.
Search for "inclusion body myositis" English only.
[There is always overlap in these lists but they should be inclusive as a result]
1: 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, and bRheumatology Unit, Department of
Medicine, Karolinska University Hospital, Solna, Karolinska Institutet,
Stockholm, Sweden.
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.
PMID: 15711230 [PubMed - in process]
2: 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.
PMID: 15708439 [PubMed - in process]
3: 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.
PMID: 15696783 [PubMed - in process]
4: Neurology. 2005 Jan 25;64(2):389.
Finger flexor weakness in inclusion body myositis.
Takamure M, Murata KY, Kawahara M, Ueno S.
PMID: 15668452 [PubMed - in process]
5: Acta Clin Belg. 2004 Sep-Oct;59(5):290-9.
Inflammatory myopathies.
Cherin P.
Service de Medecine Interne I, CHU Pitie-Salpetriere, 47 Boulevard de l'Hopital,
75013, Paris, France. patrick.cherin@psl.ap-hop-paris.fr
Publication Types:
Review
Review, Tutorial
PMID: 15641400 [PubMed - indexed for MEDLINE]
6: 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.
PMID: 15639118 [PubMed - in process]
7: 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.
PMID: 15634233 [PubMed - in process]
8: Neurology. 2004 Dec 28;63(12):2396-8.
Associations with autoimmune disorders and HLA class I and II antigens in
inclusion body myositis.
Badrising UA, Schreuder GM, Giphart MJ, Geleijns K, Verschuuren JJ, Wintzen
AR,
Maat-Schieman ML, van Doorn P, van Engelen BG, Faber CG, Hoogendijk JE, de Jager
AE, Koehler PJ, de Visser M, van Duinen SG; Dutch IBM Study Group.
Department of Neurology, K5Q, Leiden University Medical Center, PO Box 9600,
2300 RC Leiden, The Netherlands. ubadrising@lumc.nl
Whether autoimmune mechanisms play a role in the pathogenesis of inclusion
body
myositis (IBM) is unknown. Human leukocyte antigen (HLA) analysis in 52
patients, including 17 with autoimmune disorders (AIDs), showed that patients
were more likely to have antigens from the autoimmune-prone HLA-B8-DR3 ancestral
haplotype than healthy control subjects, irrespective of the presence of AIDs.
Patients lacked the apparently protective HLA-DR53 antigen. The results provide
further support for an autoimmune basis in IBM.
PMID: 15623710 [PubMed - in process]
9: 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
Review, Tutorial
PMID: 15620848 [PubMed - indexed for MEDLINE]
10: Acta Myol. 2004 Sep;23(2):90-6.
Myopathies associated with myosin heavy chain mutations.
Oldfors A, Tajsharghi H, Darin N, Lindberg C.
Department of Pathology, Sahlgrenska University Hospital, Goteborg, Sweden.
anders.oldfors@pathology.gu.se
Myosin, a molecular motor, converts chemical energy into mechanical force.
The
motor domain of myosin heavy chain (MyHC) includes an ATP binding region with
ATPase activity and an actin-binding region. Motor function is achieved by
conformational changes, at hydrolysis, of ATP causing a shift in the angle
between the actin binding head and the rod region of the molecule. The elongated
alpha-helical coiled-coil rod region of MyHC molecules constitutes the major
part of the thick filaments of the sarcomere. Three major MyHC isoforms are
expressed in human skeletal muscle (type I, MYH7, expressed in type 1 fibres;
IIa, MYH2, expressed in 2A fibres; IIx, MYH1, expressed in 2B fibres). While
mutations in slow/beta cardiac MyHC (MYH7) are a common cause of familial
hypertrophic cardiomyopathy, no skeletal myopathies have, until recently, been
associated with mutations in MyHC. A heterozygous mutation, Glu706Lys, in the
core of the head of MyHC IIa is associated with a familial congenital myopathy,
which, in most instances, has shown mild phenotypic expression in children but
progressive course in some adults. There is a relationship between the level
of
expression of mutated MyHC IIa and muscle pathology. Some adults with a
progressive course show muscle fibres with rimmed vacuoles and filaments of
the
type seen in inclusion body myositis/myopathy (IBM). Endurance training in a
group of affected patients caused a shift in the expression of myosin from fast
(IIx) to slow (I) isoforms but no reduction in the expression of MyHC IIa. A
heterozygous mutation, Arg1845Trp, in the distal rod region of slow myosin (type
I, MYH7) is associated with familial congenital myopathy, with large deposits
of
MyHC I in the subsarcolemmal region of type 1 muscle fibres, "Myosin storage
myopathy". These patients showed slowly progressive muscle weakness but
no overt
cardiomyopathy. These two muscle diseases, which are caused by mutations in
MyHC, form the basis of a novel entity: "Myosin myopathies".
PMID: 15605950 [PubMed - in process]
11: Acta Myol. 2004 Sep;23(2):79-84.
Journey into muscular dystrophies caused by abnormal glycosylation.
Muntoni F.
Dubowitz Neuromuscular Centre, Department of Paediatrics, Imperial College
of
Medicine, Hammersmith Hospital, London, UK. f.muntoni@imperial.ac.uk
An increasing number of genes encoding for putative or demonstrated
glycosyltransferases are being associated with muscular dystrophies of variable
severity, ranging from severe congenital onset and associated structural eye
and
brain changes, to relatively mild forms with onset into adulthood. Five of these
genes (POMT1; POMGnT1; FXRP; Fukutin; LARGE) encode for proteins involved in
the
glycosylation of alpha-dystroglycan and, indeed, abnormal glycosylation of this
molecule is a common finding in all the respective conditions (Walker Warburg
syndrome; Muscle-Eye-Brain disease; congenital muscular dystrophy type 1C and
Limb girdle muscular dystrophy type 21; Fukuyama muscular dystrophy; congenital
muscular dystrophy type 1D). A 6th gene, GNE, responsible for the hereditary
form of inclusion body myositis, encodes for a glycosyltransferase the
substrate(s) of which is, however, still unclear. This article provides an
overview of the clinical, biochemical and genetic features of this group of
disorders.
PMID: 15605948 [PubMed - in process]
12: Neurology. 2004 Dec 14;63(11):2191-2.
Primary respiratory failure in inclusion body myositis.
Voermans NC, Vaneker M, Hengstman GJ, ter Laak HJ, Zimmerman C, Schelhaas HJ,
Zwarts MJ.
Neuromuscular Centre Nijmegen, Department of Neurology, University Medical
Centre Nijmegen, The Netherlands.
PMID: 15596785 [PubMed - in process]
13: Curr Opin Rheumatol. 2004 Nov;16(6):707-13.
Have recent immunogenetic investigations increased our understanding of disease
mechanisms in the idiopathic inflammatory myopathies?
Chinoy H, Ollier WE, Cooper RG.
Rheumatic Diseases Centre, Hope Hospital, Salford M6 8HD, UK.
PURPOSE OF REVIEW: The idiopathic inflammatory myopathies (IIM) continue to
provide a challenge given the variable effectiveness of the available
treatments, and immunogenetic studies are ongoing to further elucidate IIM
disease mechanisms. This review examines how recent research has improved our
understanding of the mechanisms that lead to IIM. RECENT FINDINGS: HLA-DRB1
studies in a large homogenous cohort of UK Caucasian patients have confirmed
that polymyositis (PM) and dermatomyositis (DM) are not genetically identical
diseases while other studies have shown that tumor necrosis factor alpha is
genetically implicated in disease susceptibility. Some remarkable results from
an international collaboration, correlating gene-environment interactions,
clearly suggest that ultraviolet light is capable of modulating both clinical
and immunologic features of IIMs. Studies on microchimerism are unraveling
interesting associations in juvenile DM patients, and bolstering the hypothesis
that myositis may be an 'allo-immune' disease. mRNA gene expression profiling
is
helping to increase our understanding of myositis pathogenesis, whilst animal
models have provided new information on the roles of Th1 responses and nitric
oxide synthase in muscle disease. New candidate genes have been examined in
inclusion body myositis (IBM), and a novel gene transfer experiment has been
conducted, which led to significant changes in expression of the IBM phenotype.
SUMMARY: Improving the understanding of the immunogenetics and
immunopathogenesis of the IIMs may in the future provide novel therapeutic
targets, and thus improve outcomes in these difficult diseases.
Publication Types:
Review
PMID: 15577608 [PubMed - indexed for MEDLINE]
14: Curr Opin Rheumatol. 2004 Nov;16(6):700-6.
Myositis: an update on pathogenesis.
Christopher-Stine L, Plotz PH.
Division of Rheumatology, Johns Hopkins University School of Medicine,
Baltimore, Maryland, USA.
PURPOSE OF REVIEW: The etiology and much about the pathogenesis of the
inflammatory myopathies remain a mystery. In this review, we investigate recent
research efforts to understand the pathogenesis of the diverse entities of
polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM),
diseases that result from interactions between environmental risk factors and
genetic susceptibility. RECENT FINDINGS: Over the past year, there has been
considerable progress toward better understanding of IBM, with relatively few
developments toward understanding PM and DM. Although these diseases may share
some common clinical phenotypic and serologic components, they differ on a
molecular and cellular level. SUMMARY: The need for definitive, safer therapies
in these diseases makes vital the search for defining detailed pathogenesis
of
inflammation and muscle fiber damage at the molecular level.
Publication Types:
Review
PMID: 15577607 [PubMed - indexed for MEDLINE]
15: Curr Opin Rheumatol. 2004 Nov;16(6):684-91.
Is it really myositis? A consideration of the differential diagnosis.
Nirmalananthan N, Holton JL, Hanna MG.
Neurogenetics Group, National Hospital for Neurology and Neurosurgery, Queen
Square, London WC1N 3BG, UK.
PURPOSE OF REVIEW: The idiopathic inflammatory myopathies are an important
and
treatable group of disorders. However, the potential toxicity associated with
the immune therapeutic regimens used to treat these disorders may be
significant; therefore, accurate diagnosis before such treatment is essential.
The differential diagnosis is potentially large. Accurate diagnosis usually
depends on a combination of careful clinical assessment in conjunction with
detailed laboratory investigations. Muscle biopsy remains essential in achieving
an accurate diagnosis that will then guide treatment. This review describes
the
diagnostic approach used. RECENT FINDINGS: There has been debate over the
requirements for an accurate diagnosis of inflammatory myopathy (i.e.,
polymyositis and dermatomyositis). It is increasingly recognized that there
can
be clinical and muscle histopathologic overlap between the features of
inflammatory myopathies and those of other muscle disorders, in particular,
the
genetic muscular dystrophies. Pathologic findings of inflammation and major
histocompatibility complex upregulation, although typical of inflammatory
myopathies, have been shown to occur in some muscular dystrophies, complicating
the diagnostic process. Inclusion body myositis is much less responsive to
immunotherapy and is now recognized as the most common acquired muscle disease
in those older than 50 years of age. It is likely that genetic muscular
dystrophies and inclusion body myositis account for some cases of apparently
"treatment-resistant" myositis. SUMMARY: A thorough clinical assessment,
including a detailed family history, complemented by electromyography and
creatine kinase measurements, should be undertaken in any patient with presumed
idiopathic inflammatory myopathy. In addition, a muscle biopsy remains essential
in all cases. A precise tissue diagnosis confirming features of an active
inflammatory process should be achieved before immunosuppressive treatment is
commenced. An increasing array of immunocytochemical and histioenzymatic stains
now allows a full analysis and will help to confirm or exclude virtually all
the
differential diagnostic possibilities considered in this review. Electron
microscopy may also be valuable in selected cases. Close collaboration between
clinicians and muscle pathologists is essential in allowing the most accurate
interpretation of myopathologic findings in the clinical context.
Publication Types:
Review
PMID: 15577605 [PubMed - indexed for MEDLINE]
16: Neuropathol Appl Neurobiol. 2004 Dec;30(6):624-34.
Tau aggregates are abnormally phosphorylated in inclusion body myositis and
have
an immunoelectrophoretic profile distinct from other tauopathies.
Maurage CA, Bussiere T, Sergeant N, Ghesteem A, Figarella-Branger D, Ruchoux
MM,
Pellissier JF, Delacourte A.
