in the endoplasmic reticulum (ER)
membrane. Herp was proposed to improve ER-folding, decrease ER protein load,
and
participate in ER-associated degradation (ERAD). Intra-muscle-fiber
ubiquitinated multiprotein-aggregates containing, among other proteins, either
amyloid-beta (Abeta) or phosphorylated tau are characteristic of sporadic
inclusion-body myositis (s-IBM). ER stress and proteasome inhibition appear
to
play a role in s-IBM pathogenesis. We have now studied Herp in s-IBM muscle
fibers and in ER-stress-induced or proteasome-inhibited cultured human muscle
fibers. In s-IBM muscle fibers: (i) Herp was strongly immunoreactive in the
form
of aggregates, which co-localized with Abeta, GRP78, and beta2 proteasome
subunit; (ii) Herp mRNA and protein were increased. In ER-stress-induced
cultured human muscle fibers: (i) Herp immunoreactivity was diffusely increased;
(ii) Herp mRNA and protein were increased. In proteasome-inhibited cultured
human muscle fibers: (i) Herp immunoreactivity was in the form of aggregates;
(ii) Herp protein was increased, but its mRNA was not. Accordingly, in s-IBM
muscle fibers: (i) increase of Herp might be due to both ER-stress and
proteasome inhibition; (ii) co-localization of Herp with Abeta, proteasome,
and
ER-chaperone GRP78 could reflect its possible role in processing and degradation
of cytotoxic proteins in ER.
Publication Types:
Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16441512 [PubMed - indexed for MEDLINE]
58: Neurology. 2006 Jan 24;66(2 Suppl 1):S97-101.
Brain and brawn: parallels in oxidative strength.
Moreira PI, Honda K, Zhu X, Nunomura A, Casadesus G, Smith MA, Perry G.
Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106,
USA.
Neuronal oxidative stress occurs early in the progression of Alzheimer disease
(AD), significantly before the development of the pathologic hallmarks,
neurofibrillary tangles, and senile plaques. Study of Down syndrome, cases with
autosomal dominant mutation, and sporadic AD all suggest amyloid-beta deposition
and hyperphosphorylated tau function as compensatory responses and downstream
adaptations to ensure that neuronal cells do not succumb to oxidative damage.
Amyloid-beta and tau hyperphosphorylation also define vulnerable muscle cells
in
sporadic inclusion-body myositis (s-IBM). The role of the structural changes
of
s-IBM, as in AD, remains to be determined but may mark a critical response
yielding a novel balance in oxidant homeostasis.
Publication Types:
Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 16432155 [PubMed - indexed for MEDLINE]
59: Neurology. 2006 Jan 24;66(2 Suppl 1):S93-6.
Retraction in:
Daroff RB, Griggs RC. Neurology. 2006 Dec 12;67(11):2087.
Preferential degradation of oxidized proteins by the 20S proteasome may be
inhibited in aging and in inflammatory neuromuscular diseases.
Davies KJ, Shringarpure R.
The Ethel Percy Andrus Gerontology Center, Division of Molecular & Computational
Biology, University of Southern California, Los Angeles, CA, USA. Kelvin@usc.edu
Free radicals produced by chronic inflammation cause cumulative damage to
cellular macromolecules and appear to contribute to senescence/aging,
age-related disorders, and neuromuscular degenerative diseases such as
inclusion-body myositis. Proteins are major targets for oxidative damage (in
addition to DNA and lipids) and the accumulation of oxidized proteins has been
reported in many aging and disease models. In young and healthy individuals,
moderately oxidized soluble cell proteins are selectively and rapidly degraded
by the 20S proteasome. The mechanism of selective proteolysis appears to depend
upon oxidation-induced protein unfolding, with increasing surface hydrophobicity
as (previously shielded) hydrophobic residues are exposed from the interior.
The
20S proteasome can preferentially bind to and degrade such mildly oxidized,
hydrophobic proteins without a need for ubiquitin targeting or ATP activation.
Severely oxidized, aggregated, and crosslinked proteins, however, are poor
substrates for degradation and actually inhibit the proteasome. During aging,
and in many age-related diseases/disorders, the proteasome is progressively
inhibited by binding to increasing levels of oxidized and cross-linked protein
aggregates. Cellular aging and inflammatory neuromuscular degenerative diseases
probably include both an increase in the generation of reactive oxygen species
as well as a decline in proteasome activity, resulting in the progressive
accumulation of oxidatively damaged protein aggregates that eventually
contribute to cellular dysfunction and senescence.
Publication Types:
Research Support, N.I.H., Extramural
Retracted Publication
Review
PMID: 16432154 [PubMed - indexed for MEDLINE]
60: Neurology. 2006 Jan 24;66(2 Suppl 1):S74-8.
Common structure and toxic function of amyloid oligomers implies a common
mechanism of pathogenesis.
Glabe CG, Kayed R.
Department of Molecular Biology and Biochemistry, University of California,
Irvine, CA 92697, USA. cglabe@uci.edu
Recent findings indicate that soluble amyloid oligomers may represent the
primary pathologic species in degenerative diseases. These amyloid oligomers
share common structural features and the ability to permeabilize membranes,
suggesting that they also share a common primary mechanism of pathogenesis.
Membrane permeabilization by amyloid oligomers may initiate a common group of
downstream pathologic processes, including intracellular calcium dyshomeostasis,
production of reactive oxygen species, altered signaling pathways, and
mitochondrial dysfunction that represent key effectors of cellular dysfunction
and cell death in amyloid-associated degenerative disease, such as sporadic
inclusion-body myositis.
Publication Types:
Review
PMID: 16432151 [PubMed - indexed for MEDLINE]
61: Neurology. 2006 Jan 24;66(2 Suppl 1):S65-8.
Inclusion-body myositis and Alzheimer disease: two sides of the same coin,
or
different currencies altogether?
Murphy MP, Golde TE.
Department of Molecular and Cellular Biochemistry, Sanders-Brown Center on
Aging, University of Kentucky, Lexington, KY 40536, USA. mpmurp3@uky.edu
Publication Types:
Comparative Study
Review
PMID: 16432148 [PubMed - indexed for MEDLINE]
62: Neurology. 2006 Jan 24;66(2 Suppl 1):S59-64.
Immunotherapeutic relief from persistent infections and amyloid disorders.
McGavern DB.
Division of Virology, Department of Neuropharmacology, The Scripps Research
Institute, La Jolla, CA, USA. mcgad@scripps.edu
Persistent infections and amyloid disorders afflict a significant number of
people worldwide. It would appear at first glance that the treatment of these
afflictions should be entirely unrelated; however, in both cases components
of
the adaptive immune system have been harnessed in an attempt to provide some
therapeutic relief. Given that the ability of a pathogen to establish
persistence often depends in part on a shortcoming of the adaptive immune
response, it seems logical to devise immunotherapies with the intention of
supplementing (or replacing) the insufficient immunologic element. A case in
point is an intervention referred as immunocytotherapy, which relies upon the
adoptive transfer of pathogen-specific T lymphocytes into a persistently
infected host. Remarkably, the adoptively transferred T lymphocytes not only
have the capacity to clear the persistent infection, but can also provide the
recipient with protection against subsequent rechallenge (i.e., immunologic
memory). Treatment of amyloid disorders (e.g., Alzheimer disease, sporadic
inclusion-body myositis) with a similar therapeutic approach is complicated
by
the fact that the aberrant protein accumulations are self-derived. Focusing
the
adaptive response on these aberrant self-proteins has the potential to result
in
autoimmune pathology. This review critically evaluates the importance of
immunotherapeutic approaches for the treatment of persistent infections and
amyloid disorders, and attempts to delineate the interventions that are most
likely to succeed in an exceedingly complex disorder such as sporadic
inclusion-body myositis.
Publication Types:
Review
PMID: 16432147 [PubMed - indexed for MEDLINE]
63: Neurology. 2006 Jan 24;66(2 Suppl 1):S56-8.
Controlling autoimmunity in sporadic inclusion-body myositis.
Steinman L.
Department of Neurology and Neurological Sciences, Beckman Center for Molecular
Medicine, Stanford University, Stanford, CA 94305, USA. Steinman@stanford.edu
Publication Types:
Review
PMID: 16432146 [PubMed - indexed for MEDLINE]
64: Neurology. 2006 Jan 24;66(2 Suppl 1):S49-55.
Mitochondrial abnormalities in inclusion-body myositis.
Oldfors A, Moslemi AR, Jonasson L, Ohlsson M, Kollberg G, Lindberg C.
Department of Pathology, Sahlgrenska University Hospital, Goteborg, Sweden.
anders.oldfors@pathology.gu.se
Mitochondrial changes are frequently encountered in sporadic inclusion-body
myositis (s-IBM). Cytochrome c oxidase (COX)-deficient muscle fibers and
large-scale mitochondrial DNA (mtDNA) deletions are more frequent in s-IBM than
in age-matched controls. COX deficient muscle fibers are due to clonal expansion
of mtDNA deletions and point mutations in segments of muscle fibers. Such
segments range from 75 microm to more than 1,000 microm in length. Clonal
expansion of the 4977 bp "common deletion" is a frequent cause of
COX deficient
muscle fiber segments, but many other deletions also occur. The deletion
breakpoints cluster in a few regions that are similar to what is found in human
mtDNA deletions in general. Analysis in s-IBM patients of three nuclear genes
associated with multiple mtDNA deletions, POLG1, ANT1 and C10orf2, failed to
demonstrate any mutations. In s-IBM patients with high number of COX-deficient
fibers, the impaired mitochondrial function probably contribute to muscle
weakness and wasting. Treatment that has positive effects in mitochondrial
myopathies may be tried also in s-IBM.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16432145 [PubMed - indexed for MEDLINE]
65: Neurology. 2006 Jan 24;66(2 Suppl 1):S39-48.
Inclusion-body myositis: a myodegenerative conformational disorder associated
with Abeta, protein misfolding, and proteasome inhibition.
Askanas V, Engel WK.
USC Neuromuscular Center, Department of Neurology, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA,
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 successful treatment. We
summarize our most recent findings, which provide a better understanding of
the
steps in the pathogenetic cascade. We suggest that s-IBM is primarily a
myodegenerative disease. Intriguing are the phenotypic similarities between
s-IBM muscle fibers and the brains of Alzheimer disease, the most common
neurodegenerative disease of older persons. In s-IBM, abnormal accumulation
of
the amyloid-beta (Abeta) precursor protein and its proteolytic fragment, Abeta,
associated with the aging intracellular milieu of the muscle fiber, appear to
be
key upstream pathogenic events. We propose that the identified abnormal
accumulation, misfolding, and aggregation of proteins, perhaps provoked by the
aging milieu and aggravated by the oxidative stress, lead to the s-IBM-specific
vacuolar degeneration and atrophy of muscle fibers.
Publication Types:
Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 16432144 [PubMed - indexed for MEDLINE]
66: Neurology. 2006 Jan 24;66(2 Suppl 1):S33-8.
Inflammatory, immune, and viral aspects of inclusion-body myositis.
Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Bethesda, MD 20892-1382, USA.
dalakasm@ninds.nih.gov
Muscle biopsies from patients with sporadic inclusion-body myositis (sIBM)
consistently demonstrate that the inflammatory T cells almost invariably invade
intact (not vacuolated) fibers, whereas the vacuolated fibers are rarely invaded
by T cells. This indicates two concurrently ongoing processes, an autoimmune
mediated by cytotoxic T cells and a degenerative manifested by the vacuolated
muscle fibers and deposits of amyloid-related proteins. The autoimmune features
of IBM are highlighted by the strong association of the disease with: a) HLA
I,
II antigens, in frequency identical to classic autoimmune diseases; b) other
autoimmune disorders in up to 32% of the patients, autoantibodies,
paraproteinemias, or immunodeficiency; c) HIV and HTLV-I infection with
increasingly recognized frequency (up to 13 known cases); and d)
antigen-specific, cytotoxic, and clonally expanded CD8+ autoinvasive T cells
with rearranged T-cell receptor genes that persist over time, even in different
muscles, and invade muscle fibers expressing MHC-I antigen and costimulatory
molecules. In contrast to IBM, in various dystrophies the inflammatory cells
are
clonally diverse and the muscle fibers do not express MHC-I or costimulatory
molecules in the pattern seen in IBM. Like other chronic autoimmune conditions
with coexisting inflammatory and degenerative features (i.e., primary
progressive MS), IBM is resistant to conventional immunotherapies. Recent data
suggest that strong anti-T cell therapies can be promising and they are the
focus of ongoing research.
Publication Types:
Review
PMID: 16432143 [PubMed - indexed for MEDLINE]
67: Neurology. 2006 Jan 24;66(2 Suppl 1):S30-2.
The current status of treatment for inclusion-body myositis.
Griggs RC.
Department of Neurology, University of Rochester School of Medicine and
Dentistry, Rochester, NY 14642, USA. Robert_Griggs@URMC.Rochester.edu
There is no established treatment that improves, arrests, or slows the
progression of inclusion-body myositis (IBM). Many anti-inflammatory,
immunosuppressant, or immunomodulating agents have been administered to patients
with IBM but the design of clinical trials was such that it can only be
concluded that none produced rapid improvement. The natural history of the
disease is for stabilization or improvement in a third of patients for 6 months
or more. Thus some agents that did not produce dramatic benefit may have been
prematurely abandoned. However, because high-dose prednisone worsens strength
while decreasing inflammation but increases amyloid accumulation, alternative
targets for intervention and novel treatment strategies are needed.
Publication Types:
Review
PMID: 16432142 [PubMed - indexed for MEDLINE]
68: Neurology. 2006 Jan 24;66(2 Suppl 1):S20-9.
Inclusion-body myositis: clinical, diagnostic, and pathologic aspects.
Engel WK, Askanas V.
The Neuromuscular Center, Department of Neurology, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA,
USA. askanas@hsc.usc.edu
The diagnostic aspects of sporadic inclusion-body myositis (s-IBM), and a few
comments on our own approach to its treatment, are presented to foster the goals
of this symposium, which was organized to provoke new ideas concerning the cause
and treatment of this currently unsolvable disease. s-IBM is the most common,
progressive, debilitating muscle disease beginning in persons over age 50 years,
and it is more common in men. Diagnostic parameters reviewed are clinical,
muscle-biopsy histochemistry, electrophysiologic and CSF evaluations. Overall,
the degenerative phenomena in s-IBM muscle fibers seem to be the major cause
of
the progressive, unstoppable weakness, rather than the lymphocytic inflammation.
Available treatments are of only slight, temporary benefit for only some s-IBM
patients, indicating a desperate need for definitive therapies.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 16432141 [PubMed - indexed for MEDLINE]
69: Neurology. 2006 Jan 24;66(2 Suppl 1):S123-4.
Pilot trial of etanercept in the treatment of inclusion-body myositis.
Barohn RJ, Herbelin L, Kissel JT, King W, McVey AL, Saperstein DS, Mendell JR.