INSERM U422, Faculte de Medecine, 1 place de Verdun, Lille cedex, France.
ca-maurage@chru-lille.fr
Sporadic inclusion body myositis (s-IBM) is the most frequent progressive
acquired inflammatory myopathy in people older than 50 years. Abnormal
aggregates of 'Alzheimer's proteins', including tau proteins, have been
previously demonstrated in s-IBM. In the present study, we have investigated
by
immunohistochemistry and immunoblotting analysis the presence of tau proteins
in
muscle biopsy samples from patients with s-IBM and other myopathies with rimmed
vacuoles, using newly developed antibodies raised against tau protein epitopes
found in Alzheimer's disease brain. Tau immunoreactivity was shown in rimmed
vacuoles or inclusions, preferentially with antibodies directed against
phosphorylated carboxy-terminal epitopes of tau proteins. Cytoplasmic reactivity
was also demonstrated in atrophic, nonvacuolated fibres, as well as in
non-necrotic fibres invaded by inflammatory cells. Abnormally phosphorylated
tau
aggregates were also found in other compartments of the muscle fibre in s-IBM
and other myopathies. Tau immunoblotting showed an electrophorectic profile
of a
doublet within the range of 60-62 kDa isovariants, which was different from
tauopathies of the central nervous system. Finally, the unique pattern of
immunoreactivity of s-IBM samples towards anti-tau antibodies is a new clue
to a
possible distinct subclass of peripheral tauopathy, different from the
tauopathies of the central nervous system.
PMID: 15541003 [PubMed - indexed for MEDLINE]
17: Tissue Antigens. 2004 Nov;64(5):575-80.
Two major histocompatibility complex haplotypes influence susceptibility to
sporadic inclusion body myositis: critical evaluation of an association with
HLA-DR3.
Price P, Santoso L, Mastaglia F, Garlepp M, Kok CC, Allcock R, Laing N.
School of Surgery and Pathology, University of Western Australia, Nedlands,
Australia. pprice@cyllene.uwa.edu.au
Previous studies of sporadic inclusion body myositis (sIBM) have shown a strong
association with HLA-DR3 and other components of the 8.1 ancestral haplotype
(AH) (HLA-A1, B8, DR3), where the susceptibility locus has been mapped to the
central major histocompatibility complex (MHC) region between HLA-DR and C4.
Here, the association with HLA-DR3 and other genes in the central MHC and class
II region was further investigated in a group of 42 sIBM patients and in an
ethnically similar control group (n = 214), using single-nucleotide
polymorphisms and microsatellite screening. HLA-DR3 (marking DRB1*0301 in
Caucasians) was associated with sIBM (Fisher's test). However, among
HLA-DR3-positive patients and controls, carriage of HLA-DR3 without
microsatellite and single-nucleotide polymorphism alleles of the 8.1AH (HLA-A1,
B8, DRB3*0101, DRB1*0301, DQB1*0201) was marginally less common in patients.
Patients showed no increase in carriage of the 18.2AH (HLA-A30, B18, DRB3*0202,
DRB1*0301, DQB1*0201) or HLA-DR3 without the central MHC of the 8.1AH, further
arguing against HLA-DRB1 as the direct cause of susceptibility. Genes between
HLA-DRB1 and HOX12 require further investigation. BTL-II lies in this region
and
is expressed in muscle. Carriage of allele 2 (exon 6) was more common in
patients. BTL-II(E6)*2 is characteristic of the 35.2AH (HLA-A3, B35, DRB1*01)
in
Caucasians and HLA-DR1, BTL-II(E6)*2, HOX12*2, RAGE*2 was carried by several
patients. The 8.1AH and 35.2AH may confer susceptibility to sIBM independently
or share a critical allele.
PMID: 15496200 [PubMed - in process]
18: J Pathol. 2004 Nov;204(3):241-7.
The prion protein in human neuromuscular diseases.
Kovacs GG, Kalev O, Gelpi E, Haberler C, Wanschitz J, Strohschneider M, Molnar
MJ, Laszlo L, Budka H.
National Institute of Psychiatry and Neurology, Budapest, Hungary.
The basis of human prion diseases affecting the nervous system is accumulation
of a disease-associated conformer (PrPSc) of the normal cellular prion protein
(PrPC). Earlier studies demonstrated increased expression of PrPC in inclusion
body myositis (IBM), dermato-, and polymyositis, as well as neurogenic muscle
atrophy. To define the spectrum and reliability of PrPC immunoreactivity, its
expression was examined systematically in a series of pathologically
characterized muscular disorders by means of immunohistochemistry, confocal
laser microscopy, and immunogold electron microscopy. Anti-PrPC immunolabelling
of rimmed vacuoles was observed in IBM, inclusions of myofibrillary myopathy,
targets, regenerating, and atrophic fibres, mononuclear cells, in addition to
ragged red fibres in mitochondrial myopathies, and focal sarcolemmal
immunostaining in non-diseased controls. Quantitative analysis demonstrated
that, in neurogenic muscle lesions, anti-PrPC staining detects a significantly
broader spectrum of fibres than anti-vimentin or anti-NCAM. In dystrophic
muscle, PrPC expression was mainly restricted to regenerating fibres. In IBM,
PrPC expression was not confined to rimmed vacuoles or vacuolated fibres and
only a small percentage (7.1%) of rimmed vacuoles were PrPC positive.
Ultrastructurally, PrPC was observed in the cytoplasm of lymphocytes, in the
myofibrillar network of targets, and in rimmed vacuoles. Knowledge of disease
circumstances with altered expression of PrPC is important in the setting of
a
potentially increased chance for extraneural PrPC-PrPSc conversion. In addition,
our observations suggest that PrPC may have a general stress-response effect
in
various neuromuscular disorders. Copyright (c) 2004 Pathological Society of
Great Britain and Ireland.
PMID: 15476279 [PubMed - indexed for MEDLINE]
19: FEBS Lett. 2004 Oct 8;576(1-2):57-62.
Transglutaminase catalyzes differential crosslinking of small heat shock
proteins and amyloid-beta.
Boros S, Kamps B, Wunderink L, de Bruijn W, de Jong WW, Boelens WC.
Department of Biochemistry 161, Nijmegen Center for Molecular Life Sciences,
University of Nijmegen, P.O. Box 9101, 6500HB Nijmegen, The Netherlands.
Crosslinking of proteins by tissue transglutaminase (tTG) is enhanced in amyloid
(Abeta) deposits characteristic of Alzheimer's disease and sporadic inclusion
body myositis. Small heat shock proteins (sHsps) also occur in amyloid deposits.
We here report the substrate characteristics for tTG of six sHsps. Hsp27, Hsp20
and HspB8 are both lysine- and glutamine-donors, alphaB-crystallin only is a
lysine-donor, HspB2 a glutamine-donor, and HspB3 no substrate at all. Close
interaction of proteins stimulates crosslinking efficiency as crosslinking
between different sHsps only takes place within the same heteromeric complex.
We
also observed that alphaB-crystallin, Hsp27 and Hsp20 associate with Abeta in
vitro, and can be readily crosslinked by tTG. Copyright 2004 Federation of
European Biochemical Societies
PMID: 15474010 [PubMed - indexed for MEDLINE]
20: Neurology. 2004 Sep 28;63(6):1114-7.
Mutant ubiquitin UBB+1 is accumulated in sporadic inclusion-body myositis muscle
fibers.
Fratta P, Engel WK, Van Leeuwen FW, Hol EM, Vattemi G, 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.
Mutant ubiquitin (UBB+1), a product of "molecular misreading," is
toxic to cells
because its ubiquitinated form inhibits the proteasome, contributing to
accumulation of misfolded proteins and their ensuing toxicity. The authors
demonstrate in 10 sporadic inclusion body myositis (s-IBM) muscle biopsies that
UBB+1 is accumulated in aggregates containing amyloid-beta and
phosphorylated-tau. In s-IBM, UBB+1 may be pathogenic by inhibiting proteasome,
thereby promoting accumulation of cytotoxic misfolded amyloid-beta and
phosphorylated-tau.
PMID: 15452314 [PubMed - in process]
21: Folia Neuropathol. 2004;42 Suppl A:69-76.
Contribution of neuropathology to the understanding of human prion disease.
Kovacs GG, Kalev O, Budka H.
National Institute of Psychiatry and Neurology, Department of Neuropathology,
and Hungarian Reference Centre for Human Prion Diseases, Huvosvolgyi ut 116,
H-1021 Budapest, Hungary. kovacsgg@opni.hu
Neuropathology is an important tool for definitive diagnosis of sporadic,
genetic, and acquired prion disease. Classical neuropathological hallmark is
the
highly disease-specific spongiform change accompanied by neuronal loss, astro-
and microgliosis. Spongiform change of the neuropil consists of either
microcystic or confluent vacuoles and varies greatly within the same brain.
In
addition, the most important aspect of confirmatory diagnosis is the
demonstration of disease-associated prion protein (PrP(d)) by
immunohistochemistry or Western blotting. Different PrP(d) immunostaining
patterns include patchy/perivacuolar surrounding spongiform change,
diffuse/synaptic, perineuronal, or plaque type. The latter includes unicentric
kuru-type plaques or multicentric plaques as in the peculiar genetic prion
disorder, Gerstmann-Straussler-Scheinker disease. PrP(d) immunostaining patterns
correlate well with phenotypes defined by the polymorphic codon 129 and the
type
of protease resistant PrP(d) seen on Western blots. PrP(d) immunoreactivity
in
the cerebellum may be highly informative about disease subtypes. Although the
central nervous system is the major site of PrP(d) accumulation, it may also
be
observed in peripheral nerves as adaxonal deposits; in skeletal muscle as
granular immunoreactivity in particular in abundance in a unique instance of
concomitant Creutzfeldt-Jakob disease and inclusion body myositis; as well as
associated with dendritic cells and macrophages in vessel walls. A subset of
inhibitory GABAergic neurons is selectively affected in experimental and human
prion disease. The central pathogenetic cascade includes oxidative stress and
apoptosis. Deposition of terminal complement components on neurons accompanies
tissue damage.
Publication Types:
Review
Review, Tutorial
PMID: 15449461 [PubMed - indexed for MEDLINE]
22: Muscle Nerve. 2004 Aug 18;31(2):260-265 [Epub ahead of print]
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. Muscle Nerve 2004.
PMID: 15389648 [PubMed - as supplied by publisher]
23: J Biol Chem. 2004 Dec 17;279(51):53524-32. Epub 2004 Sep 22.
Calcium dyshomeostasis in beta-amyloid and tau-bearing skeletal myotubes.
Christensen RA, Shtifman A, Allen PD, Lopez JR, Querfurth HW.
Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts
University School of Medicine, 736 Cambridge St., Boston, MA 02135, USA.
The relative scarcity of inclusion-affected muscle cells or markers of cell
death in inclusion body myositis (IBM) is in distinction to the specific and
early intracellular deposition of several Alzheimer's Disease (AD)-related
proteins. The current study examined the possible correlation between myotube
beta-amyloid and/or Tau accumulations and a widespread mishandling of
intracellular muscle calcium concentration that could potentially account for
the unrelenting weakness in affected patients. Cultured myogenic cells
(C(2)C(12)) expressed beta-amyloid-42 (Abeta(42)) and fetal Tau peptides, as
human transgenes encoded by herpes simplex virus, either individually or
concurrently. Co-expression of Abeta(42) in C(2)C(12) myotubes resulted in
hyperphosphorylation of Tau protein that was not observed when Tau was expressed
alone. Resting calcium concentration and agonist-induced RyR-mediated Ca(2+)
release were examined using calcium-specific microelectrodes and Fluo-4
epifluorescence, respectively. Co-expression of Abeta(42) and Tau cooperatively
elevated basal levels of myoplasmic-free calcium, an effect that was accompanied
by depolarization of the plasma membrane. Sarcoplasmic reticulum (SR) calcium
release, induced by KCl depolarization, was not affected by Abeta(42) or Tau.
In
contrast, expression of Abeta(42), Tau, or Abeta(42) together with Tau resulted
in enhanced sensitivity of ryanodine receptors to activation by caffeine.
Notably, expression of beta-amyloid, alone, was sufficient to result in an
increased sensitivity to direct activation by caffeine. Current results indicate
that amyloid proteins cooperate to raise resting calcium levels and that these
effects are associated with a passive SR Ca(2+) leak and Tau
hyperphosphorylation in skeletal muscle.
PMID: 15385569 [PubMed - indexed for MEDLINE]
24: Curr Opin Neurol. 2004 Oct;17(5):561-7.
Inflammatory disorders of muscle: progress in polymyositis, dermatomyositis
and
inclusion body myositis.
Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Bethesda, Maryland 20892-1382, USA.
dalakasm@ninds.nih.gov
PURPOSE OF REVIEW: To provide an update on the major advances in inflammatory
myopathies. RECENT FINDINGS: Polymyositis is an uncommon disorder that can be
misdiagnosed when the old, and never validated, criteria of Bohan and Peter
are
used. New diagnostic criteria were recently introduced, in which the MHC/CD8
complex is considered a specific immunopathological marker because it
distinguishes the antigen-driven inflammatory cells that characterize
polymyositis and sporadic inclusion-body myositis from the non-specific,
secondary inflammation seen in other disorders, such as dystrophies. In sporadic
inclusion-body myositis the inflammatory cells invade non-vacuolated fibers,
whereas the vacuolated fibers are not invaded by T cells, implying two
independent processes, a primary immune process with antigen-driven T cells
identical to polymyositis, and a degenerative process in which beta-amyloid
and
amyloid-related proteins participate in vacuolar degeneration. In polymyositis
and sporadic inclusion-body myositis, antigen-specific and clonally expanded
autoinvasive T cells persist for years, even in different muscles, as
reconfirmed by proof-of-principle techniques involving CDR3 spectratyping
combined with laser microdissected single-cell polymerase chain reaction of
the
T-cell receptor genes. The formation of immunological synapse between
autoinvasive T cells and muscle fibers was recently strengthened by the
upregulation of co-stimulatory molecules ICOS/ICOS-L and PD-L1. A new, distinct
myopathy characterized by T-cell-triggered macrophage hyperactivation has now
been recognized in patients with dermatomyositis-like disease. SUMMARY: Despite
recent progress, the antigen(s) responsible for T-cell activation in
polymyositis and sporadic inclusion-body myositis and the cause of vacuolar
degeneration in sporadic inclusion-body myositis remain unclear. Newer, more
aggressive immunotherapies may be encouraging, but control trials are needed
to
prove efficacy.
PMID: 15367860 [PubMed - in process]
25: J Virol. 2004 Oct;78(19):10320-7.
Direct evidence for a chronic CD8+-T-cell-mediated immune reaction to tax within
the muscle of a human T-cell leukemia/lymphoma virus type 1-infected patient
with sporadic inclusion body myositis.
Ozden S, Cochet M, Mikol J, Teixeira A, Gessain A, Pique C.
Unite d'Epidemiologie et Physiopathologie des Virus Oncogenes, Paris, France.
Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) infection can lead to
the
development of HTLV-1-associated myelopathy/tropical spastic paraparesis
(HAM/TSP), concomitantly with or without other inflammatory disorders such as
myositis. These pathologies are considered immune-mediated diseases, and it
is
assumed that migration within tissues of both HTLV-1-infected CD4(+) T cells
and
anti-HTLV-1 cytotoxic T cells represents a pivotal event. However, although
HTLV-1-infected T cells were found in inflamed lesions, the antigenic
specificity of coinfiltrated CD8(+) T cells remains to be determined. In this
study, we performed both ex vivo and in situ analyses using muscle biopsies
obtained from an HTLV-1-infected patient with HAM/TSP and sporadic inclusion
body myositis. We found that both HTLV-1-infected CD4(+) T cells and CD8(+)
T
cells directed to the dominant Tax antigen can be amplified from muscle cell
cultures. Moreover, we were able to detect in two successive muscle biopsies
both tax mRNA-positive mononuclear cells and T cells recognized by the
Tax11-19/HLA-A*02 tetramer and positive for perforin. These findings provide
the
first direct demonstration that anti-Tax cytotoxic T cells are chronically
recruited within inflamed tissues of an HTLV-1 infected patient, which validates
the cytotoxic immune reaction model for the pathogenesis of HTLV-1-associated
inflammatory disease.
Publication Types:
Case Reports
PMID: 15367598 [PubMed - indexed for MEDLINE]
26: Neurology. 2004 Aug 24;63(4):718-20.
Randomized pilot trial of high-dose betaINF-1a in patients with inclusion body
myositis.
Muscle Study Group.
Neuromuscular Disease Center, 601 Elmwood Avenue, Box 673, Rochester, NY
14642-8673. Rabi_Tawil@URMC.Rochester.edu
Beta-interferon-1a (betaINF-1a) is well tolerated at low dose (30 microg
IM/week) in inclusion body myositis (IBM). The authors investigated the safety
and tolerability of high-dose (60 microg IM/week) betaINF-1a in a randomized,
placebo-controlled trial in IBM. Twenty-seven of the 30 subjects enrolled
completed the study. The adverse event profile was similar for the placebo and
betaINF-1a groups. betaINF-1a, at a dose of 60 microg IM/week, is well tolerated
in IBM, but no differences in muscle strength or mass were observed between
the
placebo and betaINF-1a groups at 6 months in this pilot study.
PMID: 15326251 [PubMed - in process]
27: Neurology. 2004 Aug 10;63(3):587-8.
Interferon beta-responsive inclusion body myositis in a hepatitis C virus
carrier.
Yakushiji Y, Satoh J, Yukitake M, Yamaguchi K, Nakamura I, Nishino I, Kuroda Y.
The Division of Neurology, Department of Internal Medicine, Saga University
School of Medicine, Saga, Japan. yakushij@hsp.ncvc.go.jp
PMID: 15304605 [PubMed - in process]
28: Neurology. 2004 Jul 27;63(2):402-3; author reply 403.
Comment on:
Neurology. 2003 Aug 12;61(3):316-21.
Polymyositis: an overdiagnosed entity.
Hengstman GJ, van Engelen BG.
Publication Types:
Comment
Letter
PMID: 15282847 [PubMed - indexed for MEDLINE]
29: Neurology. 2004 Jul 27;63(2):402; author reply 403.
Comment on:
Neurology. 2003 Aug 12;61(3):316-21.
Polymyositis: an overdiagnosed entity.
Bradley WG.
Publication Types:
Case Reports
Comment
Letter
PMID: 15282846 [PubMed - indexed for MEDLINE]
30: Neurology. 2004 Jul 27;63(2):403-4; author reply 404.
Comment on:
Neurology. 2003 Aug 12;61(3):288-9.
Unicorns, dragons, polymyositis, and other mythical beasts.
Askanas V, Engel WK.
Publication Types:
Comment
Letter
PMID: 15277658 [PubMed - indexed for MEDLINE]
31: J Chem Neuroanat. 2004 Jul;27(4):237-46.
Transgenic mice expressing the human C99 terminal fragment of betaAPP: effects
on cytochrome oxidase activity in skeletal muscle and brain.
Strazielle C, Dumont M, Fukuchi K, Lalonde R.
Laboratoire de Pathologie Moleculaire et Cellulaire en Nutrition (EMI-INSERM
0014) and Service de Microscopie Electronique, Faculte de Medecine, Universite
Henri Poincare, Nancy I, France. straziel@persmail.uhp-nancy.fr
In order to furnish a combined model of relevance to human inclusion-body
myopathy and Alzheimer's disease, transgenic mice expressing human betaAPP-C99
in skeletal muscle and brain under the control of the cytomegalovirus/beta-actin
promoter were produced (Tg13592). These transgenic mice develop Abeta deposits
in muscles but not in brain. Cell metabolic activity was analyzed in brain
regions and muscle by cytochrome oxidase (CO) histochemistry, the terminal
enzyme of the electron transport chain. By comparison to age-matched controls
of
the C57BL/6 strain, CO activity was selectively increased in dark skeletal
muscle fibers of Tg13592 mice. In addition, only increases in CO activity were
obtained in those brain regions where a significant difference appeared. The
CO
activity of Tg13592 mice was elevated in several thalamic nuclei, including
laterodorsal, ventromedial, and midline as well as submedial, intralaminar,
and
reticular. In contrast, the groups did not differ in most cortical regions,
except for prefrontal, secondary motor, and auditory cortices, and in most
brainstem regions, except for cerebellar (fastigial and interpositus) nuclei
and
related areas (red and lateral vestibular nuclei). No variation in cell density
and surface area appeared in conjunction with these enzymatic alterations. The
overproduction of betaAPP-C99 fragments in brain without (amyloidosis did not
appear to affect the metabolic activity of structures particularly vulnerable
in
Alzheimer's disease.
PMID: 15261330 [PubMed - indexed for MEDLINE]
32: Pharmacol Ther. 2004 Jun;102(3):177-93.
The use of intravenous immunoglobulin in the treatment of autoimmune
neuromuscular diseases: evidence-based indications and safety profile.
Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Diseases
and
Stroke, National Institutes of Health, MSC 1382, Room 4N248, Building 10, 10
Center Drive, Bethesda, MD 20892-1382, USA. dalakasm@ninds.nih.gov
Intravenous immunoglobulin (i.v.Ig) has multiple actions on the immunoregulatory
network that operate in concert with each other. For each autoimmune
neuromuscular disease, however, there is a predominant mechanism of action that
relates to the underlying immunopathogenetic cause of the respective disorder.
The best understood actions of i.v.Ig include the following: (a) modulation
of
pathogenic autoantibodies, an effect relevant in myasthenia gravis (MG),
Lambert-Eaton myasthenic syndrome (LEMS), Guillain-Barre syndrome (GBS), chronic
inflammatory demyelinating polyneuropathy (CIDP), and stiff-person syndrome
(SPS); (b) inhibition of complement activation and interception of membranolytic
attack complex (MAC) formation, an action relevant to the complement-mediated
mechanisms involved in GBS, CIDP, MG, and dermatomyositis (DM); (c) modulation
of the inhibitory or activation Fc receptors on macrophages invading targeted
tissues in nerve and muscle, as seen in CIDP, GBS, and inflammatory myopathies;
(d) down-regulation of pathogenic cytokines and adhesion molecules; (e)
suppression of T-cell functions; and (f) interference with antigen recognition.
Controlled clinical trials have shown that i.v.Ig is effective as first-line
therapy in patients with GBS, CIDP, and multifocal motor neuropathy (MMN), and
as second-line therapy in DM, MG, LEMS, and SPS. In paraproteinemic IgM anti-MAG
(myelin-associated glycoprotein) demyelinating polyneuropathies and inclusion
body myositis (IBM), the benefit is variable, marginal, and not statistically
significant. i.v.Ig has a remarkably good safety record for long-term
administration, however, the following side effects have been observed: mild,
infusion-rate-related reactions, such as headaches, myalgia, or fever; moderate
but inconsequential events, such as aseptic meningitis and skin rash; and
severe, but rare, complications, such as thromboembolic events and renal tubular
necrosis. Future studies are needed to (a) find the appropriate dose and
frequency of infusions that maintain a response; (b) address pharmacoeconomics,
comparing the high cost of i.v.Ig to the cost of the other therapies, which,
although less expensive, cause significantly more long-term side effects; (c)
determine why some patients respond better than others; and (d) examine the
merits of combining i.v.Ig with other immunosuppressive drugs.
Publication Types:
Review
Review, Tutorial
PMID: 15246245 [PubMed - indexed for MEDLINE]
33: Muscle Nerve. 2004 Jul;30(1):102-10.
Annexin expression in inflammatory myopathies.
Probst-Cousin S, Berghoff C, Neundorfer B, Heuss D.
Center of Neuromuscular Disorders, Department of Neurology,
Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, D-91054
Erlangen, Germany. stefan.probst-cousin@neuro.imed.uni-erlangen.de
The pathogenesis of the inflammatory myopathies is still unclear, making their
treatment largely empirical. Improved understanding of the molecular mechanisms
of inflammatory muscle injury may, however, lead to the development of more
specific immunotherapies. To elucidate a possible pathogenic contribution of
calcium-binding proteins such as the annexins, we immunohistochemically
investigated muscle biopsy specimens from patients with dermatomyositis (10
cases), polymyositis (9 cases), and inclusion-body myositis (4 cases), compared
to control cases comprising sarcoid myopathy (3 cases), Duchenne muscular
dystrophy (DMD; 4 cases), and normal muscle (3 cases). We found expression of
annexins A1, A2, A4, and A6 in the vascular endothelium of all cases. Myofibers
expressed annexins A5, A6, and A7 diffusely and weakly in the cytosol, whereas
annexins A5 and A7 were also particularly localized to the sarcolemma. In the
inflammatory myopathies, in areas of myonecrosis in DMD, and in granulomatous
lesions of sarcoid myopathy, reactivity of annexins A1, A2, A4, A5, and A6 was
observed in macrophages and T-lymphocytes. Whereas the latter annexins appear
to
be nonspecific indicators of activation, annexin A1 upregulation may represent
endogenous anti-inflammatory mechanisms that merit further investigation.
PMID: 15221885 [PubMed - indexed for MEDLINE]
34: Acta Neuropathol (Berl). 2004 Sep;108(3):257-9. Epub 2004 Jun 24.
Rimmed vacuoles in facioscapulohumeral muscular dystrophy: a unique
ultrastructural feature.
Neudecker S, Krasnianski M, Bahn E, Zierz S.
Department of Neurology, Martin-Luther-University Halle-Wittenberg,
Ernst-Grube-Str. 40, 06097, Halle (Saale), Germany.