Department of Neurology, University of Kansas Medical Center, Kansas City,
KS
66160, USA. rbarohn@kumc.edu
Inclusion-body myositis (IBM) is an inflammatory muscle disease that has proven
resistant to treatment. Tumor necrosis factor molecules have been detected in
muscle biopsies from patients with IBM. Etanercept is a TNFalpha receptor fusion
protein that binds and inactivates tumor necrosis factor. Nine patients were
treated with etanercept at a dose of 25 mg, two times a week for an average
of
17 +/- 6.1 months. Each patient was evaluated using quantitative strength
testing. Their data were compared to two different control groups. The first
control group consisted of patients who participated in trials of
beta-interferon-1A and had received placebo. There was no significant
difference. The second control group was a natural history cohort of IBM
patients. There was no statistically significant difference between the treated
group and the natural history group at 6 and 12 months when looking at elbow
flexors, or 6 months when looking at hand grip. In the treated patients there
was a small but significant improvement (p = 0.002) in handgrip at 12 months.
Publication Types:
Clinical Trial
Comparative Study
PMID: 16432140 [PubMed - indexed for MEDLINE]
70: Neurology. 2006 Jan 24;66(2 Suppl 1):S114-7.
RNA interference as potential therapy for neurodegenerative disease:
applications to inclusion-body myositis?
Paulson H.
Department of Neurology, Carver College of Medicine, University of Iowa, Iowa
City, IA 52242, USA. henry-paulson@uiowa.edu
The discovery of RNA interference (RNAi) has led to powerful new approaches
to
silence targeted genes in a sequence-specific manner. The potential therapeutic
application of RNAi to neurologic disease is highlighted by the recent success
of several laboratories in suppressing the expression of neurodegenerative
disease genes in transgenic mouse models. Here I discuss potential applications
of RNAi to inclusion-body myositis (IBM) after first reviewing its application
more generally to neurologic disease. The clearest application of RNAi to IBM
is
as a research tool to identify critical target genes that contribute to
pathogenesis. Provided that proximal pathogenic targets are identified, RNAi
could surface as a potential therapeutic strategy to modulate their expression.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 16432138 [PubMed - indexed for MEDLINE]
71: Neurology. 2006 Jan 24;66(2 Suppl 1):S110-3.
Comment in:
Neurology. 2006 Jun 27;66(12):1959; author reply 1959.
Treatment and prevention of the amyloidoses: can the lessons learned be applied
to sporadic inclusion-body myositis?
Buxbaum JN.
Department of Molecular and Experimental Medicine, The Keck Autoimmune Disease
Center, The Scripps Research Institute, La Jolla, CA, USA. jbux@scripps.edu
The amyloid fibril represents a final common pathologic pathway for a variety
of
human proteins, all of which have a propensity to misfold. Each seems to require
a predisposing event to realize its fibrillogenic potential. It may be mutation,
inappropriate or incomplete cleavage, overproduction, or the availability of
a
template for misfolding. Therapies have been based on decreasing the stimulus
(inflammation in the case of AA) reducing the number of producing cells (AL)
and
a variety of approaches to removing the extracellular aggregates. Sporadic
inclusion-body myositis (sIBM), while physically resembling the extracellular
amyloidoses, is an intracellular disease, hence imposes the additional
requirement of developing a therapy that can access and function inside the
affected or potentially affected, cell. Current approaches to the treatment
of
other forms of amyloidosis are discussed in the context of their applicability,
or lack thereof, to sIBM.
Publication Types:
Comparative Study
Research Support, N.I.H., Extramural
Review
PMID: 16432137 [PubMed - indexed for MEDLINE]
72: Neurology. 2006 Jan 24;66(2 Suppl 1):S1-6.
A perspective on sporadic inclusion-body myositis: the role of aging and
inflammatory processes.
Finch CE.
Andrus Gerontology Center, Department of Biological Sciences, University of
Southern California, Los Angeles, CA 90089-0191, USA. cefinch@usc.edu
Sporadic inclusion-body myositis (sIBM) is an age-related condition manifested
after midlife. This review points out salient features of sIBM that are shared
with normal aging in muscle and with inflammatory changes in vascular atheromas
and senile plaques of Alzheimer disease (AD). The amyloid precursor protein
(APP) and derived Abeta peptides are found in both AD and sIBM. Because
transgenic expression of human APP induces sIBM like changes, it is of potential
interest that an inducer of APP, IL-1, increases during aging in mouse muscle.
Because various subsets of the usual aging changes in aging brain, muscle, and
vessels can be attenuated in rodents by caloric intake and possibly in humans
by
drugs with anti-inflammatory and anticoagulant activities, this study suggests
that diet and inflammation may be useful experimental variations in exploring
the pathogenesis of sIBM.
Publication Types:
Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 16432135 [PubMed - indexed for MEDLINE]
73: Autoimmun Rev. 2006 Feb;5(2):93-100. Epub 2005 Jun 17.
Difference in adhesion molecule expression (ICAM-1 and VCAM-1) in juvenile
and
adult dermatomyositis, polymyositis and inclusion body myositis.
Sallum AM, Kiss MH, Silva CA, Wakamatsu A, Vianna MA, Sachetti S, Marie SK.
Department of Pediatrics--University of Sao Paulo Medical School, Brazil.
adrianasallum@ig.com.br
To assess the differential expression of adhesion molecules ICAM-1 and VCAM-1
in
vessels and muscle fibers in acquired inflammatory myopathy, a series comprising
thirty-seven muscle biopsy specimens from patients with JDM, fifteen with DM,
fifteen with PM and seven with IBM was studied. Histochemical and
immunohistochemical tests (StreptABCcomplex/HRP) for ICAM-1 and VCAM-1
(Dakopatts) were performed in serial frozen sections. ICAM-1 expression in
vessels was significantly (p<0.0001) more present in JDM than PM, DM or IBM.
However, in muscle fibers, ICAM-1 expression was absent in both JDM and IBM,
but
present in 33.4% and 40% in PM and DM respectively (p<0.0001). VCAM-1 expression
in vessels was significantly more present in PM and DM than JDM and IBM
(p<0.0001) while VCAM-1 expression in muscle fibers was almost absent in
the
four groups (p=0.2632). These findings emphasize the importance of adhesion
molecules in the pathophysiology of the inflammatory myopathies, mainly the
marked ICAM-1 expression in vessels in JDM, corroborating the microvascular
involvement in this disease. In contrast, VCAM-1 seems not to play a major role
in JDM, as previously described in PM, DM and IBM. Adhesion molecule expression
in JDM presents a differential characteristic when compared to PM, DM and IBM.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16431335 [PubMed - indexed for MEDLINE]
74: Ann Rheum Dis. 2006 Feb;65(2):242-5.
Clinical characteristics of patients with myositis and autoantibodies to
different fragments of the Mi-2 beta antigen.
Hengstman GJ, Vree Egberts WT, Seelig HP, Lundberg IE, Moutsopoulos HM, Doria
A,
Mosca M, Vencovsky J, van Venrooij WJ, van Engelen BG.
Neuromuscular Centre Nijmegen, Department of Neurology, University Medical
Centre Nijmegen, PO Box 9101, Internal Code 935, 6500 HB Nijmegen, The
Netherlands. g.hengstman@neuro.umcn.nl.
OBJECTIVES: To assess the clinical implications of autoantibodies directed
against different parts of the Mi-2 beta autoantigen in patients with myositis.
METHODS: A systematic assessment of the clinical, laboratory, and histological
characteristics of 48 anti-Mi-2 positive patients from six European centres
was
made. Anti-Mi-2 autoantibodies were determined with an ELISA using four
overlapping fragments spanning the entire amino acid sequence of the
autoantigen. Data were compared with results for a large group of anti-Mi-2
negative patients with myositis published previously. RESULTS: Anti-Mi-2
autoantibodies were found in dermatomyositis, polymyositis, and inclusion body
myositis. In general, myositis with anti-Mi-2 autoantibodies was characterised
by relatively mild disease, sometimes accompanied by extra-muscular symptoms,
including arthralgia, arthritis, Raynaud's phenomenon, and interstitial lung
disease. Cardiac disease was not seen, and treatment response was fair. No
differences were found between patients with autoantibodies to different
fragments of the Mi-2 beta antigen, except for a potentially increased risk
of
cancer in patients with antibodies directed to the N-terminal fragment of the
autoantigen. CONCLUSIONS: Anti-Mi-2 autoantibodies are not a marker of a
specific subtype of myositis. No significant differences between patients with
autoantibodies to different fragments of the Mi-2 beta autoantigen are found,
with the possible exception of an increased risk of cancer in patients with
antibodies to the N-terminal fragment.
Publication Types:
Comparative Study
Multicenter Study
Research Support, Non-U.S. Gov't
PMID: 16410528 [PubMed - indexed for MEDLINE]
75: J Neurochem. 2006 Feb;96(3):777-89. Epub 2006 Jan 9.
Neprilysin participates in skeletal muscle regeneration and is accumulated
in
abnormal muscle fibres of inclusion body myositis.
Broccolini A, Gidaro T, Morosetti R, Gliubizzi C, Servidei T, Pescatori M,
Tonali PA, Ricci E, Mirabella M.
Department of Neuroscience, Catholic University, Rome, Italy.
a.broccolini@rm.unicatt.it
Neprilysin (NEP, EP24.11), a metallopeptidase originally shown to modulate
signalling events by degrading small regulatory peptides, is also an
amyloid-beta- (Abeta) degrading enzyme. We investigated a possible role of NEP
in inclusion body myositis (IBM) and other acquired and hereditary muscle
disorders and found that in all myopathies NEP expression was directly
associated with the degree of muscle fibre regeneration. In IBM muscle, NEP
protein was also strongly accumulated in Abeta-bearing abnormal fibres. In
vitro, during the experimental differentiation of myoblasts, NEP protein
expression was regulated at the post-transcriptional level with a rapid increase
in the early stage of myoblast differentiation followed by a gradual reduction
thereafter, coincident with the progression of the myogenic programme. Treatment
of differentiating muscle cells with the NEP inhibitor
dl-3-mercapto-2-benzylpropanoylglycine resulted in impaired differentiation
that
was mainly associated with an abnormal regulation of Akt activation. Therefore,
NEP may play an important role during muscle cell differentiation, possibly
through the regulation, either directly or indirectly, of the insulin-like
growth factor I-driven myogenic programme. In IBM muscle increased NEP may be
instrumental in (i) reducing the Abeta accumulation in vulnerable fibres and
(ii) promoting a repair/regenerative attempt of muscle fibres possibly through
the modulation of insulin-like growth factor I-dependent pathways.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
PMID: 16405511 [PubMed - indexed for MEDLINE]
76: Clin Rev Allergy Immunol. 2005 Dec;29(3):255-69.
Intravenous immunoglobulin in patients with anti-GAD antibody-associated
neurological diseases and patients with inflammatory myopathies: effects on
clinicopathological features and immunoregulatory genes.
Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Bethesda, MD, USA. dalakasm@ninds.nih.gov
Controlled trials with intravenous immunoglobulin (IVIg) were conducted in
patients with Stiff-Person Syndrome (SPS) and dermatomyositis (DM), two
humorally mediated neurological disorders, and in inclusion body myositis (IBM),
a T-cell-mediated inflammatory myopathy. The clinical efficacy was compared
with
alterations on tissue expression of complement, cytokines, chemokines, adhesion
molecules, and immunoregulatory genes. The following patients were randomized
in
three separate trials to receive IVIg or placebo for 3 mo: (a) 16 patients with
anti-GAD antibody-positive SPS; (b) 15 patients with DM resistant to therapies;
and (c) 19 patients with IBM. After a washout, they crossed to the alternative
therapy for another 3 mo. Efficacy was based on the difference in the respective
disease scores from baseline to the second and third month of the infusions.
In
patients with SPS and DM, the scores changed positively and significantly from
months 1 through 3, but returned to baseline when the patients crossed to
placebo. In contrast, the scores in the placebo-randomized group remained
constant or worsened from months 1 to 3, but improved significantly after
crossing to IVIg. The muscle scores of patients with IBM did not significantly
change between IVIg or placebo. In SPS, the anti-GAD65 antibody titers declined
after IVIg but not after placebo. In DM, there was reduction of complement
consumption, interception of membranolytic attack complex formation,
downregulation of inflammation, fibrosis, cytokines, chemokines and adhesion
molecules, and alterations in thousands of immunoregulatory genes. We conclude
that IVIg is a safe and effective therapy for patients with SPS and DM
unresponsive to other agents. In tissues, IVIg restores tissue cytoarchitecture
by suppressing the inflammatory mediators at the protein, mRNA, and gene level.
Publication Types:
Comparative Study
Randomized Controlled Trial
PMID: 16391401 [PubMed - indexed for MEDLINE]
77: Neurol Sci. 2005 Dec;26(5):303-9.
Clinical and muscle magnetic resonance imaging study of an Italian family with
autosomal dominant inclusion body myopathy not linked to known genetic loci.
Rodolico C, Toscano A, Patitucci A, Muglia M, Gaeta M, D'Arrigo G, Migliorato
A,
Messina S, Quattrone A, Messina C, Vita G.
Department of Neurosciences, Psychiatry and Anaesthesiology, University of
Messina, A.O.U. G. Martino, Via C. Valeria, I-98125, Italy. crodolico@unime.it
The objective was to report a clinical, pathological and muscle magnetic
resonance (MR) study of an Italian family with an autosomal dominant inclusion
body myopathy (AD-IBM). Eight subjects (age range 20-56 years; 5 females and
3
males) belonging to four generations were studied. Onset of disturbances (distal
weakness at lower limbs) ranged from 20 to 28 years. CK levels were increased
to
five times. Only in an early stage oedema of involved muscles has been
demonstrated by muscle MR. Quadriceps femoris was characteristically spared;
in
the last phases a mild involvement of the vasti became evident with persistent
sparing of the rectus femori. Rimmed vacuoles and hyperphosphorylated tau
filaments were evident at muscle biopsy. Linkage analysis excluded the
association of the disease to chromosome loci 14q11, 17p13.1, 2p13, 19p13. The
study suggests that quadriceps sparing is a characteristic feature also of
AD-IBM. This finding could represent a muscle-image hallmark helpful in
diagnosis of autosomal dominant muscular disorders.
Publication Types:
Comparative Study
PMID: 16388363 [PubMed - indexed for MEDLINE]
78: Age Ageing. 2006 Jan;35(1):91-4.
Inclusion body myositis: an underdiagnosed myopathy of older people.
Munshi SK, Thanvi B, Jonnalagadda SJ, Da Forno P, Patel A, Sharma S.
Department of Medicine for the Elderly, Leicester Royal Infirmary, Infirmary
Square, Leicester LE1 5WW, UK. sunil.munshi@uhl-tr.nhs.uk
Inclusion body myositis (IBM), a condition characterised by progressive muscle
weakness and inclusion bodies visible on muscle biopsy, is the most common type
of myopathy in patients over 50 years of age. However, it is not only under
diagnosed but frequently misdiagnosed as polymyositis and hence wrongly treated
with steroids. In the evaluation of progressive weakness in older Caucasian
males, IBM should be an important diagnostic consideration. Treatment-resistant
'polymyositis' in patients over 50 years of age is often IBM. If there is no
histological confirmation, the diagnostic criteria allow for a category of
'possible IBM'. Sometimes, the diagnosis is missed because of the slow
progression of the disease and a lack of suspicion on the part of physicians.