Rimmed vacuoles (RV) are a characteristic pathological feature in inclusion
body
myositis, but may also occur in other neuromuscular disorders, such as distal
myopathies, oculopharyngeal myopathy, polymyositis, rigid spine syndrome,
congenital myopathies, and some limb girdle muscular dystrophies, as well as
in
various neurogenic diseases. We describe a patient with RV in familial
facioscapulohumeral muscular dystrophy (FSHD) associated with an FSHD-typical
deletion on chromosome 4q35. Thus, FSHD should be included in the differential
diagnosis of neuromuscular disorders with RV.
Publication Types:
Case Reports
PMID: 15221332 [PubMed - indexed for MEDLINE]
35: J Neuropathol Exp Neurol. 2004 Jun;63(6):650-9.
Insulin-like growth factor I in inclusion-body myositis and human muscle
cultures.
Broccolini A, Ricci E, Pescatori M, Papacci M, Gliubizzi C, D'Amico A, Servidei
S, Tonali P, Mirabella M.
Department of Neuroscience, Catholic University, Rome, Italy.
a.broccolini@rm.unicatt.it
Possible pathogenic mechanisms of sporadic inclusion-body myositis (sIBM)
include abnormal production and accumulation of amyloid beta (A beta), muscle
aging, and increased oxidative stress. Insulin-like growth factor I (IGF-I),
an
endocrine and autocrine/paracrine trophic factor, provides resistance against
A
beta toxicity and oxidative stress in vitro and promotes cell survival. In this
study we analyzed the IGF-I signaling pathway in sIBM muscle and found that
16.2% +/- 2.5% of nonregenerating fibers showed increased expression of IGF-I,
phosphatidylinositide 3'OH-kinase, and Akt. In the majority of sIBM abnormal
muscle fibers, increased IGF-I mRNA and protein correlated with the presence
of
A beta cytoplasmic inclusions. To investigate a possible relationship between
A
beta toxicity and IGF-I upregulation, normal primary muscle cultures were
stimulated for 24 hours with the A beta(25-35) peptide corresponding to the
biologically active domain of A beta. This induced an increase of IGF-I mRNA
and
protein in myotubes at 6 hours, followed by a gradual reduction thereafter.
The
level of phosphorylated Akt showed similar changes. We suggest that in sIBM.
IGF-I overexpression represents a reactive response to A beta toxicity, possibly
providing trophic support to vulnerable fibers. Understanding the signaling
pathways activated by IGF-I in sIBM may lead to novel therapeutic strategies
for
the disease.
PMID: 15217093 [PubMed - indexed for MEDLINE]
36: J Neuropathol Exp Neurol. 2004 May;63(5):484-98.
Proteasomal expression, induction of immunoproteasome subunits, and local MHC
class I presentation in myofibrillar myopathy and inclusion body myositis.
Ferrer I, Martin B, Castano JG, Lucas JJ, Moreno D, Olive M.
Instituto de Neuropatologia, Servicio de Anatomia Patologica, Hospital
Universitario de Bellvitge, Hospitalet de Llobregat, Spain. 8082ifa@comb.es
Inclusion body myositis (IBM) and myofibrillar myopathy (MM) are diseases
characterized by the abnormal accumulation of proteins in muscle fibers,
including desmin, alphaB-crystallin, gelsolin, actin, kinases, and phospho-tau,
along with ubiquitin in muscle fibers, suggesting abnormal protein degradation
as a possible cause of the surplus myopathy. Since the ubiquitin-proteasome
system plays a crucial role in non-lysosomal protein degradation, the present
study has examined by immunohistochemistry the expression of components of the
catalytic core of 20S proteasomes and its regulators: 19S and PA28alpha/beta,
and the expression of immunoproteasome subunits LMP2, LMP7, and MECL1 in 8
patients with MM and 10 patients with IBM. The patients with MM were from 6
unrelated families, 2 sporadic cases, I with autosomal recessive and 5 with
autosomal dominant inheritance. One sporadic patient had a de novo R406W
mutation in the desmin gene, and 1 patient with autosomal dominant MM had a
single amino acid deletion at position 366 in the desmin gene. Increased
immunoreactivity to 20S, 19S, and PA28alpha/beta colocalizing abnormal protein
deposits, as revealed in consecutive serial sections, was seen in all cases
with
MM and IBM. In all cases, the subunits of the immunoproteasome LMP2, LMP7, and
MECL1 colocalized with proteasomal immunoreactivity and abnormal protein
accumulation. Immunohistochemistry revealed focal MHC class I immunoreactivity
in the cytoplasmic membrane of muscle fibers in IBM and in association with
protein aggregates in IBM, and to a lesser degree, in MM. The present findings
provide a link between abnormal protein accumulation and altered proteasomal
expression in IBM and MM.
PMID: 15198127 [PubMed - indexed for MEDLINE]
37: Can J Gastroenterol. 2004 Jun;18(6):397-9.
Injection of botulinum toxin A to the upper esophageal sphincter for
oropharyngeal dysphagia in two patients with inclusion body myositis.
Liu LW, Tarnopolsky M, Armstrong D.
Hamilton Health Sciences, Hamilton, Ontario, Canada. liuwc@mcmaster.ca
Inclusion body myositis (IBM) is a progressive degenerative skeletal muscle
disease leading to weakening and atrophy of both proximal and distal muscles.
Dysphagia is reported in up to 86% of IBM patients. Surgical cricopharyngeal
myotomy may be effective for cricopharyngeal dysphagia and there is one
published report that botulinum toxin A, injected into the cricopharyngeus
muscle using a hypopharyngoscope under general anesthesia, relieved
IBM-associated dysphagia. This report presents the first documentation of
botulinum toxin A injection into the upper esophageal sphincter using a flexible
esophagogastroduodenoscope under conscious sedation, to reduce upper esophageal
sphincter pressure and successfully alleviate oropharyngeal dysphagia in two
IBM
patients.
Publication Types:
Case Reports
PMID: 15190396 [PubMed - indexed for MEDLINE]
38: Rev Med Interne. 2004 Jun;25 Suppl 1:S14-6.
The molecular pathophysiology in inflammatory myopathies.
Dalakas MC.
Neuromuscular Diseases Section, NINDS, National Institutes of Health, NIH,
National Institute of Neurological Diseases and Stroke, 10 Center Drive, MSC
1382, Building 10, Room 4N248, Bethesda, MD 20892-1382, USA.
dalakasm@ninds.nih.gov
Publication Types:
Review
PMID: 15165685 [PubMed - indexed for MEDLINE]
39: Eur Neurol. 2004;51(4):215-20. Epub 2004 May 17.
Apolipoprotein E and alpha-1-antichymotrypsin polymorphisms in sporadic
inclusion body myositis.
Gossrau G, Gestrich B, Koch R, Wunderlich C, Schroder JM, Schroeder S, Reichmann
H, Lampe JB.
Department of Neurology, Medical Clinic II, Technical University Dresden,
Dresden, Germany. ggossrau@uni-bonn.de
Sporadic inclusion body myositis (s-IBM) is a progressive muscle disease of
unknown aetiology. Characteristically, intracellular amyloid deposits are
detectable, including beta-amyloid precursor protein, phosphorylated tau,
alpha1-antichymotrypsin (alpha1-ACT) and apolipoprotein E (ApoE). Polymorphisms
and mutations of the encoding genes have been identified in a variety of
neurodegenerative diseases including Alzheimer's disease (AD). Beside other
factors, polymorphisms may lead to protein accumulation in both diseases. In
particular, polymorphisms within the ApoE and alpha1-ACT gene have been
implicated in the aetiology of AD and s-IBM. We analysed ApoE and alpha1-ACT
gene polymorphisms in 35 s-IBM patients. We could not identify any statistical
significant correlation between distinct ApoE and alpha1-ACT genotypes and the
risk of developing s-IBM. Additionally, ApoE and alpha1-ACT genotypes seem not
to influence the onset age of s-IBM. A combination of different alpha1-ACT and
ApoE genotypes appears not to enhance the risk of developing s-IBM. Therefore,
allelic variations of alpha1-ACT and ApoE are unlikely to be genetic key factors
in the aetiology of s-IBM. Copyright 2004 S. Karger AG, Basel
PMID: 15159602 [PubMed - indexed for MEDLINE]
40: Best Pract Res Clin Rheumatol. 2004 Jun;18(3):345-58.
Paediatric idiopathic inflammatory muscle disease.
Wedderburn LR, Li CK.
Rheumatology Unit, Institute of Child Health, University College London, 30
Guilford Street, London WC1N 1EH, UK. l.wedderburn@ich.ucl.ac.uk
The paediatric idiopathic inflammatory myopathies (IIMs) are a group of rare
but
serious systemic autoimmune conditions of childhood. The most common of the
paediatric IIMs is juvenile dermatomyositis (JDM), while polymyositis and
inclusion body myositis are rare in children. JDM has a significantly different
spectrum of disease from adult dermatomyositis. Juvenile myositis can also occur
as part of other systemic autoimmune diseases such as scleroderma and systemic
lupus erythematosus. There has recently been significant progress towards the
development and validation of tools to measure disease activity and damage in
the paediatric IIMs. In addition, several new therapeutic avenues have been
used
to treat JDM. This review will discuss developments in the diagnostic criteria
for JDM, the clinical types and course of these conditions, recent progress
in
disease assessment, treatment options and new developments in research into
the
pathogenesis of paediatric IIM.
Publication Types:
Review
Review, Tutorial
PMID: 15158745 [PubMed - indexed for MEDLINE]
41: Best Pract Res Clin Rheumatol. 2004 Jun;18(3):331-44.
Adult inflammatory myopathies.
Christopher-Stine L, Plotz PH.
Division of Rheumatology, Department of Medicine, Johns Hopkins University
School of Medicine, Baltimore, MD 21205, USA.
The major inflammatory myopathies of adults-dermatomyositis, polymyositis and
inclusion body myositis-are uncommon and can be difficult to distinguish from
many conditions that mimic them clinically. They have a high morbidity; they
are
not infrequently the first sign of an associated malignancy; and they may be
a
part of another connective tissue disease. Their pathogenetic features suggest
that they are different illnesses. Dermatomyositis and polymyositis are clearly
inflammatory, both clinically and histologically, and both generally respond
to
therapy directed towards inflammation. Inclusion body myositis is now generally
recognized as the most common myopathy presenting in patients over the age of
50
years, and it responds only modestly and sometimes not at all to
immunosuppressive therapy. In this review, we have summarised the major newly
recognized features of pathogenesis, the involvement of extramuscular organs,
the differential diagnosis, diagnostic approaches and the main lines of therapy.
Publication Types:
Review
Review, Tutorial
PMID: 15158744 [PubMed - indexed for MEDLINE]
42: JAMA. 2004 May 19;291(19):2367-75.
Comment in:
JAMA. 2004 Sep 22;292(12):1429; author reply 1429-30.
Intravenous immunoglobulin in autoimmune neuromuscular diseases.
Dalakas MC.
Neuromuscular Diseases Section, National Institutes of Health, National
Institute of Neurological Disorders and Stroke, Bethesda, Md 20892, USA.
dalakasm@ninds.nih.gov
CONTEXT: Intravenous immunoglobulin (IVIG) enhances immune homeostasis by
modulating expression and function of Fc receptors, interfering with activation
of complement and production of cytokines, providing anti-idiotypic antibodies,
and affecting the activation and effector functions of T and B cells. These
mechanisms may explain the effectiveness of IVIG in autoimmune neuromuscular
disorders. OBJECTIVE: To systematically review the current status of the
treatment of autoimmune neuromuscular diseases with IVIG, with emphasis on
controlled trials. DATA SOURCES: Peer-reviewed publications identified through
MEDLINE (1966-2003), EMBASE (1974-2003), and references from bibliographies
of
pertinent articles. Each autoimmune neuromuscular disease term was searched
in
combination with the term intravenous immunoglobulin. STUDY SELECTION AND DATA
EXTRACTION: Criteria for selection of studies included controlled study design,
English language, and clinical pertinence. Data quality was based on venue of
publication and relevance to clinical care. DATA SYNTHESIS: Outcomes of
controlled trials indicate that IVIG at a total dose of 2 g/kg is effective
as
first-line therapy in Guillain-Barre syndrome, chronic inflammatory
demyelinating polyneuropathy, and multifocal motor neuropathy and as second-line
therapy in stiff-person syndrome, dermatomyositis, myasthenia gravis, and
Lambert-Eaton myasthenic syndrome. In other controlled studies, IVIG produced
a
modest, variable, and transient but not statistically significant benefit in
patients with inclusion body myositis and paraproteinemic anti-myelin-associated
glycoprotein antibody demyelinating polyneuropathy. Intravenous immunoglobulin
is not effective in patients with multiple sclerosis who have established
weakness or optic neuritis. In myasthenia gravis, it should be reserved for
difficult cases or before thymectomy in lieu of plasma exchange. CONCLUSION:
Intravenous immunoglobulin is effective in many autoimmune neurologic diseases,
but its spectrum of efficacy, especially as first-line therapy, and the
appropriate dose for long-term maintenance therapy are not fully established.
Further controlled studies of IVIG, combined with a dose-finding effect,
pharmacoeconomics, and quality-of-life assessments, are warranted to improve
the
evidence base for clinical practice.
Publication Types:
Review
PMID: 15150209 [PubMed - indexed for MEDLINE]
43: FEBS Lett. 2004 May 21;566(1-3):105-9.
The homozygous M712T mutation of UDP-N-acetylglucosamine
2-epimerase/N-acetylmannosamine kinase results in reduced enzyme activities
but
not in altered overall cellular sialylation in hereditary inclusion body
myopathy.
Hinderlich S, Salama I, Eisenberg I, Potikha T, Mantey LR, Yarema KJ, Horstkorte
R, Argov Z, Sadeh M, Reutter W, Mitrani-Rosenbaum S.
Charite - Universitatsmedizin Berlin, Campus Benjamin Franklin, Institut fur
Biochemie und Molekularbiologie, Arnimallee 22, 14195 Berlin-Dahlem, Germany.
stephan.hinderlich@charite.de
Hereditary inclusion body myopathy (HIBM) is a neuromuscular disorder, caused
by
mutations in UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase,
the
key enzyme of sialic acid biosynthesis. In Middle Eastern patients a single
homozygous mutation occurs, converting methionine-712 to threonine. Recombinant
expression of the mutated enzyme revealed slightly reduced N-acetylmannosamine
kinase activity, in agreement with the localization of the mutation within the
kinase domain. B lymphoblastoid cell lines derived from patients expressing
the
mutated enzyme also display reduced UDP-N-acetylglucosamine 2-epimerase
activity. Nevertheless, no reduced cellular sialylation was found in those cells
by colorimetric assays and lectin analysis, indicating that HIBM is not directly
caused by an altered overall expression of sialic acids.
PMID: 15147877 [PubMed - indexed for MEDLINE]
44: Hum Mutat. 2004 Jun;23(6):632.
Novel GNE mutations in Italian families with autosomal recessive hereditary
inclusion-body myopathy.
Broccolini A, Ricci E, Cassandrini D, Gliubizzi C, Bruno C, Tonoli E, Silvestri
G, Pescatori M, Rodolico C, Sinicropi S, Servidei S, Zara F, Minetti C, Tonali
PA, Mirabella M.
Department of Neuroscience, Catholic University, Rome, Italy.
a.broccolini@rm.unicatt.it
The most common form of autosomal recessive (AR) hereditary inclusion-body
myopathy (HIBM), originally described in Persian-Jewish families, is
characterized by onset in early adult life with weakness and atrophy of distal
lower limb muscles, which progress proximally and relatively spare the
quadriceps. AR HIBM is associated with mutations in the UDP-N-acetylglucosamine
2-epimerase/N-acetylmannosamine kinase gene (GNE) on chromosome 9p12-13. In
the
present study we have identified seven novel GNE mutations in patients from
five
unrelated Italian families with clinical and pathologic features indicative
of
AR HIBM. Four were missense mutations (c.1556A>G [p.N519S], c.79C>T [p.P27S],
c.1798G>A [p.A600T] and c.616G>A [p.G206S]), two consisted in a single-base
deletion (c.616delG [p.G206fsX4] and c.1130delT [p.I377fsX16]) and one in an
intronic single-base insertion (c.1070+2dupT). These latter findings further
extend the type of GNE mutations associated with HIBM. Furthermore, in one
patient we also identified the c.737G>A [p.R246Q] missense mutation that
corresponds to the one previously reported in a family from the Bahamas.
Interestingly, in two of our families distinct mutations affected nucleotide
c.616 in exon 3 (c.616delG and c.616G>A). The possibility of specific portions
of the gene being more prone to mutations remains to be elucidated. Copyright
2004 Wiley-Liss, Inc.
PMID: 15146476 [PubMed - indexed for MEDLINE]
45: J Neurol Neurosurg Psychiatry. 2004 Jun;75(6):917-20.
Sporadic inclusion body myositis: morphology, regeneration, and cytoskeletal
structure of muscle fibres.
Arnardottir S, Borg K, Ansved T.
Department of Clinical Neuroscience, Division of Neurology, Karolinska Hospital,
Stockholm, Sweden. snjolaug.arnardottir@ks.se
OBJECTIVE: To characterise morphological abnormalities in relation to muscle
fibre type in sporadic inclusion body myositis (s-IBM). METHODS: 14 muscle
biopsies from 11 patients with s-IBM were characterised for morphological
abnormalities and fibre type composition as well as muscle fibre regeneration
and cytoskeletal structure, using histochemical and immunohistochemical
techniques. RESULTS: Morphological abnormalities included inflammatory
infiltrates and "rimmed vacuoles," and pronounced variation in fibre
size. There
were no significant differences in fibre type composition between s-IBM patients
and controls based on the myofibrillar ATPase staining. A differential effect
on
muscle fibre sizes was noted, type II fibres being smaller in the s-IBM patients
than in the controls. Conversely, the mean type I muscle fibre diameter in the
s-IBM patients was larger than in the controls, though this difference was not
significant. An ongoing intense regeneration process was present in s-IBM
muscle, as indicated by the expression of neonatal myosin heavy chain, vimentin,
and CD56 (Leu-19) in most of the muscle fibres. The cytoskeletal proteins
dystrophin and desmin were normally expressed in s-IBM muscle fibres that were
not undergoing degeneration or regeneration. CONCLUSIONS: There are extensive
morphological and morphometric alterations in s-IBM, affecting different muscle
fibre types in different ways. The cytoskeletal structure of type I and II
muscle fibres remains unaffected in different stages of the disease.
PMID: 15146016 [PubMed - indexed for MEDLINE]
46: Acta Neuropathol (Berl). 2004 Jul;108(1):37-42. Epub 2004 May 08.
Expression and distribution of the nitric oxide synthases in idiopathic
inflammatory myopathies.
De Paepe B, Racz GZ, Schroder JM, De Bleecker JL.
Department of Neurology, Ghent University Hospital, De Pintelaan 185, 9000,
Belgium.
Different immune effector mechanisms have been characterised in the idiopathic
inflammatory myopathies (IIM): in polymyositis (PM) and sporadic inclusion body
myositis (sIBM), T-cell-mediated cytotoxicity targets nonnecrotic muscle fibres,
whereas in dermatomyositis (DM) the complement-mediated immune response is
directed against the microvasculature. As nitric oxide (NO) has an important
function in cell signalling and in the cytotoxicity displayed by activated
macrophages, it is potentially involved in the immunopathogenesis of IIM. Using
immunohistochemical, in situ hybridisation and Western blotting techniques,
we
visualised the three isoforms of NO synthase (NOS) in muscle tissues from normal
controls and from patients diagnosed with IIM. The levels of both constitutive
isoforms of NOS (endothelial, i.e., eNOS, and neuronal, i.e., nNOS) were
unchanged in IIM as compared with normal muscle. Both protein and mRNA of the
inducible form (iNOS) were detected in half of the control biopsies. Constant
and increased iNOS protein expression was found in endomysial infiltrates of
PM
and sIBM, whereas perimysial inflammatory cells in DM were largely negative.
We
developed a quantitative Western blotting protocol which confirmed the
constitutive nature of nNOS and eNOS and the significant induction of iNOS in
PM. Our results appoint iNOS with a dual function: a limited and transient role
in normal muscle physiology and an active cytotoxic role in PM and sIBM.
PMID: 15138776 [PubMed - indexed for MEDLINE]
47: Neuromuscul Disord. 2004 May;14(5):337-45.
119th ENMC international workshop: trial design in adult idiopathic inflammatory
myopathies, with the exception of inclusion body myositis, 10-12 October 2003,
Naarden, The Netherlands.
Hoogendijk JE, Amato AA, Lecky BR, Choy EH, Lundberg IE, Rose MR, Vencovsky
J,
de Visser M, Hughes RA.
Department of Neurology, University Medical Center, Heidelberg laan 100,
Utrecht, CX 3584, The Netherlands. j.hoogendijk@neuro.azu.nl
Publication Types:
Congresses
PMID: 15099594 [PubMed - indexed for MEDLINE]
48: Clin Neuropathol. 2004 Mar-Apr;23(2):76-9.
Necrotizing myopathy with microvascular deposition of the complement membrane
attack complex.
De Bleecker J, Vervaet V, Van den Bergh P.
Department of Neurology, Ghent University Hospital, Ghent, Belgium.
jan.debleecker@Ugent.be
Necrotizing myopathy without prominent inflammatory changes is increasingly
being recognized as a form of inflammatory myopathy, different from
dermatomyositis, polymyositis and sporadic inclusion-body myositis. We report
a
patient with a chronic steroid-responsive myopathy and an ill-defined overlap
syndrome. The muscle biopsy showed thickened capillaries and arterioles and
deposition of the membrane attack complex in the replicated mural elements of
some vessels. The surface of all muscle fibers showed major histocompatibility
class I immunoreactivity. Similar patients have rarely been reported, either
suffering from an undifferentiated connective tissue disorder or a carcinoma.
The link between the muscle fiber necrosis and the microangiopathy is unclear.
Absence of prominent inflammatory changes in a diagnostic muscle biopsy does
not
exclude the diagnosis of a treatable autoimmune inflammatory myopathy.
Publication Types:
Case Reports
PMID: 15074581 [PubMed - indexed for MEDLINE]
49: Brain. 2004 May;127(Pt 5):1182-90. Epub 2004 Mar 26.
Upregulated inducible co-stimulator (ICOS) and ICOS-ligand in inclusion body
myositis muscle: significance for CD8+ T cell cytotoxicity.
Schmidt J, Rakocevic G, Raju R, Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
j.schmidt@gmx.org
Interactions between inducible co-stimulatory molecule (ICOS) and ICOS-ligand
(ICOS-L) are crucial for T-cell co-stimulation, effector cell differentiation
and memory CD8+ T-cell activation. Because in the muscle of patients with
sporadic inclusion body myositis (sIBM) clonally expanded CD8+ T cells invade
major histocompatibility complex (MHC) class I-expressing muscle fibres, we
investigated ICOS.ICOS-L interactions and correlated their expression with
perforin, a marker for cytotoxic effector function by autoinvasive CD8+ T cells.
The mRNA from 20 muscle biopsies of sIBM, 20 non-inflammatory or dystrophic
controls, two dermatomyositis (DM) and two polymyositis (PM) patients was
reverse transcribed and reamplified by semi-quantitative and quantitative
reverse transcription-polymerase chain reaction (RT-PCR), using primers for
ICOS, ICOS-L and perforin. The glyceraldehyde 3-phosphate dehydrogenase
(GAPDH)-normalized ratio of ICOS, ICOS-L and perforin expression was compared
with the degree of endomysial inflammation. Protein expression of ICOS, ICOS-L
and perforin was confirmed by immunohistochemistry. We demonstrate that ICOS-L
mRNA was upregulated in sIBM (arbitrary units, median +/- SEM: 48.6 +/- 14.9)
compared with controls (6.2 +/- 17.8, P < 0.05) and significantly correlated
with the expression of ICOS (53.9 +/- 16.6 versus 6.7 +/- 8.9 in controls, P
<
0.001). By triple labelling immunohistochemistry, the CD8+ T cells in sIBM and
PM were found to invade ICOS-L- and MHC class I-co-expressing muscle fibres.
Among the autoinvasive CD8+ T cells, however, only a subset of approximately
5-10% were ICOS positive, and thereby perceptive for ICOS.ICOS-L signalling
at
the immunological synapse. In contrast, in Duchenne muscular dystrophy and DM,
although ICOS and ICOS-L mRNA expression was also increased, the majority of
ICOS-L- and ICOS-positive cells were in the perimysial regions and connective
tissue. The mRNA for perforin was increased in sIBM (28.1 +/- 8.7) compared
with
controls (4.3 +/- 11.2, P = 0.18), and significantly correlated with mRNA of
ICOS, ICOS-L and the degree of endomysial inflammation as assessed in coded
haematoxylin/eosin tissue sections. By triple immunohistochemical staining and
cell counting, perforin granules were found in 71% of the autoinvasive CD8+
T
cells that were also ICOS positive. Our data indicate that in sIBM there is
upregulation of ICOS.ICOS-L co-stimulatory signalling in association with
enhanced perforin expression by the autoinvasive CD8+ T cells. The findings
support previous suggestions that in IBM, the muscle fibres have the capacity
for antigen presentation, thereby activating a specific subset among the
autoinvasive CD8+ T cells to exert a cytotoxic effect. The observations
strengthen the immunopathogenesis of sIBM, and offer the basis for future
therapeutic interventions targeting ICOS.ICOS-L co-stimulatory interactions.