The following case report and literature review will explore many of these
issues.
Publication Types:
Case Reports
PMID: 16364943 [PubMed - indexed for MEDLINE]
79: Neurology. 2005 Dec 16; [Epub ahead of print]
Inclusion-body myositis and Alzheimer disease. Two sides of the same coin,
or
different currencies altogether?
Murphy MP, Golde TE.
From the Department of Molecular and Cellular Biochemistry (M.P.M.),
Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY; and the
Department of Neuroscience (T.E.G.), Mayo Clinic College of Medicine,
Jacksonville, FL.
PMID: 16361388 [PubMed - as supplied by publisher]
80: Neurology. 2005 Dec 16; [Epub ahead of print]
Controlling autoimmunity in sporadic inclusion-body myositis.
Steinman L.
From the Department of Neurology and Neurological Sciences, Beckman Center
for
Molecular Medicine, Stanford University, Stanford, CA.
PMID: 16361386 [PubMed - as supplied by publisher]
81: Neurology. 2005 Dec 16; [Epub ahead of print]
Inclusion-body myositis. Clinical and pathologic aspects, and basic research
potentially relevant to treatment.
Askanas V, Dalakas MC, Engel WK.
From the Department of Neurology (Drs. Askanas and Engel), University of
Southern California, Keck School of Medicine, Los Angeles; and National
Institutes of Health (Dr. Dalakas), Neuromuscular Diseases Section, NINDS,
Bethesda.
PMID: 16361370 [PubMed - as supplied by publisher]
82: J Clin Rheumatol. 2005 Oct;11(5):264-6.
Rituximab in the treatment of refractory dermatomyositis.
Chiappetta N, Steier J, Gruber B.
Department of Rheumatology, Stony Brook University Hospital, Stony Brook, New
York 11794, USA. nhazlett@gmail.com
Dermatomyositis is an inflammatory myopathy characterized by muscle weakness
and
inflammation. In contrast to polymyositis and inclusion body myositis, humoral
immune mechanisms appear to contribute to the pathogenesis of dermatomyositis.
A
56-year-old man with dermatomyositis resistant to conventional therapies was
treated with 6 weekly infusions of the anti-CD-20 monoclonal antibody,
rituximab, at a dosage of 100 mg/m in addition to other agents. The patient
demonstrated a remarkable clinical response as indicated by an increase in
muscle strength and a decline in creatine kinase enzymes. B-cell depletion
therapy with rituximab used alone or in combination with other immunosuppressive
therapies may be a viable option in patients with dermatomyositis as well as
other autoimmune diseases refractory to current therapies.
Publication Types:
Case Reports
PMID: 16357773 [PubMed - indexed for MEDLINE]
83: Neurology. 2005 Dec 13;65(11):1782-7.
Erratum in:
Neurology. 2006 Feb 28;66(4):493. Bregoli, L S [corrected to Bregoli, L].
Plasma cells in muscle in inclusion body myositis and polymyositis.
Greenberg SA, Bradshaw EM, Pinkus JL, Pinkus GS, Burleson T, Due B, Bregoli
L,
O'Connor KC, Amato AA.
Division of Neuromuscular Disease, Department of Neurology, Brigham and Women's
Hospital, Harvard Medical School, Boston, MA, USA. sagreenberg@partners.org
BACKGROUND: Previous immunohistochemical studies of muscle from patients with
inclusion body myositis and polymyositis found many more T cells than B cells,
suggesting a role for intramuscular cell-mediated immune mechanisms rather than
humoral mechanisms. METHODS: Microarray studies were performed on muscle biopsy
specimens from 40 patients with inclusion body myositis (IBM; n = 23),
polymyositis (PM; n = 6), and without neuromuscular disease (n = 11). Reverse
transcription PCR of selected immunoglobulin gene transcripts was performed
on
two patient samples. Qualitative immunohistochemical studies for B-cell lineage
cell surface markers were performed on 28 muscle specimens and quantitative
studies performed on a subset of 19 untreated patients with IBM or PM. CD138+
cells were isolated from muscle using laser capture microdissection, and
immunoglobulin transcripts were PCR amplified to determine the presence or
absence of immunoglobulin gene rearrangements unique to the B-cell lineage.
RESULTS: Immunoglobulin gene transcripts accounted for 59% in IBM and 33% in
PM
of the most stringently defined highest differentially expressed muscle
transcripts compared with normal. Plasma cells, terminally differentiated B
cells expressing CD138 but not CD19 or CD20, are present in IBM and PM muscle
in
numbers several times higher than B cells. CONCLUSIONS: There are differentiated
B cells in the form of CD138+ plasma cells within the muscle of patients with
inclusion body myositis and polymyositis. The principle of linked recognition
of
B-cell activation predicts several strategies for autoantigen discovery that
could not otherwise be pursued through the study of the infiltrating T-cell
population alone.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16344523 [PubMed - indexed for MEDLINE]
84: Hum Mol Genet. 2006 Jan 15;15(2):189-99. Epub 2005 Dec 1.
Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic
reticulum-associated degradation.
Weihl CC, Dalal S, Pestronk A, Hanson PI.
Department of Neurology, Washington University School of Medicine, 660 South
Euclid Avenue, St Louis, MO 63110, USA. weihlc@neuro.wustl.edu
Mutations in the AAA+ protein (ATPase associated with a variety of cellular
activities) p97/VCP (valosin-containing protein) cause a dominantly inherited
syndrome of inclusion body myopathy with Paget's disease of the bone and
fronto-temporal dementia (IBMPFD). p97/VCP is a ubiquitously expressed protein
that participates in a number of cellular processes including endoplasmic
reticulum-associated degradation (ERAD). p97/VCP aids in the extraction of
ubiquitinated proteins from the endoplasmic reticulum (ER) and facilitates their
delivery to the proteasome. This study focuses on the effects of
disease-associated p97/VCP mutations on this pathway. We show that p97/VCP
containing the most prevalent IBMPFD-associated mutation, R155H, has normal
ATPase activity and hexameric structure. However, when expressed in cultured
cells, both this and a second IBMPFD-associated p97/VCP mutant increase the
overall level of ubiquitin-conjugated proteins and specifically impair
degradation of mutant DeltaF508-CFTR handled by the ERAD pathway. These effects
are similar to those previously described for an ATPase deficient p97/VCP mutant
and suggest that IBMPFD mutations impair p97/VCP cellular function. In a subset
of cells, IBMPFD mutations also promote formation of aggregates that contain
p97/VCP, ubiquitin conjugates and ER-resident proteins. Undegraded mutant
DeltaF508-CFTR also accumulates in these aggregates. We conclude that IBMPFD
mutations in p97/VCP disrupt ERAD and that this may contribute to the
pathogenesis of IBMPFD.
Publication Types:
Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16321991 [PubMed - indexed for MEDLINE]
85: Alzheimer Dis Assoc Disord. 2005 Oct-Dec;19 Suppl 1:S44-7.
Autosomal dominant inclusion body myopathy, Paget disease of bone, and
frontotemporal dementia.
Kimonis VE, Watts GD.
Division of Genetics, Children's Hospital Boston, Harvard Medical School,
Boston, Massachusetts 02115, USA. virginia.kimonis@childrens.harvard.edu
Autosomal dominant proximal limb girdle or inclusion body myopathy, associated
with Paget disease of bone and frontotemporal dementia (IBMPFD) is a recently
described disorder that maps to chromosome 9p21.1-p12. We refined the critical
locus and identified the gene as the Valosin Containing Protein (VCP) gene,
a
member of the AAA-ATPase superfamily using a candidate gene approach. Six
missense mutations were found to co-segregate with affected individuals only,
two of these representing mutation hot spots. We report the clinical and
molecular findings in 99 individuals in 13 families. VCP is associated with
a
variety of cellular activities, including the control of cell cycle, membrane
fusion, and the ubiquitin-proteasome degradation pathway. Previous studies have
associated VCP mutants in cell lines with vacuole formation and aggregate
formation. Identification of VCP as the gene causing IBMPFD has important
implications for understanding the pathogenesis of neurodegenerative disorders.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16317258 [PubMed - indexed for MEDLINE]
86: Acta Myol. 2005 Jul;24(1):17-24.
Sporadic inclusion-body myositis: a proposed key pathogenetic role of the
abnormalities of the ubiquitin-proteasome system, and protein misfolding and
aggregation.
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@hsc.usc.edu
Sporadic inclusion-body myositis (s-IBM), the most common muscle disease of
older persons, is of unknown cause and there is no successful treatment. We
summarize our most recent findings in s-IBM muscle fibers, which demonstrate
abnormalities of the ubiquitin-proteasome system, and abnormal accumulation,
misfolding and aggregation of proteins. We propose that these changes, possibly
provoked by the aging intra-muscle fiber cellular milieu, and aggravated by
the
oxidative stress, play a key pathogenic role in s-IBM. This evidence strongly
suggests that mechanisms other than the immune/inflammatory response play the
important role in s-IBM muscle fiber degeneration.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16315367 [PubMed - indexed for MEDLINE]
87: FASEB J. 2006 Jan;20(1):118-20. Epub 2005 Nov 17.
Expression of toll-like receptors by human muscle cells in vitro and in vivo:
TLR3 is highly expressed in inflammatory and HIV myopathies, mediates IL-8
release and up-regulation of NKG2D-ligands.
Schreiner B, Voss J, Wischhusen J, Dombrowski Y, Steinle A, Lochmuller H,
Dalakas M, Melms A, Wiendl H.
Department of General Neurology, Hertie-Institute for Clinical Brain Research,
Eberhard-Karls-University Tuebingen, Tuebingen, Germany.
The particular microenvironment of the skeletal muscle can be the site of
complex immune reactions. Toll-like receptors (TLRs) mediate inflammatory
stimuli from pathogens and endogenous danger signals and link the innate and
adaptive immune system. We investigated innate immune responses in human muscle.
Analyzing TLR1-9 mRNA in cultured myoblasts and rhabdomyosarcoma cells, we found
constitutive expression of TLR3. The TLR3 ligand Poly (I:C), a synthetic analog
of dsRNA, and IFN-gamma increased TLR3 levels. TLR3 was mainly localized
intracellularly and regulated at the protein level. Poly (I:C) challenge 1)
activated nuclear factor-kappaB (NF-kappaB), 2) increased IL-8 release, and
3)
up-regulated NKG2D ligands and NK-cell-mediated lysis of muscle cells. We
examined muscle biopsy specimens of 6 HIV patients with inclusion body
myositis/polymyositis (IBM/PM), 7 cases of sporadic IBM and 9 nonmyopathic
controls for TLR3 expression. TLR3 mRNA levels were elevated in biopsy specimens
from patients with IBM and HIV-myopathies. Muscle fibers in inflammatory
myopathies expressed TLR3 in close proximity of infiltrating mononuclear cells.
Taken together, our study suggests an important role of TLR3 in the
immunobiology of muscle, and has substantial implications for the understanding
of the pathogenesis of inflammatory myopathies or therapeutic interventions
like
vaccinations or gene transfer.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16293707 [PubMed - indexed for MEDLINE]
88: Medicine (Baltimore). 2005 Nov;84(6):338-49.
Immunogenetic risk and protective factors for the idiopathic inflammatory
myopathies: distinct HLA-A, -B, -Cw, -DRB1 and -DQA1 allelic profiles and motifs
define clinicopathologic groups in caucasians.
O'Hanlon TP, Carrick DM, Arnett FC, Reveille JD, Carrington M, Gao X, Oddis
CV,
Morel PA, Malley JD, Malley K, Dreyfuss J, Shamim EA, Rider LG, Chanock SJ,
Foster CB, Bunch T, Plotz PH, Love LA, Miller FW.
National Institute of Environmental Health Sciences, Rockville, MD 20892-0958,
USA. ohanlont@niehs.nih.gov
The idiopathic inflammatory myopathies (IIM) are systemic connective tissue
diseases in which autoimmune pathology is suspected to promote chronic muscle
inflammation and weakness. We have performed low to high resolution genotyping
to characterize the allelic profiles of HLA-A, -B, -Cw, -DRB1, and -DQA1 loci
in
a large population of North American Caucasian patients with IIM representing
the major clinicopathologic groups (n = 571). We confirmed that alleles of the
8.1 ancestral haplotype were important risk markers for the development of IIM,
and a random forests classification analysis suggested that within this
haplotype, HLA-B*0801, DRB1*0301 and/ or closely linked genes are the principal
HLA risk factors. In addition, we identified several novel HLA factors
associated distinctly with 1 or more clinicopathologic groups of IIM. The
DQA1*0201 allele and associated peptide-binding motif (KLPLFHRL) were exclusive
protective factors for the CD8+ T cell-mediated IIM forms of polymyositis (PM)
and inclusion body myositis (IBM) (pc < 0.005). In contrast, HLA-A*68 alleles
were significant risk factors for dermatomyositis (DM) (pc = 0.0021), a distinct
clinical group thought to involve a humorally mediated immunopathology. While
the DQA1*0301 allele was detected as a possible risk factor for IIM, PM, and
DM
patients (p < 0.05), DQA1*03 alleles were protective factors for IBM (pc
=
0.0002). Myositis associated with malignancies was the most distinctive group
of
IIM wherein HLA Class I alleles were the only identifiable susceptibility
factors and a shared HLA-Cw peptide-binding motif (AGSHTLQWM) conferred
significant risk (pc = 0.019). Together, these data suggest that HLA
susceptibility markers distinguish different myositis phenotypes with divergent
pathogenetic mechanisms. These variations in associated HLA polymorphisms may
reflect responses to unique environmental triggers resulting in the tissue
pathospecificity and distinct clinicopathologic syndromes of the IIM.
Publication Types:
Research Support, N.I.H., Extramural
PMID: 16267409 [PubMed - indexed for MEDLINE]
89: Neurology. 2005 Oct 25;65(8):1304-5.
Inclusion body myopathy and Paget disease is linked to a novel mutation in
the
VCP gene.
Haubenberger D, Bittner RE, Rauch-Shorny S, Zimprich F, Mannhalter C, Wagner
L,
Mineva I, Vass K, Auff E, Zimprich A.
Department of Neurology, Medical University of Vienna, Vienna, Austria.
Mutations in the valosin-containing protein (VCP) on chromosome 9p13-p12 were
recently found to be associated with hereditary inclusion body myopathy, Paget
disease of the bone, and frontotemporal dementia (IBMPFD). We identified a novel
missense mutation in the VCP gene (R159H; 688G>A) segregating with this disease
in an Austrian family of four affected siblings, who exhibited progressive
proximal myopathy and Paget disease of the bone but without clinical signs of
dementia.