PMID: 15047591 [PubMed - indexed for MEDLINE]
50: Neuromuscul Disord. 2004 Apr;14(4):265-73.
Localization of the alpha-chemokine SDF-1 and its receptor CXCR4 in idiopathic
inflammatory myopathies.
De Paepe B, Schroder JM, Martin JJ, Racz GZ, De Bleecker JL.
Department of Neurology, Ghent University Hospital, De Pintelaan 185, B-9000
Ghent, Belgium.
We studied the distribution of stromal cell-derived factor 1 isoforms alpha
and
beta, and their receptor CXCR4, in polymyositis, sporadic inclusion body
myositis and dermatomyositis using in situ hybridization, immunohistochemistry,
immunofluorescence and Western blotting. In control muscle, polymyositis and
sporadic inclusion body myositis, stromal cell-derived factor-1alpha expression
was noted in muscle fibers, while stromal cell-derived factor-1beta and CXCR4
were predominantly localized to capillaries and arterioles. In dermatomyositis,
stromal cell-derived factor-1beta immunoreactivity of blood vessels was focally
increased. The vast majority of inflammatory cells in idiopathic inflammatory
myopathies were CXCR4 positive. A subset of helper T-cells and macrophages
expressed stromal cell-derived factor-1alpha, while only rare inflammatory cells
expressed stromal cell-derived factor-1beta. A significant increase of stromal
cell-derived factor-1alpha and CXCR4 was observed in protein extracts of
idiopathic inflammatory myopathies in comparison with normal controls. The
abundance of both CXCR4 and its ligand stromal cell-derived factor-1 implicates
their interaction in the pathogenesis of idiopathic inflammatory myopathies
and
identifies these proteins as possible targets for selective immune therapy.
PMID: 15019705 [PubMed - indexed for MEDLINE]
51: Neuromuscul Disord. 2004 Apr;14(4):246-52.
Childhood macrophagic myofasciitis-consanguinity and clinicopathological
features.
Nevo Y, Kutai M, Jossiphov J, Livne A, Neeman Z, Arad T, Popovitz-Biro R, Atsmon
J, Shapira Y, Soffer D.
The Institute for Child Development and Pediatric Neurology Unit, Tel Aviv
Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Beit
Habriut Strauss, 14 Balfour Street, Tel Aviv 65211, Israel.
nevo@tasmc.health.gov.il
Macrophagic myofasciitis has been almost exclusively detected in adults only.
We
describe six children of Arab Moslem origin with this disorder. Three presented
with hypotonia, developmental delay and seizures and were evaluated for a
mitochondrial disorder. The other three children had hypotonia and predominantly
motor delay. Five of the six families were consanguineous. A massive collection
of macrophages was present in the fascia and adjacent epimysium in all biopsies.
The macrophages were periodic-acid-Schiff positive and immunoreactive for CD68.
One biopsy which was evaluated by electron microscopy and energy-dispersive
X-ray microanalysis showed crystalline structures containing aluminum in
macrophages. Two children with motor delay and hypotonia were treated with oral
prednisone for 3 months with no clinical improvement. Genetic predisposition
probably accounts for the variability in the prevalence of macrophagic
myofasciitis in different populations. At least in childhood, there seems to
be
no connection between macrophagic myofasciitis as a pathological entity and
the
clinical symptoms and signs.
PMID: 15019702 [PubMed - indexed for MEDLINE]
52: Mol Genet Metab. 2004 Mar;81(3):196-202.
Hypoglycosylation of alpha-dystroglycan in patients with hereditary IBM due
to
GNE mutations.
Huizing M, Rakocevic G, Sparks SE, Mamali I, Shatunov A, Goldfarb L, Krasnewich
D, Gahl WA, Dalakas MC.
Medical Genetics Branch, National Human Genome Research Institute/NIH, Bethesda,
MD, USA.
Hereditary inclusion body myopathy (HIBM) is an adult onset neuromuscular
disorder associated with mutations in the gene
UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE), whose
product is the rate limiting bi-functional enzyme catalyzing the first two steps
of sialic acid biosynthesis. Loss of GNE activity in HIBM is thought to impair
sialic acid production and interfere with proper sialylation of glycoconjugates,
but it remains unclear how such a defect would lead to muscle destruction and
muscle weakness. Hypoglycosylation of alpha-dystroglycan, a central protein
of
the skeletal muscle dystrophin-glycoprotein complex, results in disturbed
interactions with extracellular matrix proteins. This has recently been
identified as the pathomechanism involved in several congenital muscular
dystrophies. We examined the glycosylation status of alpha-dystroglycan in
muscle biopsies of four HIBM patients of non-Iranian Jewish origin (one
American, two Indians, and one Greek). Two of these patients carry novel
compound heterozygous GNE mutations on exon 2 and exon 9. All four muscle
biopsies showed absent or markedly reduced immunolabeling with two different
antibodies (VIA4 and IIH6) to glycosylated epitopes of alpha-dystroglycan.
Normal labeling was found using antibodies to the core alpha-dystroglycan
protein, beta-dystroglycan, and laminin alpha-2. These findings resemble those
found for other congenital muscular dystrophies, suggesting that HIBM may be
a
"dystroglycanopathy," and providing an explanation for the muscle
weakness of
patients with GNE mutations.
PMID: 14972325 [PubMed - indexed for MEDLINE]
53: Ann Rheum Dis. 2004 Mar;63(3):297-301.
Comment in:
Ann Rheum Dis. 2004 Aug;63(8):1005; discussion 1005-6.
Interstitial lung disease, a common manifestation of newly diagnosed polymyositis
and dermatomyositis.
Fathi M, Dastmalchi M, Rasmussen E, Lundberg IE, Tornling G.
Division of Respiratory Medicine, Department of Medicine, Karolinska Institutet,
Stockholm, Sweden. Maryam.Fathi@ks.se
OBJECTIVES: To estimate the prevalence and predictors of interstitial lung
disease in newly diagnosed polymyositis and dermatomyositis. METHODS: A
prospective study in which consecutive patients with newly diagnosed poly- and
dermatomyositis, regardless of clinical symptoms of pulmonary disease, were
investigated with chest x ray, high resolution computed tomography (HRCT),
pulmonary function tests, and biochemical and autoantibody analysis. Patients
with inclusion body myositis, malignancy, other defined inflammatory connective
tissue diseases (CTDs), or antibody profile indicating other CTDs were excluded.
RESULTS: Between March 1998 and September 2000, 26 new cases of poly- or
dermatomyositis were diagnosed; 17 of those patients were included in the study.
Interstitial lung disease (ILD), defined as radiological signs on chest x ray
examination/HRCT or restrictive ventilatory defect, were found in 11 (65%)
patients and were more common in men than in women. Arthritis and occurrence
of
anti-Jo-1 antibodies were found more often in patients with ILD than in those
without. There was no statistically significant association between respiratory
symptoms, other serological or laboratory variables and ILD. CONCLUSIONS: ILD
is
a common early manifestation in patients with poly- and dermatomyositis and
is
not always related to clinical symptoms. Chest x ray examination, HRCT,
pulmonary function tests, and analysis of anti-Jo-1 antibodies should be
included in the initial investigation of patients with myositis regardless of
respiratory symptoms.
PMID: 14962966 [PubMed - indexed for MEDLINE]
54: Curr Treat Options Neurol. 2004 Mar;6(2):155-161.
Inflammatory Myopathies.
Grogan PM, Katz JS.
Department of Neurology, Wilford Hall Medical Center, 2200 Bergquist Drive,
Suite 1,San Antonio, TX 78236, USA.
Therapies that suppress or modify the immune system remain the primary treatment
for the idiopathic inflammatory myopathies. Dermatomyositis (DM) and
polymyositis (PM) are the two conditions that respond best to immunotherapy.
Although there are no randomized controlled trials, corticosteroids,
specifically high-dose oral prednisone, remain the cornerstone of management.
Recent controlled clinical trials show that intravenous immunoglobulin (IVIg)
is
an efficacious treatment in DM. Expert clinicians are generally using this as
a
second-line agent or as an adjunct to prednisone. IVIg has a relatively benign
side effect profile compared with chronic steroid use, but the cost of
treatment, the need for repetitive treatment cycles, and the potential for
serious adverse effects have kept it from being a first-line agent in DM. There
have been no trials performed using IVIg in PM. Chronic immunosuppressant
medications, including azathioprine, cyclosporine, and methotrexate, are also
available for long-term management in patients with recalcitrant disease or
side
effects from extended corticosteroid use. These agents lack the troubling side
effects of prednisone and are less costly than IVIg, but require close medical
monitoring for adverse reactions to blood, kidney, lung, or liver. Newer
medications with potentially more benign side effect profiles, such as
mycophenolate mofetil and etanercept, are currently being studied, but knowledge
of how effective they are and how quickly they work are not yet available.
Inclusion body myositis has proven resistant to immunosuppressive medications.
The response has been so consistently poor and so easily contrasted with DM
that
the authors wonder why these conditions are so routinely lumped together in
chapters and review articles. Clearly, this is based solely on the common
pathologic feature of inflammation, rather than a clear understanding of how
these conditions occur, or why they do or do not respond to treatment.
PMID: 14759347 [PubMed - as supplied by publisher]
55: Muscle Nerve. 2004 Feb;29(2):261-6.
Overexpression of semicarbazide-sensitive amine oxidase in human myopathies.
Olive M, Unzeta M, Moreno D, Ferrer I.
Institut de Neuropatologia, Hospital Universitari de Bellvitge, 08907 Hospitalet
de Llobregat, Barcelona, Spain. 25169mop@comb.es
Oxidative stress has been implicated in the pathogenesis of several muscle
diseases. Semicarbazide-sensitive amine oxidase (SSAO) metabolizes oxidative
deamination of primary aromatic and aliphatic amines. In the oxidative
reactions, amine substrates are converted into the aldehyde, followed by the
production of ammonia and H(2)O(2). Although normal levels in muscle are very
low, SSAO is expressed in almost all mammalian tissues. In this study, we
examined the possible implication of SSAO as an additional source of oxidative
stress in the pathogenesis of muscle disorders. The expression of SSAO was
examined immunohistochemically in muscle biopsy specimens from patients with
inclusion-body myositis (IBM; n = 5), desmin-related myopathy (DRM; n = 3),
dermatomyositis (n = 3), granulomatous (sarcoid) myopathy (n = 2), muscle
denervation-reinnervation (n = 3), and rhabdomyolysis (n = 2), as well as from
control subjects (n = 3). Strong SSAO immunoreactivity was present in vacuolated
and nonvacuolated fibers in IBM, in abnormal fibers in DRM, and in degenerating
and regenerating fibers in dermatomyositis and rhabdomyolysis. In addition,
SSAO
overexpression was observed in muscle fibers adjacent to granulomas in sarcoid
myopathy. These results suggest that SSAO is a source of oxidative stress in
diseased human skeletal muscle and that it contributes to oxidative
stress-induced damage in various inflammatory and other myopathies.
Alternatively, the expression of SSAO in muscle fibers may be a consequence
of
muscle fiber injury.
PMID: 14755492 [PubMed - indexed for MEDLINE]
56: Immunol Allergy Clin North Am. 2003 Nov;23(4):699-712.
Aluminum inclusion macrophagic myofasciitis: a recently identified condition.
Gherardi RK, Authier FJ.
Muscle and Nerve Group, Henri Mondor University Hospital, Creteil, France.
lauret@univ-paris12.fr
The authors conclude that the persistence of aluminum hydroxide at the site
of
intramuscular injection is a novel finding which has an exact significance that
remains to be established fully. It seems mandatory to evaluate possible
long-term adverse effects induced by this compound, because this issue has not
been addressed (in the past, aluminum hydroxide was believed to be cleared
quickly from the body). If safety concerns about the long-term effects of
aluminum hydroxide are confirmed, novel and alternative vaccine adjuvants to
rescue vaccine-based strategies should be proposed to ensure the enormous
benefit for public health that these vaccines provide worldwide.
Publication Types:
Review
Review, Tutorial
PMID: 14753387 [PubMed - indexed for MEDLINE]
57: Arch Neurol. 2004 Jan;61(1):132-5.
Polymyositis: an ongoing discussion about a disease entity.
Bronner IM, Linssen WH, van der Meulen MF, Hoogendijk JE, de Visser M.
Department of Neurology, Sint Lucas Andreas Hospital, Jan Tooropstraat 164,
1061
AE Amsterdam, the Netherlands. i.bronner@slaz.nl
Since its first description more than a century ago, there has been much debate
about the diagnostic entity polymyositis. Because initial observations were
of
individuals with dermatomyositis, it appeared that polymyositis was not possible
without skin lesions. Distinctive clinical and histologic features of
polymyositis were not established until the late 20th century. The
identification of inclusion body myositis as a distinct entity has further
refined nosographic classification.
Publication Types:
Historical Article
PMID: 14732633 [PubMed - indexed for MEDLINE]
58: Acta Neuropathol (Berl). 2004 Mar;107(3):197-203. Epub 2004 Jan 08.
Coexistence of X-linked recessive Emery-Dreifuss muscular dystrophy with
inclusion body myositis-like morphology.
Fidzianska A, Rowinska-Marcinska K, Hausmanowa-Petrusewicz I.
Neuromuscular Unit, MRC, Polish Academy of Science, 1a Banacha Str., 02-097
Warsaw, Poland. neurmyol@cmdik.pan.pl
We reported three cases (two familial and one sporadic) of X-linked
Emery-Dreifuss muscular dystrophy (EDMD), genetically documented. Two patients
demonstrated a typical inclusion body myositis (IBM)-like morphology. The third
patient had only minor changes. Patients had elbow and ankle contractures,
progressive wasting of humeroperoneal muscles and cardiac failure (pacemaker
implantation in all). There was a mutation within the Xq28 gene and complete
absence of emerin in the nuclear membrane. Mononuclear cell infiltrations,
rimmed vacuoles, amyloid deposits, as well as cytoplasmic and nuclear
tubulofilamentous muscle inclusions were most unusual findings. Coexistence
of
IBM-like morphology and X-linked recessive EDMD might indicate that pathological
features of IBM are nonspecific and may be present in other neuromuscular
disorders.
PMID: 14712398 [PubMed - indexed for MEDLINE]
59: J Neurol Neurosurg Psychiatry. 2004 Jan;75(1):136-9.
Diagnostic value of MHC class I staining in idiopathic inflammatory myopathies.
van der Pas J, Hengstman GJ, ter Laak HJ, Borm GF, van Engelen BG.
Neuromuscular Centre, Institute of Neurology, University Medical Centre,
Nijmegen, Netherlands.
BACKGROUND: Identification of mononuclear cellular infiltrates in skeletal
muscle tissue is the histological cornerstone of the diagnosis of idiopathic
inflammatory myopathy (IIM). However, these infiltrates are not always present.
OBJECTIVE: To determine whether MHC class I antigen expression on the
sarcolemma, which is absent in normal muscle tissue, is upregulated in IIM and
could serve as an additional diagnostic test. METHODS: Expression of MHC class
I
antigens was studied in 224 muscle samples of 61 adult patients with IIM (9
dermatomyositis, 23 polymyositis, 29 inclusion body myositis) and 163 controls
(normal subjects and patients with various neuromuscular disorders) in a
prospective blinded manner. RESULTS: The sensitivity of the test for diagnosing
IIM was 78% (95% confidence interval (CI), 66% to 88%), with a specificity of
95% (91% to 98%). The sensitivity before the start of immunosuppressive
treatment was 89% (76% to 96%). The sensitivity was not changed by including
all
patients who had been on immunosuppressive treatment for less than four weeks
before muscle biopsy (sensitivity 90% (79% to 97%)). False positive results
were
found in only seven controls (4%), six of whom had a muscular dystrophy.
CONCLUSIONS: Detection of sarcolemmal MHC class I is a valid test for IIM. It
is
not affected by the short term use of immunosuppressive agents (less than four
weeks) and it should be incorporated in the histological evaluation when the
diagnosis of IIM is under consideration or needs to be excluded.
Publication Types:
Clinical Trial
PMID: 14707323 [PubMed - indexed for MEDLINE]
60: Ann Neurol. 2004 Jan;55(1):121-5.
Creutzfeldt-Jakob disease and inclusion body myositis: abundant
disease-associated prion protein in muscle.
Kovacs GG, Lindeck-Pozza E, Chimelli L, Araujo AQ, Gabbai AA, Strobel T, Glatzel
M, Aguzzi A, Budka H.
Institute of Neurology, University of Vienna, and Austrian Reference Centre
for
Human Prion Diseases, Vienna, Austria.
Pathologicalprion protein (PrP(Sc)) is the hallmark of prion diseases affecting
primarily the central nervous system. Using immunohistochemistry,
paraffin-embedded tissue blot, and Western blot, we demonstrated abundant
PrP(Sc) in the muscle of a patient with sporadic Creutzfeldt-Jakob disease and
inclusion body myositis. Extraneural PrP(C)-PrP(Sc) conversion in
Creutzfeldt-Jakob disease appears to become prominent when PrP(C) is abundantly
available as substrate, as in inclusion body myositis muscle.
Publication Types:
Case Reports
PMID: 14705121 [PubMed - indexed for MEDLINE]
61: Am J Pathol. 2004 Jan;164(1):1-7.
Endoplasmic reticulum stress and unfolded protein response in inclusion body
myositis muscle.
Vattemi G, Engel WK, McFerrin J, Askanas V.
Department of Neurology, University of Southern California Neuromuscular Center,
University of Southern California Keck School of Medicine, Good Samaritan
Hospital, Los Angeles, California 90017-1912, USA.
Proteins in the endoplasmic reticulum (ER) require an efficient system of
molecular chaperones whose role is to assure their proper folding and to prevent
accumulation of unfolded proteins. The response of cells to accumulation of
unfolded proteins in the ER is termed "unfolded protein response"
(UPR). UPR is
a functional mechanism by which cells attempt to protect themselves against
ER
stress, resulting from the accumulation of the unfolded/misfolded proteins.
Because intracellular inclusions, containing either amyloid-beta (Abeta) or
phosphorylated tau, are the characteristic feature of sporadic inclusion body
myositis (s-IBM) muscle biopsies, we studied expression and immunolocalization
of five ER chaperones, calnexin, calreticulin, GRP94, BiP/GRP78, and ERp72,
in
s-IBM and control muscle biopsies. Physical interaction of the ER chaperones
with amyloid-beta precursor protein (AbetaPP) was studied by a combined
immunoprecipitation/immunoblotting technique in s-IBM and control muscle
biopsies, and in AbetaPP-overexpressing cultured human muscle fibers. In all
s-IBM muscle biopsies, all five of the ER chaperones were immunodetected in
the
form of inclusions that co-localized with amyloid-beta. By immunoblotting,
expression of ER chaperones was greatly increased as compared to the controls.
By immunoprecipitation/immunoblotting experiments, ER chaperones
co-immunoprecipitated with AbetaPP. Our studies provide evidence of the UPR
in
s-IBM muscle and demonstrate for the first time that the ER chaperones calnexin,
calreticulin, GRP94, BiP/GRP78, and ERp72 physically associate with AbetaPP
in
s-IBM muscle, suggesting their playing a role in AbetaPP folding and processing.
PMID: 14695312 [PubMed - indexed for MEDLINE]
62: Neuromuscul Disord. 2003 Dec;13(10):830-4.
A novel homozygous missense mutation in the GNE gene of a patient with
quadriceps-sparing hereditary inclusion body myopathy associated with muscle
inflammation.
Krause S, Schlotter-Weigel B, Walter MC, Najmabadi H, Wiendl H, Muller-Hocker
J,
Muller-Felber W, Pongratz D, Lochmuller H.
Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians
University, Munich, Germany.
An adult-onset hereditary inclusion body myopathy with sparing of the quadriceps
muscle was originally described in Iranian Jews and assigned to a locus on
chromosome 9p12-p13. Recently, mutations of the
UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene were
reported to cause hereditary inclusion body myopathy and one type of distal
myopathy in a world-wide distribution. Importantly, the lack of muscle
inflammation was used to distinguish hereditary inclusion body myopathy from
the
sporadic form of inclusion body myopathy. We report a case of a
quadriceps-sparing myopathy in a non-Jewish, Iranian patient with a high degree
of muscle inflammation. A novel homozygous G-to-A mutation (128933G-->A)
in exon
7 changing a valine to isoleucine (V367I) in the epimerase domain of the GNE
gene was found. We conclude that muscle inflammation is not sufficient to
exclude the diagnosis of hereditary inclusion body myopathy.
Publication Types:
Case Reports
PMID: 14678807 [PubMed - indexed for MEDLINE]
63: J Neurol. 2003 Nov;250(11):1313-7.
Analysis of HLA class I and II alleles in sporadic inclusion-body myositis.
Lampe JB, Gossrau G, Kempe A, Fussel M, Schwurack K, Schroder R, Krause S,
Kohnen R, Walter MC, Reichmann H, Lochmuller H.
Klinik fur Neurologie, Technische Universitat Dresden, Fetscherstrasse 74,
01307, Dresden, Germany. johannes.lampe@schering.de
Sporadic inclusion body myositis (s-IBM) is characterised by progressive
weakness of proximal and distal limb muscles. Most patients are aged over 50
years at disease onset. Muscle biopsy reveals an inflammatory myopathy and
cytoplasmic amyloid deposits. The mononuclear infiltrate is dominated by CD8+
T-cells. Several investigators have described associations between s-IBM and
certain HLA antigens and alleles. However, to date neither HLA class I nor II
alleles have been analysed in a large series of patients. We typed various HLA
class I and II alleles in 47 patients suffering from s-IBM using sequence
specific-primer pairs (SSPPCR). The results were compared with published German
controls. Additional Bonferroni adjustment was performed over all allele groups
corresponding to serologically defined antigens within one HLA class I or II
locus. After Bonferroni adjustment, we found a significant increase in frequency
of the following HLA alleles for s-IBM patients when compared with normal
controls: A*03 (p = 0.0002), B*08 (p = 0.002), DRB1*03 (p = 0.0000002), and
DQB1*05 (p = 0.02). HLA typing may be helpful to distinguish between subgroups
of s-IBM patients. Moreover, HLA analysis may aid in identifying patients who
might profit from future therapeutic strategies.
PMID: 14648147 [PubMed - indexed for MEDLINE]
64: Lancet. 2003 Nov 22;362(9397):1762-3; author reply 1763.
Comment on:
Lancet. 2003 Sep 20;362(9388):971-82.
Diagnostic criteria for polymyositis and dermatomyositis.
Miller FW, Rider LG, Plotz PH, Isenberg DA, Oddis CV.
Publication Types:
Comment
Letter
PMID: 14643132 [PubMed - indexed for MEDLINE]
65: Muscle Nerve. 2003 Dec;28(6):659-82.
Cytokines, chemokines, and cell adhesion molecules in inflammatory myopathies.
Figarella-Branger D, Civatte M, Bartoli C, Pellissier JF.
Laboratoire de Biopathologie Nerveuse et Musculaire (EA 3281), Faculte de
Medecine Timone, Universite de la Mediterranee, 27 Boulevard Jean Moulin, 13385
Marseille, France. Dominique.Figarella-Branger@medecine.univ-mrs.fr
The inflammatory myopathies include dermatomyositis (DM), polymyositis (PM),
and
sporadic inclusion-body myositis (s-IBM). In DM, the main immune effector
response appears to be humoral and directed against the microvasculature,
whereas in both PM and s-IBM, cytotoxic CD8+ T cells and macrophages invade
and
eventually destroy nonnecrotic muscle fibers expressing major histocompatibility
complex class I. The need for more specific and safer therapies in inflammatory
myopathies has prompted researchers to better decipher the molecular events
associated with inflammation and muscle fiber loss in these diseases. The
complex specific migration of leukocyte subsets to target tissues requires a
coordinated series of events, namely activation of leukocytes, adhesion to the
vascular endothelium, and migration. Cell adhesion molecules (CAM) and
chemokines play a major role in this multistep process. In addition, cytokines
by stimulating CAM expression and orchestrating T-cell differentiation also
influence the immune response. This review focuses on recent advances in
defining the molecular events involved in leukocyte trafficking in inflammatory
myopathies. Specific topics include a concise summary of clinical features,
pathological findings and immunopathology observed in inflammatory myopathies,
background information about cytokines, chemokines and cell adhesion molecules,
and the expression of these molecules in inflammatory myopathies.
Publication Types:
Review
PMID: 14639580 [PubMed - indexed for MEDLINE]
66: Eur Neurol. 2004;51(1):10-4. Epub 2003 Nov 18.
Increase in transglutaminase 2 in idiopathic inflammatory myopathies.