PMID: 16247064 [PubMed - indexed for MEDLINE]
90: Neuromuscul Disord. 2005 Nov;15(11):753-9. Epub 2005 Sep 28.
IBM-type inclusions in a patient with slow-channel syndrome caused by a mutation
in the AChR epsilon subunit.
Fidzianska A, Ryniewicz B, Shen XM, Engel AG.
Neuromuscular Unit, Medical Research Centre, Pol. Ac. Sci. Pawinskiego 5, 02-106
Warsaw, Poland. neurmyol@cmdik.pan.pl
We report a patient with a slow-channel congenital myasthenic syndrome who
carries a novel slow-channel mutation in the epsilon subunit of the
acetylcholine receptor and has tubulofilamentous inclusion bodies, in skeletal
muscle of the type observed in hereditary and sporadic inclusion body myositis.
Ultrastructural analysis of a muscle specimen obtained at the age of 9 years
showed an endplate myopathy typical of the slow-channel syndrome. Twenty years
later, a second muscle specimen again showed the endplate myopathy as well
numerous nuclear and cytoplasmic tubulofilamentous inclusion bodies. Molecular
genetic studies revealed a novel valine to phenylalanine mutation (epsilonV259F)
in the M2 domain of the acetylcholine receptor. Coexistence of the slow-channel
syndrome with a feature of IBM has not been observed before.
Publication Types:
Case Reports
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16198106 [PubMed - indexed for MEDLINE]
91: Transfusion. 2005 Oct;45(10):1640-57.
Use of intravenous immunoglobulin for treatment of neurologic conditions: a
systematic review.
Fergusson D, Hutton B, Sharma M, Tinmouth A, Wilson K, Cameron DW, Hebert PC.
Clinical Epidemiology Program, Ottawa Health Research Institute, Ottawa,
Ontario, Canada. dafergusson@ohri.ca
BACKGROUND: Given the increasing use of intravenous immunoglobulin (IVIG) for
various neurologic conditions and uncertainty pertaining to its benefits and
harms, a systematic review was conducted of randomized controlled trials (RCTs)
evaluating IVIG for all neurologic indications for which there was at least
one
published trial. STUDY DESIGN AND METHODS: For this systematic review, a
systematic search strategy was applied to MEDLINE (1966-June 2003) and the
Cochrane Register of Controlled Trials (June 2003) to identify potentially
eligible RCTs comparing IVIG to placebo or an active control. All dosage
regimens were considered. Abstracts were excluded, and no restriction was placed
on language of publication. Two investigators independently performed data
extraction with a standardized form. Measures of effect were calculated for
each
trial independently, and studies were pooled based on clinical and methodologic
judgment as to its appropriateness. Where pooling of trials was inappropriate,
a
qualitative discussion of findings is provided. RESULTS AND CONCLUSIONS:
Thirty-seven trials representing 14 conditions were identified. IVIG is more
effective than placebo for treatment of relapsing-remitting multiple sclerosis
and idiopathic chronic inflammatory demyelinating polyneuropathy. There is also
potential benefit for treatment of multifocal motor neuropathy, myasthenia
gravis, dermatomyositis, stiff-person syndrome, and Lambert-Eaton myasthenic
syndrome. There was insufficient evidence to determine whether IVIG therapy
was
more effective than plasma exchange for Guillain-Barre syndrome. There was also
insufficient evidence regarding paraprotein-associated polyneuropathy. No
evidence of benefit was observed for secondary progressive multiple sclerosis
or
inclusion body myositis.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
Review
PMID: 16181216 [PubMed - indexed for MEDLINE]
92: Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13544-9. Epub 2005 Sep 8.
Discovering statistically significant pathways in expression profiling studies.
Tian L, Greenberg SA, Kong SW, Altschuler J, Kohane IS, Park PJ.
Department of Preventive Medicine, Feinberg School of Medicine, Northwestern
University, 680 North Lake Shore Drive, Chicago, IL 60611, USA.
Accurate and rapid identification of perturbed pathways through the analysis
of
genome-wide expression profiles facilitates the generation of biological
hypotheses. We propose a statistical framework for determining whether a
specified group of genes for a pathway has a coordinated association with a
phenotype of interest. Several issues on proper hypothesis-testing procedures
are clarified. In particular, it is shown that the differences in the
correlation structure of each set of genes can lead to a biased comparison among
gene sets unless a normalization procedure is applied. We propose statistical
tests for two important but different aspects of association for each group
of
genes. This approach has more statistical power than currently available methods
and can result in the discovery of statistically significant pathways that are
not detected by other methods. This method is applied to data sets involving
diabetes, inflammatory myopathies, and Alzheimer's disease, using gene sets
we
compiled from various public databases. In the case of inflammatory myopathies,
we have correctly identified the known cytotoxic T lymphocyte-mediated
autoimmunity in inclusion body myositis. Furthermore, we predicted the presence
of dendritic cells in inclusion body myositis and of an IFN-alpha/beta response
in dermatomyositis, neither of which was previously described. These predictions
have been subsequently corroborated by immunohistochemistry.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
PMID: 16174746 [PubMed - indexed for MEDLINE]
93: Curr Opin Neurol. 2005 Oct;18(5):497-503.
Diagnosis, pathogenesis and treatment of inclusion body myositis.
Oldfors A, Lindberg C.
Goteborg Neuromuscular Center, Department of Pathology, Sahlgrenska University
Hospital, Goteborg, Sweden. anders.oldfors@pathology.gu.se
PURPOSE OF REVIEW: We provide an update of progress gained from research into
sporadic inclusion body myositis (s-IBM). RECENT FINDINGS: Most research on
s-IBM has focused on the inflammatory reaction or the accumulation of
pathological proteins in vacuolated muscle fibres. The inflammatory reaction
is
characterized by clonal expansions of lymphocytes, predominantly CD8 cytotoxic
T
cells, which invade and destroy muscle fibres. That costimulatory molecules
have
been identified demonstrates that muscle fibres can act as antigen presenting
cells, and the expression of various chemokines in muscle indicates their
importance in the immunopathogenesis of s-IBM. The region of interest for a
susceptibility gene in the major histocompatibility complex has been narrowed,
and for the first time it has been demonstrated that a chronic viral infection
can trigger the inflammatory process leading to s-IBM. The nature of the
accumulated material associated with the vacuoles has been extensively
investigated over the past few years. Amyloid-beta and phosphorylated tau
protein in intracellular inclusions are a characteristic finding in s-IBM, which
may lead to calcium dyshomeostasis and endoplasmic reticulum stress. The
proteasomal system is upregulated, including immunoproteasomes. 'Molecular
misreading' leading to ubiquitin mRNA mutations and accumulation of pathological
ubiquitin in muscle fibres may be associated with proteasomal dysfunction. There
is still no efficient treatment for s-IBM, but the effects of new, more specific
immunotherapies have begun to be explored. SUMMARY: Recent findings indicate
that both inflammatory reaction and abnormal protein accumulation are important
for the pathogenesis in s-IBM. The link between them continues to await
elucidation.
Publication Types:
Review
PMID: 16155431 [PubMed - indexed for MEDLINE]
94: Mol Genet Metab. 2005 Sep-Oct;86(1-2):244-9.
Single nucleotide polymorphisms in the dystroglycan gene do not correlate with
disease severity in hereditary inclusion body myopathy.
Gottlieb E, Ciccone C, Darvish D, Naiem-Cohen S, Dalakas MC, Savelkoul PJ,
Krasnewich DM, Gahl WA, Huizing M.
Medical Genetics Branch, National Human Genome Research Institute, National
Institutes of Health, Bethesda MD, USA.
Aberrant glycosylation of dystroglycan occurs in certain muscular dystrophies,
including hereditary inclusion body myopathy (HIBM). HIBM harbors a widely
varying clinical severity and age of onset, which raised the suspicion of the
presence of disease modifier genes. We considered the highly polymorphic
dystroglycan gene (DAG1) as a feasible candidate modifier gene. DAG1 genomic
DNA
was sequenced for 32 HIBM patients, mainly of Persian-Jewish descent. Five novel
DAG1 single nucleotide polymorphisms (SNPs) were identified, bringing the total
number of SNPs to 19. However, no direct correlation between DAG1 SNPs and
clinical severity of HIBM could be detected. Several identified SNPs substitute
an amino acid and might modulate dystroglycan function or glycosylation status,
and deserve further research. These data are valuable for future studies on
the
role of DAG1 in HIBM and other muscular dystrophies, especially those
dystrophies that involve abnormal glycosylation of dystroglycan.
PMID: 16112887 [PubMed - indexed for MEDLINE]
95: Hum Pathol. 2005 Aug;36(8):917-21.
Comment in:
Hum Pathol. 2006 Oct;37(10):1367-8; author reply 1368.
Positive troponin T without cardiac involvement in inclusion body myositis.
Schwarzmeier JD, Hamwi A, Preisel M, Resl C, Preusser M, Sluga E, Horcher E,
Shehata MM.
Hematology Department, Internal Medicine I, Medical University of Vienna, A-1097
Vienna, Austria. josef.schwarzmeier@meduniwien.ac.at
Cardiac troponin T (cTnT) is considered as a specific marker for acute
myocardial infarction. Here, we present a case with elevated cTnT, determined
by
a third-generation assay, without signs of a myocardial lesion. Routine
investigation of a 66-year-old female patient with indolent B-cell lymphoma
revealed increased serum levels of creatine kinase (CK), MB fraction of CK
(CK-MB), and cTnT, although she did not complain of cardiac symptoms.
Electrocardiographic monitoring, echocardiography, magnetic resonance computed
angiography, and percutaneous coronary angiography excluded myocardial damage.
However, the close follow-up showed a steady increase of CK-MB and cTnT levels
and gradual development of weakness in both thighs. A biopsy of the right
quadriceps muscle led to the diagnosis of inclusion body myositis. In contrast
to cTnT, cardiac troponin I could not be detected retrospectively in any of
her
serum samples. These results demonstrate for the first time that cTnT is
elevated in patients with inclusion body myositis.
Publication Types:
Case Reports
PMID: 16112010 [PubMed - indexed for MEDLINE]
96: Microsc Res Tech. 2005 Jul;67(3-4):114-20.
Molecular pathology and pathogenesis of inclusion-body myositis.
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
We summarize the molecular phenotype, diagnostic criteria, and the newest
advances related to seeking the pathogenic mechanism(s) of sporadic
inclusion-body myositis (s-IBM), a muscle disease usually of persons over age
50. On the basis of our research, several processes seem to be important in
relation to the still-speculative pathogenesis: 1) increased transcription and
accumulation of amyloid-beta precursor protein (AbetaPP), and accumulation of
its proteolytic fragment Abeta; 2) abnormal accumulation of cholesterol,
caveolin-1, and apolipoprotein E; 3) oxidative stress; 4) accumulations of
intramuscle fiber multiprotein aggregates; and 5) evidence that
unfolded/misfolded proteins participate in s-IBM pathogenesis. Our basic
hypothesis is that overexpression of AbetaPP within the aging muscle fibers
is
an early upstream event causing a subsequent pathogenic cascade.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 16104000 [PubMed - indexed for MEDLINE]
97: Neurology. 2005 Aug 9;65(3):420-5.
Messenger RNA degradation may be inhibited in sporadic inclusion body myositis.
Nakano S, Shinde A, Ito H, Ito H, Kusaka H.
Department of Neurology, Kansai Medical University, Moriguchi-city, Japan.
nakanos@takii.kmu.ac.jp
OBJECTIVE: To integrate an immune-mediated mechanism and the disturbed protein
expression in sporadic inclusion body myositis (IBM). BACKGROUND: In IBM,
abnormal fibers harbor inclusions of some proteins found in the brains of
patients with Alzheimer disease (AD). Poly(A)-binding protein 1 (PABP1) is the
RNA binding protein that attaches to the poly(A) tail of mRNA and is involved
in
translation and mRNA degradation. Under stresses, mRNA combined with PABP1 forms
cytoplasmic granules called stress granules. METHODS: Using 12 muscle biopsies
with sporadic IBM and 46 controls, the authors localized PABP1 by
immunohistochemistry, and poly(A)-containing RNA (poly(A)+ RNA) using the in
situ hybridization method. They also immuno-localized HuR, one of the components
of stress granules. RESULTS: In IBM, a proportion of fibers, including those
vacuolated, showed an abnormal accumulation of PABP1 immuno-positive deposits.
An immunofluorescence study indicated that large PABP1 positive deposits formed
conglomerates with poly(A)+ RNA and PABP1 colocalized with HuR. Although
PABP1-positive cytoplasmic inclusions were found in disease controls, their
aggregates combined with poly(A)+ RNA were only detected in IBM. CONCLUSIONS:
The localization of PABP1 positive deposits in inclusion body myositis (IBM)
and
other diseases may correspond to the stress granules that are formed under
exposure to cellular stresses and the sites of mRNA turnover. The concomitant
aggregation of poly(A)+ RNA that is specifically found in IBM may be due to
the
inhibition of mRNA degradation, which may affect translation. The authors
speculate that an autoantibody against mRNA degradation machinery could play
a
role in this inhibition.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16087907 [PubMed - indexed for MEDLINE]
98: Am J Pathol. 2005 Aug;167(2):517-26.
Proteasome inhibition and aggresome formation in sporadic inclusion-body
myositis and in amyloid-beta precursor protein-overexpressing cultured human
muscle fibers.
Fratta P, Engel WK, McFerrin J, Davies KJ, Lin SW, Askanas V.
Department of Neurology, USC Neuromuscular Center, Good Samaritan Hospital,
Los
Angeles, CA 90017-1912, USA.
The 26S proteasome system is involved in eliminating various proteins, including
ubiquitinated misfolded/unfolded proteins, and its inhibition results in
cellular accumulation of protein aggregates. Intramuscle-fiber ubiquitinated
multiprotein-aggregates are characteristic of sporadic inclusion-body myositis
(s-IBM) muscle fibers. Two major types of aggregates exist, containing either
amyloid-beta (Abeta) or phosphorylated tau (p-tau). We have now asked whether
abnormalities of the 26S proteasome contribute to s-IBM pathogenesis and whether
the multiprotein aggregates have features of aggresomes. Using cultured human
muscle fibers we also studied the effect of amyloid-beta precursor protein
(AbetaPP) overexpression on proteasome function and the influence of proteasome
inhibition on aggresome formation. We report that in s-IBM muscle biopsies 26S
proteasome subunits were immunodetected in the gamma-tubulin-associated
aggresomes, which also contained Abeta, p-tau, ubiquitin, and HSP70. In
addition, a) expression of proteasome subunits was greatly increased, b) the
20Salpha proteasome subunit co-immunoprecipitated with AbetaPP/Abeta, and c)
the
three major proteasomal proteolytic activities were reduced. In cultured muscle
fibers, AbetaPP-overexpressing fibers displayed diminished proteasomal
proteolytic activities, and addition of proteasome inhibitor strikingly
increased aggresome formation. Accordingly, proteasome dysfunction in s-IBM
muscle fibers may play a role in accumulation of misfolded, potentially
cytotoxic proteins and may be induced by increased intracellular AbetaPP/Abeta.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
PMID: 16049336 [PubMed - indexed for MEDLINE]
99: Cochrane Database Syst Rev. 2005 Jul 20;(3):CD003643.
Immunosuppressant and immunomodulatory treatment for dermatomyositis and
polymyositis.
Choy EH, Hoogendijk JE, Lecky B, Winer JB.
Academic Department of Rheumatology, GKT School of Medicine, King's College
Hospital, Denmark Hill, London, UK, SE5 9RS. ernest.choy@kcl.ac.uk
BACKGROUND: Idiopathic inflammatory myopathies are chronic skeletal diseases
with significant mortality and morbidity despite treatment by corticosteroids.
Immunosuppressive agents and immunomodulatory therapy are used to improve
disease control and reduce the long-term side effects of corticosteroids. While
these treatments are used commonly in routine clinical practice, the optimal
therapeutic regimen remains unclear. OBJECTIVES: To systematically review the
evidence for the effectiveness of immunosuppressants and immunomodulatory
treatments for dermatomyositis and polymyositis. SEARCH STRATEGY: We searched
the Cochrane Neuromuscular Disease Group trials register (searched February
2002
and updated in November 2003) and MEDLINE (January 1966 to December 2002). We
checked bibliographies of identified trials and wrote to disease experts.
SELECTION CRITERIA: Randomised or quasi-randomised controlled trials including
patients with probable or definite dermatomyositis and polymyositis as defined
by the criteria of Bohan and Peter or definite, probable or mild/early by the
criteria of Dalakas. Patients with inclusion body myositis should have been
excluded by muscle biopsies. Any immunosuppressant or immunomodulatory treatment
including corticosteroids, azathioprine, methotrexate, ciclosporin,
chlorambucil, cyclophosphamide, intravenous immunoglobulin, interferon and
plasma exchange was considered. Primary outcome was assessment of muscle
strength after at least six months. Other outcomes were: change in disability,
number of relapses and time to relapse, number of patients in remission and
time-to-remission, cumulative corticosteroid dose and serious adverse effects.
DATA COLLECTION AND ANALYSIS: Two authors (EC and JH) independently selected
trials for inclusion in the review. Four authors independently assessed each
study. Methodological criteria and the results of each study were recorded on
data extraction forms. MAIN RESULTS: Seven potentially relevant randomised
controlled trials were identified. One trial was excluded. Three studies
compared immunosuppressant with placebo control, one trial compared one
immunosuppressant (methotrexate) with another (azathioprine), another trial
compared ciclosporin A with methotrexate and the final trial compared
intramuscular methotrexate with oral methotrexate plus azathioprine. The study
comparing intravenous immunoglobulin with placebo concluded that the former
was
superior. Two randomised placebo-controlled trials assessing plasma exchange,
leukapheresis and azathioprine produced negative results. The fourth study
compared azathioprine with methotrexate and found azathioprine and methotrexate
equally effective but methotrexate had a better side effect profile. The fifth
study comparing ciclosporin A with methotrexate and the sixth study comparing
intramuscular methotrexate with oral methotrexate plus azathioprine found no
statistically significant differences between the treatment groups.
Immunosuppressants are associated with significant side effects. AUTHORS'
CONCLUSIONS: This systematic review highlights the lack of high quality
randomised controlled trials that assess the efficacy and toxicity of
immunosuppressants in inflammatory myositis.
Publication Types:
Review
PMID: 16034905 [PubMed - indexed for MEDLINE]
100: Glycobiology. 2005 Nov;15(11):1102-10. Epub 2005 Jun 29.
Use of a cell-free system to determine UDP-N-acetylglucosamine 2-epimerase
and
N-acetylmannosamine kinase activities in human hereditary inclusion body
myopathy.
Sparks SE, Ciccone C, Lalor M, Orvisky E, Klootwijk R, Savelkoul PJ, Dalakas
MC,
Krasnewich DM, Gahl WA, Huizing M.
Medical Genetics Branch, National Human Genome Research Institute, National
Institutes of Health, Bethesda, MD, USA.
Hereditary inclusion body myopathy (HIBM) is an autosomal recessive
neuromuscular disorder associated with mutations in uridine diphosphate
(UDP)-N-acetylglucosamine (GlcNAc) 2-epimerase (GNE)/N-acetylmannosamine
(ManNAc) kinase (MNK), the bifunctional and rate-limiting enzyme of sialic acid
biosynthesis. We developed individual GNE and MNK enzymatic assays and
determined reduced activities in cultured fibroblasts of patients, with HIBM
harboring missense mutations in either or both the GNE and MNK enzymatic
domains. To assess the effects of individual mutations on enzyme activity,
normal and mutated GNE/MNK enzymatic domains were synthesized in a cell-free
in
vitro transcription-translation system and subjected to the GNE and MNK
enzymatic assays. This cell-free system was validated for both GNE and MNK
activities, and it revealed that mutations in one enzymatic domain (in GNE,
G135V, V216A, and R246W; in MNK, A631V, M712T) affected not only that domain's
enzyme activity, but also the activity of the other domain. Moreover, studies
of
the residual enzyme activity associated with specific mutations revealed a
discrepancy between the fibroblasts and the cell-free systems. Fibroblasts
exhibited higher residual activities of both GNE and MNK than the cell-free
system. These findings add complexity to the tightly regulated system of sialic
acid biosynthesis. This cell-free approach can be applied to other glycosylation
pathway enzymes that are difficult to evaluate in whole cells because their
substrate specificities overlap with those of ancillary enzymes.
PMID: 15987957 [PubMed - indexed for MEDLINE]
101: Acta Neuropathol (Berl). 2005 Aug;110(2):173-7. Epub 2005 Jun 28.
Myostatin is increased and complexes with amyloid-beta within sporadic
inclusion-body myositis muscle fibers.
Wojcik S, Engel WK, 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.
Myostatin is a negative regulator of muscle mass and strength. Sporadic
inclusion-body myositis (s-IBM) is the most common degenerative muscle disease
of older persons and is characterized by pronounced muscle wasting. s-IBM is
of
unknown etiology and pathogenesis, and it lacks definitive treatment. We have
now demonstrated in samples from 12 s-IBM biopsies that: (1) by light and
electron microscopic immunocytochemistry, myostatin/myostatin precursor is
accumulated within muscle fibers and co-localized with amyloid-beta (Abeta);
(2)
by immunoblots, both myostatin and myostatin precursor are increased; and (3)
by
immunoprecipitation, myostatin precursor complexes with Abeta. Our study
suggests that myostatin/myostatin precursor, either alone, or bound to Abeta,
may play a novel role in the pathogenesis of s-IBM.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
PMID: 15983828 [PubMed - indexed for MEDLINE]
102: J Neurol. 2005 May;252 Suppl 1:I14-8.
IVIg in myasthenia gravis, Lambert Eaton myasthenic syndrome and inflammatory
myopathies: current status.
Illa I.
Chief Neuromuscular Diseases Unit, Servei Neurologia, Hospital Sta Creu i Sant
Pau, Universitat Autonoma de Barcelona, 08025 Barcelona, Spain.
iilla@hsp.santpau.es
Intravenous immunoglobulin (IVIg) is an effective tool for the treatment of
diseases with immune pathogenesis. This article reviews the current knowledge
of
the benefits of treating with IVIg patients with myasthenia gravis (MG), Lambert
Eaton myasthenic syndrome (LEMS), dermatomyositis (DM), polymyositis (PM) and
inclusion body myositis (IBM). Myasthenia gravis: Treatment of MG with IVIg
was
reported to be beneficial in a number of case series and two randomised
controlled trials, in which efficacy was measured by clinical improvement using
myasthenic muscle score and decrease in anti-acetylcholine receptor antibodies
(AchRAb). According to the results, IVIg could be recommended for crisis and
severe exacerbation. In many other clinical conditions, such as response to
treatment of mild or moderate exacerbation, changes in steroid dosage and before
thymectomy, IVIg has also been reported to be helpful, but no controlled trials
to confirm its efficacy have been performed. Lambert-Eaton myasthenic syndrome:
A placebo-controlled crossover study reported a significant clinical improvement
in the amplitude of the resting CMAP following IVIg treatment. Further
experience from case reports also indicates that IVIg is useful in patients
with
LEMS, both as a short- and long-term treatment, especially when
immunosuppressive drugs are not fully effective. Inflammatory
myopathies/dermatomyositis: In a double-blind placebo-controlled crossover trial
in patients with DM resistant to other treatments, IVIg was shown to produce
a
significant increase of muscle strength as well as a marked improvement in
immunopathological parameters in repeated muscle biopsies (before and after
IVIg). Thus, IVIg is an important therapy in patients with DM resistant to other
conventional therapies. Polymyositis: No randomised trials have been undertaken.
One study showed clinical improvement and a reduction in the need of prednisone
in patients with chronic refractory PM. Inclusion body myositis: Three
controlled trials showed some muscle strength improvement, although the changes
did not reach statistical significance. However improvement in swallowing was
repeatedly observed, suggesting that some patients with severe dysphagia may
derive a modest benefit from IVIg therapy. CONCLUSION: Controlled trials
indicate that in MG, LEMS, and DM, IVIg at a total dose of 2 g/kg is a highly
useful therapy. Uncontrolled trials and case reports indicate benefit in many
different clinical situations, but further clinical investigation is required.
Publication Types:
Review
PMID: 15959667 [PubMed - indexed for MEDLINE]
103: Neurobiol Aging. 2006 Mar;27(3):423-32. Epub 2005 Jun 13.
Pathogenic accumulation of APP in fast twitch muscle of IBM patients and a
transgenic model.
Sugarman MC, Kitazawa M, Baker M, Caiozzo VJ, Querfurth HW, LaFerla FM.
Department of Neurobiology and Behavior, University of California, 1109
Gillespie Neuroscience Facility, Irvine, CA 92697-4545, USA.
Inclusion body myositis (IBM) is the most common age-related degenerative
skeletal muscle disorder. The aberrant intracellular accumulation of the
beta-amyloid (Abeta) peptide within skeletal muscle is a pathological hallmark
of IBM. Skeletal muscle is comprised of both slow and fast twitch fibers, which
are present in different proportions in various muscles. It remains unclear
if
fast and/or slow twitch fibers are differentially involved in IBM pathogenesis.
To better understand the molecular pathogenesis of IBM, we analyzed human IBM
muscle biopsies and muscle from a transgenic mouse model of IBM (MCK-betaAPP).
Here we report that the majority of histopathologically-affected fibers in human
IBM biopsies were type II fast fibers. Skeletal muscle from MCK-betaAPP mice
exhibited higher transgene expression and steady-state levels of human betaAPP
in fast type IIB fibers compared to slow type I fibers. These findings indicate
that fast twitch fibers may selectively accumulate and be more vulnerable to
betaAPP- and Abeta-mediated damage in IBM. These findings also highlight
parallels between the MCK-betaAPP mice and the human IBM condition.
Publication Types:
Clinical Trial
Research Support, N.I.H., Extramural
PMID: 15950323 [PubMed - indexed for MEDLINE]
104: J Neurol. 2005 Dec;252(12):1448-54. Epub 2005 Jun 17.
Inclusion body myositis. Clinical features and clinical course of the disease
in
64 patients.
Badrising UA, Maat-Schieman ML, van Houwelingen JC, van Doorn PA, van Duinen
SG,
van Engelen BG, Faber CG, Hoogendijk JE, de Jager AE, Koehler PJ, de Visser
M,
Verschuuren JJ, Wintzen AR.
Dept. of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.
u.badrising@zhsdirksland.nl
The clinical features of inclusion body myositis (IBM) were of minor importance
in the design of consensus diagnostic criteria, mainly because of controversial
views on the specificity of signs and symptoms, although some authors reported
"typical" signs. To re-assess the clinical spectrum of IBM, a single
investigator using a standard protocol studied a cohort of 64 patients
cross-sectionally. Symptom onset was before the age of 50 years in 20% of cases.
Only a few patients (14 %) started with weakness other than that of quadriceps,
finger flexor or pharyngeal muscles. The sequence of power loss was erratic,
but
onset of symptoms with quadriceps weakness predicted an earlier onset of
dysphagia in older patients (> or = 56 years) compared with younger ones
(< 56
years) (p = 0.02). Despite widespread weakness patients had favourable scores
on
three commonly used function scales and they kept their employment. Complete
wheel-chair dependency was rare (3 %). A dominant characteristic was the
anatomical distribution of afflicted muscles: ventral extremity muscle groups
were more affected than dorsal muscle groups and girdle muscles were least
affected, the latter preserving postural stability. Ankylosis, especially in
extension of the fingers,was frequently present. Together with the sparing of
intrinsic hand muscles it was helpful in the preservation of many skillful
movements. IBM has a unique distribution of muscle weakness. Ankylotic
contractures are common. We feel that their joint impact on daily functioning
is
characteristic for the disease.
Publication Types:
Comparative Study
Evaluation Studies
PMID: 15942703 [PubMed - indexed for MEDLINE]
105: Acta Neuropathol (Berl). 2005 Jun;109(6):576-82. Epub 2005 Jun 4.
Alpha-chemokine receptors CXCR1-3 and their ligands in idiopathic inflammatory
myopathies.
De Paepe B, De Keyzer K, Martin JJ, De Bleecker JL.
Department of Neurology, Ghent University Hospital, De Pintelaan 185, 9000,
Ghent, Belgium.
The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of
neuromuscular disorders subdivided into polymyositis (PM), sporadic inclusion
body myositis (sIBM) and dermatomyositis (DM). Chemokines play an essential
role
in sustained inflammation associated with IIM. We studied the distribution of
the alpha-chemokine receptors CXCR1, 2, 3 and their ligands interferon-gamma
(IFN-gamma)-inducible T cell alpha chemoattractant (I-TAC), IFN-gamma-inducible
protein of 10 kDa (IP-10), monokine induced by IFN-gamma (MIG) and
growth-related oncogene (GRO) in IIM using immunohistochemistry,
immunofluorescence and Western blotting. Abundant expression of IP-10 was
observed on macrophages and T cells surrounding and invading non-necrotic muscle
fibers in PM and sIBM and in T cells in perimysial infiltrates of DM. IP-10
was
also localized to blood vessel endothelial cells in all inflammatory and normal
muscle tissues. The distribution of other alpha-chemokines was variable: Only
low levels of MIG and I-TAC were detected; GRO was localized to the endomysial
infiltrates of some PM and sIBM samples, but not in DM. Muscle tissues were
invariably CXCR1 negative, while a subset of inflammatory cells in all IIM were
CXCR2 positive. Strong CXCR3 expression was observed on the majority of T cells
in each IIM. We describe the differential repertoire of alpha-chemokines in
IIM,
and offer additional proof of the predominance of Th1-driven reactions in the
immunopathogenesis of all three diagnostic subgroups. We suggest the
Th1-mediated immunity in general, and the CXCR3/IP-10 interaction in particular,
as potential targets for novel therapeutic intervention in IIM.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
PMID: 15937690 [PubMed - indexed for MEDLINE]
106: Brain Pathol. 2005 Apr;15(2):101-8.
Involvement of clusterin and the aggresome in abnormal protein deposits in
myofibrillar myopathies and inclusion body myositis.
Ferrer I, Carmona M, Blanco R, Moreno D, Torrejon-Escribano B, Olive M.
Institut Neuropatologia, Servei Anatomia Patologica, IDIBELL-Hospital
Universitari de Bellvitge, Spain. 8082ifa@comb.es
Myofibrillar myopathies (MM) are characterized morphologically by the presence
of non-hyaline structures corresponding to foci of dissolution of myofibrils,
and hyaline lesions composed of aggregates of compacted and degraded
myofibrillar elements. Inclusion body myositis (IBM) is characterized by the
presence of rimmed vacuoles, eosinophilic inclusions in the cytoplasm, rare
intranuclear inclusions, and by the accumulation of several abnormal proteins.
Recent studies have demonstrated impaired proteasomal expression and activity
in
MM and IBM, thus accounting, in part, for the abnormal protein accumulation
in
these diseases. The present study examines other factors involved in protein
aggregation in MM and IBM. Clusterin is a multiple-function protein which
participates in Abeta-amyloid, PrP(res) and a-synuclein aggregation in Alzheimer
disease, prionopathies and a-synucleinopathies, respectively. gamma-Tubulin
is
present in the centrosome and is an intracellular marker of the aggresome.
Moderate or strong clusterin immunoreactivity has been found in association
with
abnormal protein deposits, as revealed by immunohistochemistry, single and
double-labeling immunofluorescence and confocal microscopy, in MM and IBM, and
in target structures in denervation atrophy. Gamma-Tubulin has also been
observed in association with abnormal protein deposits in MM, IBM, and in target
fibers in denervation atrophy. These morphological findings are accompanied
by
increased expression of clusterin and gamma-tubulin in muscle homogenates of
MM
and IBM cases, as revealed by gel electrophoresis and Western blots. Together,
these observations demonstrate involvement of clusterin in protein aggregates,
and increased expression of aggresome markers in association with abnormal
protein inclusions in MM and IBM and in targets, as crucial events related to
the pathogenesis of abnormal protein accumulation and degradation in these
muscular diseases.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 15912881 [PubMed - indexed for MEDLINE]
107: Muscle Nerve. 2005 Sep;32(3):247-60.
Skeletal muscle involvement in human immunodeficiency virus (HIV)-infected
patients in the era of highly active antiretroviral therapy (HAART).
Authier FJ, Chariot P, Gherardi RK.
Hopital Henri-Mondor, Departement de Pathologie, Creteil F-94010, France.
authier@univ-paris12.fr
Skeletal muscle involvement can occur at all stages of human immunodeficiency
virus (HIV) infection, and may represent the first manifestation of the disease.
Myopathies in HIV-infected patients are classified as follows: (1)
HIV-associated myopathies and related conditions, including HIV polymyositis,
inclusion-body myositis, nemaline myopathy, diffuse infiltrative lymphocytosis
syndrome (DILS), HIV-wasting syndrome, vasculitic processes, myasthenic
syndromes, and chronic fatigue; (2) muscle complications of antiretroviral
therapy, including zidovudine and toxic mitochondrial myopathies related to
other nucleoside-analogue reverse-transcriptase inhibitors (NRTIs),
HIV-associated lipodystrophy syndrome, and immune restoration syndrome related
to highly active antiretroviral therapy (HAART); (3) opportunistic infections
and tumor infiltrations of skeletal muscle; and (4) rhabdomyolysis. Introduction
of HAART has dramatically modified the natural history of HIV disease by
controlling viral replication, but, in turn, lengthening of the survival of
HIV-infected individuals has been associated with an increasing prevalence of
iatrogenic conditions.
Publication Types:
Review
PMID: 15902690 [PubMed - indexed for MEDLINE]
108: Cancer Epidemiol Biomarkers Prev. 2005 May;14(5):1279-82.
Tumor antigen markers for the detection of solid cancers in inflammatory
myopathies.
Amoura Z, Duhaut P, Huong DL, Wechsler B, Costedoat-Chalumeau N, Frances C,
Cacoub P, Papo T, Cormont S, Touitou Y, Grenier P, Valeyre D, Piette JC.
Service de Medecine Interne, Hopital Pitie-Salpetriere, 47-83 Bd de l'Hopital,
75013 Paris, France. zahir.amoura@psl.ap-hop-paris.fr
Dermatomyositis and polymyositis patients have an increased risk of developing
cancers. We have assessed the diagnostic values of serum tumor markers for the
detection of solid cancer in dermatomyositis/polymyositis patients. Serum
carcinoembryonic antigen, CA15-3, CA19-9, and CA125 were assayed by
immunoradiometric methods in 102 dermatomyositis/polymyositis patients. All
the
patients had complete physical examination, chest X-ray, echocardiogram,
gastrointestinal tract endoscopic explorations, thoracoabdomino-pelvic computed
tomography scan, and all women had gynecologic examination and mammogram.
Exclusion criteria for study were childhood dermatomyositis, inclusion body
myositis, myositis associated with a connective tissue disease, prior history
of
cancer, and the presence of benign conditions known to elevate serum tumor
markers. After a median follow-up of 59 months, 10 (9.8%) patients had a solid
cancer. Initial elevation of CA125 was associated with an increased risk of
developing solid cancer [P = 0.0001 by Fisher's exact test; odds ratio (OR),
29.7; 95% confidence interval (95% CI), 8.2-106.6]. For CA19-9, there was a
trend towards a significant association (P = 00.7; OR, 4.5; 95% CI, 1-18.7,
respectively). Diagnostic values of elevated CA125 and CA19-9 at screening
increased when the study analysis was restricted to patients who developed a
cancer within 1 year (P < 0.0001 and P = 0.018, respectively) or to patients
without interstitial lung disease (P = 0.00001; OR, 133; 95% CI, 6.5-2733 and
P
= 0.027; OR, 9; 95% CI, 1.5-53, respectively). Individual comparisons of the
baseline and the second CA125 value showed that three of the eight patients
with
cancers versus 3 of the 76 patients without, displayed an increase of their
CA125 level (P = 0.01 by Fisher's exact test). We conclude that CA125 and CA19-9
assessment could be useful markers of the risk of developing tumors for patients
with dermatomyositis and polymyositis and should therefore be included in the
search for cancer in dermatomyositis/polymyositis patients, especially for
patients without interstitial lung disease.
PMID: 15894686 [PubMed - indexed for MEDLINE]
109: Neurol Sci. 2005 May;26 Suppl 1:S7-8.
Autoimmune muscular pathologies.
Dalakas MC.
Neuromuscular Diseases Section, NINDS, Bethesda, MD, USA. dalakasm@ninds.nih.gov
The T cell-mediated mechanism responsible for Polymyositis and inclusion Body
Myositis and the complement-mediated microangiopathy associated with
Dermatomyositis are reviewed. The management of autoimmune myopathies with the
presently available immunotherapeutic agents as well as new therapies and
ongoing trials are discussed.
Publication Types:
Review
PMID: 15883700 [PubMed - indexed for MEDLINE]
110: Brain. 2005 Aug;128(Pt 8):1887-96. Epub 2005 Apr 27.
Gene expression profile in the muscles of patients with inflammatory myopathies:
effect of therapy with IVIg and biological validation of clinically relevant
genes.
Raju R, Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Building 10 Room 4N252, 10 Center Drive,
Bethesda, MD 20892, USA.
To explore the biological significance of gene expression in the pathogenesis
of
inflammatory myopathies, we performed microarray experiments followed by
real-time PCR and immunohistochemistry on muscle biopsies obtained before and
after therapy from patients with dermatomyositis (DM) who improved and patients
with inclusion body myositis (sIBM) who did not improve after controlled trials
with three monthly intravenous immunoglobulin (IVIg) infusions. The pretreatment
biopsies showed high expression of immunoglobulin, adhesion molecules,
chemokines and cytokine genes in both sIBM and DM (sIBM > DM). In the repeated
biopsies of DM patients who clinically improved, 2206 genes were downregulated
more than 1.5-fold; in contrast, 1700 of the same genes remained unchanged in
sIBM patients who did not improve. Genes markedly downregulated in DM, but not
sIBM, were interleukin 22, Kallmann syndrome 1 (KAL-1), an adhesion molecule
shown for the first time in muscle, ICAM-1, complement C1q, and several
structural protein genes. Because mRNA for KAL-1 was selectively upregulated
in
vitro by transforming growth factor (TGF) beta1, a fibrogenic cytokine
immunolocalized in the endomysial connective tissue of pretreatment DM muscles,
the downregulation of both TGF-beta and KAL-1 after IVIg only in DM suggests
that these molecules have a functional role in connective tissue proliferation
and fibrosis. The improved muscles of DM, but not sIBM, showed upregulation
of
chemokines CXCL9 (Mig) and CXCL11, and several immunoglobulin-related genes,
suggesting an effect on muscle remodelling and regeneration. The results suggest
that IVIg modulates several immunoregulatory or structural muscle genes, but
only a subset of them associated with inflammatory mediators, fibrosis and
muscle remodelling are connected with the clinical response. Gene arrays, when
combined with clinical assessments, may provide important information in the
pathogenesis of inflammatory myopathies.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 15857930 [PubMed - indexed for MEDLINE]
111: Ann Neurol. 2005 May;57(5):664-78.
Interferon-alpha/beta-mediated innate immune mechanisms in dermatomyositis.
Greenberg SA, Pinkus JL, Pinkus GS, Burleson T, Sanoudou D, Tawil R, Barohn
RJ,
Saperstein DS, Briemberg HR, Ericsson M, Park P, Amato AA.
Department of Neurology, Division of Neuromuscular Disease, Brigham and Women's
Hospital and Harvard Medical School, Boston, MA 02115, USA.
sagreenberg@partners.org
Dermatomyositis has been modeled as an autoimmune disease largely mediated
by
the adaptive immune system, including a local humorally mediated response with
B
and T helper cell muscle infiltration, antibody and complement-mediated injury
of capillaries, and perifascicular atrophy of muscle fibers caused by ischemia.
To further understand the pathophysiology of dermatomyositis, we used
microarrays, computational methods, immunohistochemistry and electron microscopy
to study muscle specimens from 67 patients, 54 with inflammatory myopathies,
14
with dermatomyositis. In dermatomyositis, genes induced by interferon-alpha/beta
were highly overexpressed, and immunohistochemistry for the
interferon-alpha/beta inducible protein MxA showed dense staining of
perifascicular, and, sometimes all myofibers in 8/14 patients and on capillaries
in 13/14 patients. Of 36 patients with other inflammatory myopathies, 1 patient
had faint MxA staining of myofibers and 3 of capillaries. Plasmacytoid dendritic
cells, potent CD4+ cellular sources of interferon-alpha, are present in
substantial numbers in dermatomyositis and may account for most of the cells
previously identified as T helper cells. In addition to an adaptive immune
response, an innate immune response characterized by plasmacytoid dendritic
cell
infiltration and interferon-alpha/beta inducible gene and protein expression
may
be an important part of the pathogenesis of dermatomyositis, as it appears to
be
in systemic lupus erythematosus.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.
PMID: 15852401 [PubMed - indexed for MEDLINE]
112: Neuromuscul Disord. 2005 May;15(5):361-3.
Allelic heterogeneity of GNE gene mutation in two Tunisian families with
autosomal recessive inclusion body myopathy.
Amouri R, Driss A, Murayama K, Kefi M, Nishino I, Hentati F.
Department of Molecular Neurobiology and Neuropathology, National Institute
of
Neurology, 1007 La Rabta, Tunis, Tunisia. rim.sam@gnet.tn
Autosomal recessive hereditary inclusion body myopathy (AR-HIBM), with sparing
of the quadriceps, is characterized by adult-onset, with weakness and atrophy
of
distal lower limb muscles, and typical histopathological findings in muscle
biopsy. AR hIBM is associated with mutations in the UDP-N-acetylglucosamine
2-epimerase/N-acetylmannosamine kinase (GNE) gene on chromosome 9p12-13 . We
report two unrelated Tunisian families with clinical and pathological features
of AR HIBM. One distinct homozygous GNE missense mutation, M712T, previously
reported in Middle Eastern Jewish patients, and a newly identified one, L379H,
were found in one patient from each family. We conclude that AR HIBM in Tunisia
shows an allelic genetic heterogeneity.
Publication Types:
Comparative Study
PMID: 15833430 [PubMed - indexed for MEDLINE]
113: Neuromuscul Disord. 2005 May;15(5):349-54.
Preservation of in vitro muscle fiber function in dermatomyositis and inclusion
body myositis: a single fiber study.
Krivickas LS, Amato AA, Krishnan G, Murray AV, Frontera WR.
Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation
Hospital and Harvard Medical School, 125 Nashua St., Boston, MA 02114, USA.
lkrivickas@partners.org
Five patients with untreated dermatomyositis, five with inclusion body myositis,
and 16 healthy elderly volunteer subjects (controls) underwent open
(dermatomyositis and inclusion body myositis) or percutaneous (controls) muscle
biopsy. Biopsied muscles included deltoid, biceps and vastus lateralis.
Chemically skinned single muscle fibers were activated with Ca(+2); the slack
test was performed to determine maximal unloaded shortening velocity (Vo).
Parameters measured include single fiber cross sectional area, maximal force,
specific force and Vo. 429 Type I and 94 Type IIA fibers were studied. Cross
sectional area and maximal force were greater in inclusion body myositis than
dermatomyositis or control for Type I and IIA fibers. Specific force of Type
I
fibers was similar in inclusion body myositis and dermatomyositis but greater
than in controls. Vo was greater in Type I, but not IIA, fibers in
dermatomyositis compared with inclusion body myositis and controls. The force
and velocity generating capacity of single muscle fibers is preserved in
patients with dermatomyositis and inclusion body myositis suggesting that
dysfunction of the contractile proteins does not contribute to clinical muscle
weakness.
Publication Types:
Comparative Study
In Vitro
PMID: 15833427 [PubMed - indexed for MEDLINE]
114: Neurology. 2005 Apr 12;64(7):1315-6.
Personal history: resolution.
Nardin R.
Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline
Ave., TCC 810, Boston, MA 02215, USA. rnardin@bidmc.harvard.edu
Publication Types:
Editorial
PMID: 15824380 [PubMed - indexed for MEDLINE]
115: Clin Exp Rheumatol. 2005 Jan-Feb;23(1):93-6.
Steroid-responsive inclusion body myositis associated with endometrial cancer.
Alexandrescu DT, Bhagwati NS, Fomberstein B, Wolfe DE, Feliz A, Wiernik PH.
Comprehensive Cancer Center, Our Lady of Mercy Medical Center, Bronx, New York
10466, USA. mddoru@hotmail.com
Inclusion body myositis (IBM) is an uncommon chronic inflammatory myopathy.
Although the association between other myopathies and cancer has been well
established, the relationship between IBM and neoplasia is not completely
understood. Unlike polymyositis (PM) or dermatomyositis (DM), IBM rarely
responds to immunosuppressive treatment and the response is seldom long-lasting.
We describe a case of IBM associated with endometrial carcinoma that also
demonstrated a unique response to steroids alone which persisted despite cancer
relapse. The factors that are associated with a response of IBM to steroids
are
discussed. An atypical, steroid-responsive form of the disease is delineated.
Publication Types:
Case Reports
Review
PMID: 15789894 [PubMed - indexed for MEDLINE]
116: Neuropediatrics. 2005 Feb;36(1):35-9.
Congenital myopathy with tubular aggregates and tubulofilamentous IBM-type
inclusions.
Fidzianska A, Kaminska A, Ryniewicz B.
Neuromuscular Unit, Medical Research Centre, Polish Academy of Sciences, Warsaw,
Poland. neurmyol@cmdik.pan.pl
We report on a 16-year-old girl with a unique neuromuscular disorder
characterised by progressive proximal muscle weakness and numerous tubular
aggregates, intracytoplasmic, as well as intranuclear inclusions of the IBM
type
in her muscle biopsy. The clinical features of the presented case, as manifested
by the early childhood onset of the disease, proximal weakness, lumbar
hyperlordosis, and bilateral Achilles tendon contractures, were suggestive of
congenital myopathy. To the best of our knowledge, the coexistence of tubular
aggregates and tubulofilamentous inclusions of the IBM type in a child has never
been described.
Publication Types:
Case Reports
Research Support, Non-U.S. Gov't
PMID: 15776320 [PubMed - indexed for MEDLINE]
117: Muscle Nerve. 2005 May;31(5):621-7.
Beta-chemokine receptor expression in idiopathic inflammatory myopathies.
De Paepe B, De Bleecker JL.
Department of Neurology, Neuromuscular Laboratory, Ghent University Hospital,
De
Pintelaan 185, B-9000 Ghent, Belgium.
Beta-chemokines attract and activate T cells and monocytes and have a key role
in chronic inflammation. Certain beta-chemokines, such as monocyte
chemoattractant protein-1 (MCP-1), have been reported to be upregulated in the
idiopathic inflammatory myopathies (IIM). We studied the distribution of
beta-chemokine receptors in polymyositis (PM), sporadic inclusion-body myositis
(sIBM), dermatomyositis (DM), and control samples. CCR1-5 were localized to
blood vessels in all samples. In addition, increased endothelial expression
of
CCR2A was observed in IIM. Subsets of inflammatory cells, identified as
macrophages and T cells, in all three types of IIM expressed CCR2A, CCR2B, CCR3,
CCR4, and CCR5. In contrast to an earlier report, we found CCR2B to be the most
prominent MCP-1 receptor on inflammatory cells in IIM, especially in PM and
sIBM. Strong CCR4 expression was present on myonuclei of regenerating muscle
fibers. The prominence of the CCR2 receptors further underlines the importance
of the interaction with their ligand MCP-1 in the immunopathogenesis of IIM
and
puts CCR2B forward as a potential target for future therapeutic intervention.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 15772970 [PubMed - indexed for MEDLINE]
118: Ann Rheum Dis. 2005 Apr;64(4):634-7.
Familial inflammatory inclusion body myositis.
Ranque-Francois B, Maisonobe T, Dion E, Piette JC, Chauveheid MP, Amoura Z,
Papo
T.
Internal Medicine Department, La Pitie-Salpetriere Hospital, 75651 Paris,
France.
OBJECTIVE: To compare familial inflammatory inclusion body myositis (IBM) with
hereditary inclusion body myopathies and sporadic IBM. PATIENTS AND METHODS:
Clinical, biological, MRI, and histological data were analysed in two siblings
with inflammatory IBM and compared with those of patients with sporadic and
hereditary IBM. RESULTS: Both patients had a clinical phenotype of sporadic
IBM,
which differs from hereditary myopathies because of late age of
onset--respectively 65 and 66 years, and different pattern of muscular
involvement--asymmetric, mainly distal but also involving quadriceps. MRI showed
selective fatty infiltration and oedema in the extensor compartment of thigh
muscles. The diagnosis of IBM was confirmed by muscle biopsy, showing muscle
fibres containing numerous rimmed vacuoles, a characteristic shared by all types
of IBM. In contrast with hereditary IBM, histological analysis also showed
inflammatory mononuclear infiltrate invading non-necrotic fibres, ragged red
and
oxidase c negative fibres, and positive Congo red staining. Moreover, HLA class
II typing disclosed DR beta 1 0301 haplotype, which is significantly related
to
sporadic but not to hereditary IBM. With steroid treatment and monthly
intravenous immunoglobulins, the disease was stabilised in both patients at
protracted follow up. CONCLUSION: Sporadic and familial inflammatory IBM share
the same clinical, biological, MRI, and histological features.
Publication Types:
Case Reports
Review
PMID: 15769920 [PubMed - indexed for MEDLINE]
119: J Neurol Sci. 2005 Mar 15;229-230:233-40. Epub 2004 Dec 16.
Cholesterol homeostasis failure as a unifying cause of synaptic degeneration.
Koudinov AR, Koudinova NV.
Neurobiology of Lipids, P.O. Box 1665, Rehovot 76100, Israel.
alexeikoudinov@neurobiologyoflipids.org
We previously showed that fine tuning of neural cholesterol dynamics is
essential for basic synapse function, plasticity and behavior. Significant
experimental evidence indicates that cholinergic function, ionotropic and
metabotropic receptor machinery, excessive tau phosphorylation, the change of
amyloid beta (Abeta or Abeta) biochemistry, neural oxidative stress reactions,
and other features of neurodegeneration also depend on fine tuning of brain
cholesterol homeostasis. This evidence suggest that (i) cholesterol homeostasis
break is the unifying primary cause of sporadic and familial Alzheimer's disease
(AD), neuromuscular diseases (particularly inclusion-body myositis),
Niemann-Pick's type C disease and Down syndrome, and (ii) explains the overlap
of neurodegenerative hallmarks across the spectrum of neurodegenerative
diseases. Provided is evidence-based explanation of why extremely rare (but
scientifically popular) cases of AD associated with mutations in amyloid beta
protein precursor (APP) and presenilin (PS) genes, are translated into the
disorder via membrane cholesterol sensitivity of APP processing by secretases
and Abeta generation. The reciprocal effect of Abeta on cholesterol synthesis,
cellular uptake, efflux and esterification is summarized, as well as the
potential implication of such biological function for the compensatory
Abeta-assisted restoration of the synaptic long-term potentiation (LTP) and
resulting inability of tackling amyloid to cure AD.
Publication Types:
Review
PMID: 15760645 [PubMed - indexed for MEDLINE]
120: Curr Rheumatol Rep. 2005 Apr;7(2):115-24.
Exercise: an important component of treatment in the idiopathic inflammatory
myopathies.
Alexanderson H.
Department of Physical Therapy, Rheumatology Unit D2:07, Karolinska University
Hospital, Solna SE-171 76, Stockholm, Sweden. helene.alexandersson@karolinska.se
Resistive exercise is controversial for patients with idiopathic inflammatory
myopathies. This paper provides an update on exercise and clinical assessment
in
these patients. The few published studies on this topic report unchanged disease
activity from a variety of exercise regimens in patients in all stages of
disease. Reduced disability was achieved in patients with polymyositis and
dermatomyositis. In one study a slightly reduced impairment was reported in
patients with inclusion body myositis, while in another study no objective
reduction of disability could be detected. An increasing number of valid and
reliable outcome measures are available for patients with polymyositis and
dermatomyositis, but for patients with inclusion body myositis reliable and
sensitive outcome measures are still needed.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 15760590 [PubMed - indexed for MEDLINE]
121: Immunol Lett. 2005 Mar 15;97(2):245-9. Epub 2004 Dec 13.
Can tissue transglutaminase be a marker of idiopathic inflammatory myopathies?
Gendek EG, Kedziora J, Gendek-Kubiak H.
Department of Chemistry and Clinical Biochemistry, Medical University of Lodz,
Pl. Hallera 1, 90-647 Lodz, Poland. Ewa_pl2003@yahoo.com
In the normal striated muscle, tissue transglutaminase (TG2) content is
vestigial. However, this protein's presence has been reported to occur in
myoblasts and myotubes during the fetal period. Its increased expression has
been also found in the muscle tissue in the course of sporadic inclusion body
myositis, as well as in polymyositis (PM) and dermatomyositis (DM), which are
considered to be diseases of immunological origin. Based on in vitro studies,
a
substantial TG2 role in the infiltration of some T cell subsets into inflamed
tissues has been suggested lately. In this study, the immunohistochemical
reactions in the guinea pig experimental myositis specimens and in the ones
from
PM/DM patients were compared. The guinea pig tissue specimens were taken from
muscles affected by experimental myositis induced by intramuscular injections
of: 1/sera from 30 neoplasm patients with no metastases; 2/sera from 10 healthy
people; 3/sera from 2 DM patients; 4/neuropeptides (SP, NPY or VIP) and from
5/the muscles affected by the reversed passive Arthus reaction (RPAR). The
immunostaining for TG2 revealed substantial presence of this protein in single,
damaged muscle fibers and a weak reaction in regenerating fibers appearing in
PM/DM patients' specimens. From among experimental myositis specimens, a very
intensive reaction appeared only in the damaged and regenerating muscle fibers
present in the slides from guinea pig muscles injected with DM patients' sera.
Such results suggest some presence of a specific factor(s) (the one(s)
responsible for TG2 expression in the damaged muscle fibers) in DM patients'
sera. The results suggest that transglutaminase can be a marker of inflammatory
myopathies. A probable correlation between TG2 expression in muscles and
organismal immunological factors, including the complement activation status,
requires additional studies.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 15752564 [PubMed - indexed for MEDLINE]
122: Exp Cell Res. 2005 Apr 1;304(2):365-79. Epub 2004 Dec 19.
Localization of UDP-GlcNAc 2-epimerase/ManAc kinase (GNE) in the Golgi complex
and the nucleus of mammalian cells.
Krause S, Hinderlich S, Amsili S, Horstkorte R, Wiendl H, Argov Z,
Mitrani-Rosenbaum S, Lochmuller H.
Friedrich-Baur-Institute, Department of Neurology and Gene Center,
Ludwig-Maximilians-University, Genzentrum Munchen, Feodor-Lynen-Str. 25, 81377
Munchen, Germany.
The bifunctional enzyme UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine
kinase (GNE) is essential for early embryonic development and catalyzes the
rate
limiting step in sialic acid biosynthesis. Although epimerase and kinase
activities have been attributed to GNE, little is known about the regulation,
differential expression, and subcellular localization of GNE in vivo. Mutations
in GNE cause a rare inherited muscle disorder in humans called hereditary
inclusion body myopathy (HIBM). However, the role of GNE in HIBM pathogenesis
has not been defined yet. Here, we show that the GNE protein is expressed in
various mammalian cells and tissues with highest levels found in cancer cells
and liver. In human skeletal muscle, GNE protein is developmentally regulated:
high levels are found in immature myoblasts but low levels in mature skeletal
muscle. The GNE protein colocalizes with resident proteins of the Golgi
compartment in a variety of human cells including muscle. Drug-induced
disruption of the Golgi and subsequent recovery reveals co-distribution of GNE
along with Golgi-targeted proteins. This subcellular localization of GNE is
in
good agreement with its established role as the key enzyme of sialic acid
biosynthesis, since the sialylation of glycoconjugates takes place in the Golgi
complex. Surprisingly, GNE is also detected in the nucleus. Upon nocodazole
treatment, GNE redistributes to the cytoplasm suggesting that GNE may act as
a
nucleocytoplasmic shuttling protein. A regulatory role for GNE shifting between
the nuclear and the Golgi compartment is proposed. Further insight into GNE
regulation may promote the understanding of HIBM pathogenesis.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 15748884 [PubMed - indexed for MEDLINE]
123: Intern Med J. 2005 Mar;35(3):170-3.
Adult-onset inflammatory myopathy: North Canterbury experience 1989-2001.
Lynn SJ, Sawyers SM, Moller PW, O'Donnell JL, Chapman PT.
Department of Rheumatology, Christchurch Hospital, Christchurch, New Zealand.
AIM: To perform a clinical audit of all patients diagnosed with inflammatory
myopathy in the North Canterbury region. METHODS: A retrospective case note
audit of patients with a discharge diagnosis of inflammatory myopathy from June
1989 to June 2001 was performed. The audit was based at Christchurch Hospital,
New Zealand, which services a population of 430,000. RESULTS: Of 77 case notes
reviewed, 44 patients were identified who were considered to fulfil clinical
criteria for inflammatory myopathy. There was a female preponderance (80%
female, 20% male). Diagnostic categories in descending order of frequency
included: dermatomyositis (41%), polymyositis (39%), inclusion body myositis
(IBM) (14%) and overlap syndromes (6%). Malignancy-associated myositis occurred
in 20% overall (dermatomyositis 11%, polymyositis 9%). Delays in diagnosis and
late age at presentation (average 72 years) were seen in the IBM group. Proximal
limb weakness was common, but not universal at presentation (80%). A muscle
biopsy was performed in all patients and electromyography in 82%. All were
treated with high dose prednisone (0.5-1 mg/kg) of whom 29% were maintained
on
prednisone alone. Immunosuppressives/immunomodulators used included:
azathioprine (58%), methotrexate (31%), intravenous immunoglobulin (13%),
chlorambucil (13%), and cyclophosphamide (9%). Thirteen patients (42%) required
more than one agent, with three trialling five agents. There were 59 relapses
in
20 patients (45%), with mean time to first relapse of 7.8 months. At audit
completion, 33% had deceased with malignancy and respiratory failure the main
causes. CONCLUSION: Inflammatory myopathy is a challenging condition in both
diagnosis and management. Our audit has shown delays in the diagnosis of IBM,
a
relatively high incidence of malignancy and a notable risk of relapse and
mortality.
Publication Types:
Comparative Study
PMID: 15737137 [PubMed - indexed for MEDLINE]
124: Curr Opin Rheumatol. 2005 Mar;17(2):164-71.
The role of exercise in the rehabilitation of idiopathic inflammatory
myopathies.
Alexanderson H, Lundberg IE.
Department of Physical Therapy, Rheumatology Unit, Karolinska University
Hospital, Solna, Stockholm, Sweden. helene.alexandersson@karolinska.se
PURPOSE OF REVIEW: The objective of this review is to provide an update on
exercise and clinical assessment in the idiopathic inflammatory myopathies.
RECENT FINDINGS: Polymyositis, dermatomyositis and inclusion body myositis are
rare conditions with muscle weakness as a common prominent feature. Earlier,
these patients were discouraged from active exercise due to a fear of increased
muscle inflammation with recommendations to rest, perform range of motion
exercises and in some cases, isometric exercises. However, beginning in the
1990s, studies reported reduced disability in patients with chronic
polymyositis/dermatomyositis following resistive mild/moderate to intensive
muscular training and aerobic endurance training, without signs of increased
muscle inflammation. Patients with active, recent onset disease seem to benefit
from mild/moderate muscular exercise without signs of increased muscle
inflammation. There is no evidence of increased muscle inflammation following
exercise in inclusion body myositis. However the beneficial effects are unclear
as one study report increased muscle strength, while the other could not achieve
impairment reduction. SUMMARY: Studies evaluating active exercise in IIM support
the notion of safety and benefits. However, large multi-center studies are
needed to fully establish the safety and benefits of different types of
exercise. Data indicate that active exercise, adapted to disease activity and
disability should be included in the rehabilitation of patients in all stages
of
IIM. The newly developed and validated outcome measures for patients with
polymyositis and dermatomyositis help assess the effects of interventions on
disease activity and disability in clinical trials and in clinical practice.
However, there are no sensitive and valid outcome measure for patients with
inclusion body myositis.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 15711230 [PubMed - indexed for MEDLINE]
125: Neurobiol Aging. 2005 May;26(5):645-54.
Age- and region-dependent alterations in Abeta-degrading enzymes: implications
for Abeta-induced disorders.
Caccamo A, Oddo S, Sugarman MC, Akbari Y, LaFerla FM.
Department of Neurobiology and Behavior, University of California, Irvine,
1109
Gillespie Neuroscience Bldg., Irvine, CA 92697-4545, USA.
Accumulation of amyloid beta-protein (Abeta) is a fundamental feature of certain
human brain disorders such as Alzheimer's disease (AD) and Down syndrome and
also of the skeletal muscle disorder inclusion body myositis (IBM). Emerging
evidence suggests that the steady-state levels of Abeta are determined by the
balance between production and degradation. Although the proteolytic processes
leading to Abeta formation have been extensively studied, less is known about
the proteases that degrade Abeta, which include insulin-degrading enzyme (IDE)
and neprilysin (NEP). Here we measured the steady-state levels of these
proteases as a function of age and brain/muscle region in mice and humans. In
the hippocampus, which is vulnerable to AD pathology, IDE and NEP steady-state
levels diminish as function of age. By contrast, in the cerebellum, a brain
region not marked by significant Abeta accumulation, NEP and IDE levels either
increase or remain unaltered during aging. Moreover, the steady-state levels
of
IDE and NEP are significantly higher in the cerebellum compared to the cortex
and hippocampus. We further show that IDE is more oxidized in the hippocampus
compared to the cerebellum of AD patients. In muscle, we find differential
levels of IDE and NEP in fast versus slow twitch muscle fibers that varies with
aging. These findings suggest that age- and region-specific changes in the
proteolytic clearance of Abeta represent a critical pathogenic mechanism that
may account for the susceptibility of particular brain or muscle regions in
AD
and IBM.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
PMID: 15708439 [PubMed - indexed for MEDLINE]
126: Clin Neuropathol. 2005 Jan-Feb;24(1):36-41.
Inclusion body myopathy associated with motor neuron syndrome: three case
reports.
Cafforio G, Pistolesi S, D'Avino C, Galluzzi F, Patricelli A, Solito B,
Fontanini G, Siciliano G.
Department of Neuroscience, University of Pisa, Italy.
BACKGROUND: Hereditary inclusion body myopathy (h-IBM) is an autosomal-recessive
or autosomal-dominant hereditary disease characterized by peculiar findings
in
muscle biopsies which resemble those occurring in inclusion body myositis (IBM).
The absence of an inflammatory infiltrate in myofibers in h-IBM is a relevant
differential criterion between the two pathologies. Motor neuron diseases (MND)
represent a group of disorders involving both upper and lower motor neurons,
characterized by fasciculations, progressive muscle weakness, and muscle
atrophy. The most common form and prototype of MND is the amyotrophic lateral
sclerosis (ALS) or Charcot's Disease, a progressive and fatal neurodegenerative
disorder occurring in late adulthood. The pathogenesis of ALS remains still
unknown, a variety of hypotheses having been proposed to account for the
disease. The association of both pathologies is not common and offers new
hypotheses about the pathogenic mechanisms in skeletal muscle and nervous system
degeneration. PATIENTS AND METHODS: Described are three case reports in which
we
observed the clinical, laboratory and histopathological association of IBM and
MND. In one case, dementia was also present. Muscle data was obtained by muscle
biopsies and immunohistochemistry, while diagnosis of MND was supported by
common neurophysiological techniques. RESULTS: The accumulation ofphosphorylated
neurofilaments with a hereditary IBM-like pattern in skeletal muscle fibers
without accumulation of amyloid-beta protein was observed. CONCLUSIONS: A better
knowledge of the mechanisms in cellular death cascade could explain the
pathogenesis of these different degenerative disorders.
Publication Types:
Case Reports
Research Support, Non-U.S. Gov't
PMID: 15696783 [PubMed - indexed for MEDLINE]
127: Neuromuscul Disord. 2005 Feb;15(2):177-84. Epub 2004 Dec 10.
alpha-Dystroglycan does not play a major pathogenic role in autosomal recessive
hereditary inclusion-body myopathy.
Broccolini A, Gliubizzi C, Pavoni E, Gidaro T, Morosetti R, Sciandra F, Giardina
B, Tonali P, Ricci E, Brancaccio A, Mirabella M.
Department of Neuroscience, Catholic University, L.go A. Gemelli 8, 00168 Rome,
Italy.
Mutations of the GNE gene are responsible for autosomal recessive hereditary
inclusion-body myopathy (HIBM). In this study we searched for the presence of
any significant abnormality of alpha-dystroglycan (alpha-DG), a highly
glycosylated component of the dystrophin-glycoprotein complex, in 5 HIBM
patients which were previously clinically and genetically characterized.
Immunocytochemical and immunoblot analysis showed that alpha-DG extracted from
muscle biopsies was normally expressed and displayed its typical molecular mass.
Immunoblot analysis on the wheat germ lectin-enriched glycoprotein fraction
of
muscles and primary myotubes showed a reduced amount of alpha-DG in 4 out of
5
HIBM patients, compared to normal and other diseased muscles. However, such
altered lectin-binding behaviour, possibly reflecting a partial hyposialylation
of alpha-DG, did not affect the laminin binding properties of alpha-DG.
Therefore, the subtle changes within the alpha-DG glycosylation pattern,
detected in HIBM muscles, likely do not play a key pathogenic role in this
disorder.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 15694140 [PubMed - indexed for MEDLINE]
128: Curr Neurol Neurosci Rep. 2005 Feb;5(1):61-5.
Distal myopathy with rimmed vacuoles and hereditary inclusion body myopathy.
Nonaka I, Noguchi S, Nishino I.
Division of Neuromuscular Research, National Institute of Neuroscience, National
Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan.
Nonaka@ncnpmusashi.gr.jp
Distal myopathy with rimmed vacuoles (DMRV) and hereditary inclusion body
myopathy (hIBM) share similar clinical features, including onset in young
adulthood with preferential involvement of the anterior compartment of the lower
legs and sparing of the quadriceps femoris muscles. The most significant muscle
pathology is the presence of rimmed vacuoles, which appear to play a major role
in muscle atrophy and weakness. After the discovery of the gene locus in both
DMRV and hIBM on chromosome 9 and mutations in the gene encoding the enzyme
UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), it became
clear that they are allelic disorders. From gene analysis, it is evident that
these diseases are not restricted to people of Japanese and Jewish ancestry,
but
that they are widely distributed throughout all ethnic groups. Although
defective glycosylation to a muscle fiber has been suggested, the mechanism
by
which myofibrillar degeneration is followed by rimmed vacuole formation remains
to be clarified.
Publication Types:
Review
PMID: 15676110 [PubMed - indexed for MEDLINE]
129: Biochem Biophys Res Commun. 2005 Mar 4;328(1):221-6.
No overall hyposialylation in hereditary inclusion body myopathy myoblasts
carrying the homozygous M712T GNE mutation.
Salama I, Hinderlich S, Shlomai Z, Eisenberg I, Krause S, Yarema K, Argov Z,
Lochmuller H, Reutter W, Dabby R, Sadeh M, 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 group of neuromuscular
disorders characterized by adult-onset, slowly progressive distal and proximal
muscle weakness, which is caused by mutations in UDP-N-acetylglucosamine
2-epimerase/N-acetylmannosamine kinase (GNE), the key enzyme in the biosynthetic
pathway of sialic acid. In order to investigate the consequences of the mutated
GNE enzyme in muscle cells, we have established cell cultures from muscle
biopsies carrying either kinase or epimerase mutations. While all myoblasts
carrying a mutated GNE gene show a reduction in their epimerase activity, only
the cells derived from the patient carrying a homozygous epimerase mutation
present also a significant reduction in the overall membrane bound sialic acid.
These results indicate that although mutations in each of the two GNE domains
result in an impaired enzymatic activity and the same HIBM phenotype, they do
not equally affect the overall sialylation of muscle cells. This lack of
correlation suggests that the pathological mechanism of the disease may not
be
linked solely to the well-characterized sialic acid pathway.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
PMID: 15670773 [PubMed - indexed for MEDLINE]
130: Neurology. 2005 Jan 25;64(2):389.
Finger flexor weakness in inclusion body myositis.
Takamure M, Murata KY, Kawahara M, Ueno S.
Publication Types:
Case Reports
PMID: 15668452 [PubMed - indexed for MEDLINE]
131: Clin Radiol. 2005 Feb;60(2):261-7.
A comparison of inflammatory myopathies at whole-body turbo STIR MRI.
Cantwell C, Ryan M, O'Connell M, Cunningham P, Brennan D, Costigan D, Lynch
T,
Eustace S.
Cappagh National Orthopaedic Hospital, Finglas, Dublin, Eire.
Publication Types:
Comparative Study
Technical Report
PMID: 15664582 [PubMed - indexed for MEDLINE]
132: Neuromuscul Disord. 2005 Jan;15(1):32-9.
Diaphragmatic dysfunction in patients with idiopathic inflammatory myopathies.
Teixeira A, Cherin P, Demoule A, Levy-Soussan M, Straus C, Verin E, Zelter
M,
Derenne JP, Herson S, Similowski T.
UPRES EA 2397, Universite Pierre et Marie Curie Paris VI, Paris, France.
Polymyositis, dermatopolymyositis, and inclusion body myositis imply chronic
inflammation of skeletal muscles. Pulmonary complications include aspiration
pneumonia, interstitial pneumonitis, or respiratory muscle myositis. This study
aims at better describing their impact on respiratory muscle. Twenty-three
consecutive patients (12 PM, 5 DM, 6 IBM) were studied (static inspiratory and
expiratory pressures; diaphragm function in terms of the mouth and
transdiaphragmatic pressure responses to bilateral phrenic stimulation).
Pulmonary parenchymatous abnormalities were mild (6 cases) or absent. The mouth
pressure produced by phrenic stimulation was 6.83+/-3.01 cm H2O, with 18
patients (78%) diagnosed with diaphragm weakness (<10 cm H2O) and lower values
in DM (4.35+/-1.48 cm H2O) than in IBM and in PM (P<0.05). Diaphragm weakness
is
frequent and probably overlooked in inflammatory myopathies. Further studies
are
needed to delineate the clinical relevance of these results.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
PMID: 15639118 [PubMed - indexed for MEDLINE]
133: Neuropathol Appl Neurobiol. 2005 Feb;31(1):70-9.
Expression of the beta chemokines CCL3, CCL4, CCL5 and their receptors in
idiopathic inflammatory myopathies.
Civatte M, Bartoli C, Schleinitz N, Chetaille B, Pellissier JF,
Figarella-Branger D.
Laboratoire de Biopathologie Nerveuse et Musculaire (EA 3281), Faculte de
Medecine Timone, Universite de la Mediterranee, Institut de Physiopathologie
Humaine de Marseille (I.P.H.M), FR125 Marseille.
The idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases
characterized by chronic lymphocytic and macrophagic infiltration in muscle.
Because the mechanism for recruitment of these cells probably involves
chemokines, we focused on the study of the expression pattern of some beta
chemokines and receptors because it may provide a basis for selective
immunotherapy. The expression of CCL3 (MIP-1alpha), CCL4 (MIP-1beta), CCL5
(RANTES) and their main receptors (CCR1 and CCR5) was studied by
semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and
immunohistochemistry in a series of 16 IIM and five controls (four normal
muscles and one tonsil). Except for CCL5, strong expression was observed by
RT-PCR with all molecules in all IIM subtypes in comparison to control muscle.
Immunohistochemistry revealed diffuse CCL4 expression in all vessels in
dermatomyositis. In both polymyositis and sporadic inclusion body myositis
(s-IBM) it was restricted to vessels in the vicinity of inflammatory exudates.
CCL5 expression was low, restricted to a few inflammatory cells in all IIM;
CCR1
expression was mainly restricted to macrophages and s-IBM endothelial cells,
whereas CCR5 was localized in inflammatory cells invading non-necrotic muscle
fibres. Expressions of both receptors were also recorded in few muscle fibres.
In conclusion, the upregulation of beta chemokines and receptors in IIM and
their differential expression by various cells may contribute to chronic
inflammation and to the peculiar distribution of inflammatory exudates in these
diseases.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 15634233 [PubMed - indexed for MEDLINE]
134: Lancet Neurol. 2005 Jan;4(1):6-7.
Neuromuscular disorders: molecular and therapeutic insights.
Mastaglia FL.
Centre for Neuromuscular and Neurological Disorders, University of Western
Australia, Queen Elizabeth II Medical Centre, Perth, Western Australia,
Australia. flmast@cyllene.uwa.edu.au
Publication Types:
Review
PMID: 15620848 [PubMed - indexed for MEDLINE]
135: Muscle Nerve. 2005 Feb;31(2):260-5.
Reversible inflammatory and vacuolar myopathy with vitamin E deficiency in
celiac disease.
Kleopa KA, Kyriacou K, Zamba-Papanicolaou E, Kyriakides T.
Department of Clinical Neurosciences, Cyprus Institute of Neurology and
Genetics, P.O. Box 23462, Nicosia, Cyprus.
We report a patient with late-onset celiac disease and neurological
manifestations including myopathy, polyneuropathy, and ataxia. Laboratory
investigations showed anti-gliadin antibodies and severe vitamin E deficiency.
Muscle biopsy revealed inflammatory infiltrates and rimmed vacuoles, similar
to
those found in inclusion-body myositis. A gluten-free diet and vitamin E
supplementation reversed both the clinical neurological manifestations and the
abnormalities in the muscle biopsy. Anti-gliadin antibodies were no longer
present. This case illustrates the spectrum of neurological complications of
celiac disease and documents the occurrence of reversible pathology resembling
inclusion-body myopathy in the muscle.
Publication Types:
Case Reports
PMID: 15389648 [PubMed - indexed for MEDLINE]
.