Choi YC, Kim TS, Kim SY.
Department of Neurology, Brain Korea 21 Project for Medicine, Yonsei University,
College of Medicine, Seoul, Republic of Korea. ycchoi@yumc.yonsei.ac.kr
Idiopathic inflammatory myopathies (IMs), including dermatomyositis (DM),
polymyositis (PM), and sporadic inclusion body myositis (s-IBM), are
characterized by inflammatory cell infiltration in muscle tissue and muscle
fiber destruction, which leads to muscle weakness. Although the cause of IMs
is
unclear, an autoimmune pathogenesis may be involved in initiating the muscle
inflammation. Recently, we have found an aberrant expression of transglutaminase
2 (TGase 2) in s-IBM, which is closely associated with insoluble inclusion body
formation. TGase 2 is a cross-linking enzyme that generates a conformational
change of molecules via a covalent isopeptide bond. The increase in the level
of
TGase 2 expression and the inappropriate presentation of substrates/cross-linked
aggregates to the immune system may contribute to the autoimmune aspects of
IMs.
We investigated whether or not an increase in TGase 2 expression is a common
factor in muscle inflammation. Duchenne muscular dystrophy (DMD) and normal
tissues were employed as controls. Using immunocytochemistry and quantitative
RT-PCR, the level of TGase 2 expression was found to be specifically increased
in PM and DM, but not in DMD and normal controls. Therefore, the targeting of
TGase inhibition in IMs will be a challenging therapeutic approach that should
be investigated in the near future. Copyright 2004 S. Karger AG, Basel
PMID: 14631123 [PubMed - indexed for MEDLINE]
67: Intern Med. 2003 Oct;42(10):1035-8.
Comment in:
Intern Med. 2003 Oct;42(10):928-9.
Familial inclusion body myositis: a report on two Japanese sisters.
Tateyama M, Saito N, Fujihara K, Shiga Y, Takeda A, Narikawa K, Hasegawa T,
Taguchi Y, Sakuma R, Onodera Y, Ohnuma A, Tobita M, Itoyama Y.
Department of Neurology, Tohoku University School of Medicine, Sendai.
Familial occurrence of inclusion body myositis is extremely rare, and only
a few
cases in Western countries have been reported. In these reports, a strong
association of this disease with DR3 (DRB1*0301/0302) and the efficacy of
immunosuppressants suggested that an immune pathomechanism is involved in the
disease. We, for the first time, report two Japanese sisters who suffered
myopathy clinicopathologically similar to inclusion body myositis. One sister
received corticosteroid and azathioprine and the therapy relieved dysphagia.
Both of our patients had DR15(2)/4 (DRB1*1502/0405), suggesting a distinct
genetic association with the disease in the Japanese population.
Publication Types:
Case Reports
PMID: 14606722 [PubMed - indexed for MEDLINE]
68: Intern Med. 2003 Oct;42(10):928-9.
Comment on:
Intern Med. 2003 Oct;42(10):1035-8.
The familial occurrence may give a clue to the pathogenesis of inclusion body
myositis.
Mizusawa H.
Publication Types:
Comment
Editorial
PMID: 14606702 [PubMed - indexed for MEDLINE]
69: Neurol Sci. 2003 Oct;24 Suppl 4:S256-9.
High-dose intravenous immunoglobulin in inflammatory myopathies: experience
based on controlled clinical trials.
Dalakas MC.
Neuromuscular Diseases, Section National Institute of Neurological Disorders
and
Stroke National Institutes of Health, Bethesda, MD 20892-1382, USA.
Controlled clinical trials with high-dose intravenous immunoglobulin (IVIg)
have
been conducted in patients with DM and IBM, but not PM. A double-blind
placebo-controlled study in DM patients, resistant or partially responsive to
conventional therapies, showed that IVIg is very effective in improving both
the
muscle strength and the skin rash. The clinical benefit, which was impressive
in
patients with early disease, was associated with improvement in the muscle
cytoarchitecture. Quantitative histological studies in repeated muscle biopsies
showed a statistically significant increased in the size of muscle fibers and
the number of capillaries with normalization of the capillary diameter.
Resolution of the aberrant immunopathological parameters including interception
of complement activation products and downregulation of T cells, ICAM-I, VCAM,
TGF-beta and MHC-I molecules was also noted. In IBM, IVIg showed marginal, and
non statistically significant, improvements in muscle strength. Up to 20% of
patients however, demonstrated clinical improvement with increased activities
of
daily living while certain muscle groups, such as the muscles of swallowing,
showed significant improvements compared to placebo implying mild regional
benefits. In PM, small uncontrolled series have shown improvements in muscle
strength in up to 70% of the IVIg-treated patients. Because PM, as a stand-alone
clinical entity, is a very rare disease, completion of controlled trials will
be
very difficult.
Publication Types:
Review
Review, Tutorial
PMID: 14598055 [PubMed - indexed for MEDLINE]
70: Clin Rheumatol. 2003 Oct;22(4-5):324-8.
Inclusion body myositis in connective tissue disorders: case report and review
of the literature.
Derk CT, Vivino FB, Kenyon L, Mandel S.
Thomas Jefferson University Hospital, Pennsylvania, Philadelphia, USA.
chris.derk@mail.tju.edu
We report a patient with systemic lupus erythematosus (SLE) and secondary
Sjogren's syndrome (SS) who developed inclusion body myositis (IBM) which,
contrary to the typical presentation of this disorder, was symmetrical in nature
although the diagnosis was only made after electron microscopy was performed.
Therapy with increased doses of methotrexate proved to be beneficial, with the
patient having full recovery after 8 months of therapy. It appears that a subset
of IBM may be related to autoimmune disorders, an issue that was disputed in
the
past, and these patients may have a better prognosis than typical IBM patients.
This is the first case report of IBM in a patient who had the dual diagnosis
of
SLE and SS.
Publication Types:
Case Reports
Review
Review of Reported Cases
PMID: 14576992 [PubMed - indexed for MEDLINE]
71: Curr Opin Rheumatol. 2003 Nov;15(6):737-44.
Proposed pathogenetic cascade of inclusion-body myositis: importance of
amyloid-beta, misfolded proteins, predisposing genes, and aging.
Askanas V, Engel WK.
Department of Neurology, University of Southern California, Keck School of
Medicine, Good Samaritan Hospital, Los Angeles, California 90017-1912, USA.
askanas@hsc.usc.edu
PURPOSE OF REVIEW: Sporadic inclusion-body myositis, the most common muscle
disease of older persons, is of unknown cause, and there is no successful
treatment. Interest in sporadic inclusion-body myositis has been enhanced by
the
recent identification within the sporadic inclusion-body myositis muscle fibers
of several abnormally accumulated proteins, which provides novel and important
clues to the pathogenesis of sporadic inclusion-body myositis. RECENT FINDINGS:
This article summarizes the most recent findings leading to better understanding
of the players in the pathogenetic cascade. It is suggested that lymphocytic
inflammatory component is probably secondary, and it may contribute only
slightly to muscle fiber damage in sporadic inclusion-body myositis. However,
it
is proposed that the identified abnormal accumulation, aggregation, and
misfolding of proteins, combined with and perhaps provoked by an aging
intracellular milieu, more essentially lead to the vacuolar degeneration and
atrophy of the muscle fibers that are specific to sporadic inclusion-body
myositis. Abnormal accumulations of the amyloid-beta precursor protein and of
its proteolytic fragment, amyloid-beta, associated with the aging cellular
muscle fiber environment, appear to be key pathogenic events. SUMMARY: In
conceptualizing a treatment for sporadic inclusion-body myositis, the
accumulations of amyloid-beta42 and other unfolded proteins are now phenomena
to
be reckoned with. One would like to stop intracellular increase of the
unfolded/misfolded proteins by reducing their formation and/or increasing their
disposal. In addition, the identification of factors that would decrease
intra-muscle fiber expressions of beta- and gamma-secretases might lead to
decreased production of putatively myotoxic oligomeric amyloid-beta42. Better
understanding of the mechanisms and consequences of genes that predispose to
sporadic inclusion-body myositis, and of human muscle fiber aging, could also
provide new avenues toward the therapy of sporadic inclusion-body myositis.
How
to therapeutically capitalize on the new findings is now the challenge.
Publication Types:
Review
Review, Tutorial
PMID: 14569203 [PubMed - indexed for MEDLINE]
72: Curr Opin Rheumatol. 2003 Nov;15(6):679-90.
Physical activity and disablement in the idiopathic inflammatory myopathies.
Harris-Love MO.
Rehabilitation Medicine Department, National Institute of Health, Bethesda,
MD
20892, USA. mlove@nih.gov
PURPOSE OF REVIEW: The sequelae associated with idiopathic inflammatory myopathy
(IIM) often result in disability and decreased quality of life. Our
understanding of how exercise mitigates disability may be facilitated through
the use of a conceptual model. This review describes the enablement-disablement
model applied to myositis and explores the role of physical activity in the
enablement process. RECENT FINDINGS: National and international organizations
have revised their disablement models by acknowledging disability as a
relational concept, refining the relationship of disability to quality of life,
and incorporating the role of intervention through the enablement process.
Disability associated with IIM may be complicated by aging-related comorbidities
and decreased physical activity. However, data indicate that both short-term
and
long-term aerobic training results in improved aerobic capacity and decreased
disability in adults with IIM. Strengthening regimens have also resulted in
decreased functional limitations and disability for adults with polymyositis
and
dermatomyositis. While comprehensive exercise programs have not been shown to
exacerbate disease activity or damage in people with IIM, their effectiveness
for individuals with inclusion body myositis (IBM) remains uncertain. SUMMARY:
Physical activity constitutes a valuable enablement strategy that can reduce
disability in adults with IIM. Use of the disablement-enablement model and ICF
taxonomy in conjunction with outcomes across disablement domains may augment
further investigation of the effectiveness of exercise interventions. Additional
research is needed to better understand the relationship between disease
severity and optimal exercise dosage, the effects of long-term exercise in
children with IIM, and the physiologic response to exercise in people with IBM.
Publication Types:
Review
Review, Tutorial
PMID: 14569196 [PubMed - indexed for MEDLINE]
73: Eur Neurol. 2003;50(3):172-5.
Therapy with intravenous immunoglobulins: complications and side-effects.
Wittstock M, Benecke R, Zettl UK.
Department of Neurology, University of Rostock, Rostock, Germany.
matthias.wittstock@med.uni-rostock.de
Therapy with intravenous immunoglobulins (IVIG) is thought to be a safe
treatment for a number of immune-mediated neurological diseases. Published data
about prevalence of adverse effects range from 11 to 81%. The purpose of our
study was to present a representative view on adverse effects by analysis of
a
large cohort of patients treated by IVIG. In a prospective study, we analysed
117 patients (age 17-79 years) who were treated with IVIG for various
neurological diseases including chronic inflammatory demyelinating
polyneuropathy, diabetic amyotrophy, inclusion body myositis, multiple
sclerosis, Guillain-Barre syndrome, Miller-Fisher syndrome, multifocal motor
neuropathy, myasthenia gravis and polymyositis. IVIG therapy was applied at
a
dose of 0.4 g/kg body weight/day in a total of 408 therapy courses. 42.7% showed
adverse events. The majority of patients presented with minor adverse effects,
mostly asymptomatic laboratory changes. Rash or mild headache occurred in 8
patients, especially when IVIG was given with infusion flow higher than 10 g/h.
Two patients showed a severe complication with deep vein thrombosis. In summary,
beside its effectiveness in immune mediated neurological diseases, therapy with
IVIG seems to be a safe therapy. Most patients show no or minor adverse effects.
Patients with pre-existent disorders like heart or renal insufficiency or
immobilised patients, however, may be at higher risk for complications.
Copyright 2003 S. Karger AG, Basel
PMID: 14530624 [PubMed - indexed for MEDLINE]
74: Acta Neuropathol (Berl). 2004 Jan;107(1):59-65. Epub 2003 Sep 26.
Expression of lysosome-related proteins and genes in the skeletal muscles of
inclusion body myositis.
Kumamoto T, Ueyama H, Tsumura H, Toyoshima I, Tsuda T.
Division of Neurology and Neuromuscular Disorders, Department of Immunology
and
Allergy, Oita Medical University, Idaigaoka 1-1, Hasama, 879-5593, Oita, Japan.
kumagoro@oita-med.ac.jp
Despite the unknown etiology and pathogenesis of sporadic inclusion body
myositis (s-IBM), investigators have speculated that the lysosome system in
muscle fiber plays a central role in rimmed vacuole formation, a hallmark of
s-IBM. We explored the role of receptor-mediated intracellular transport and
autophagy in the lysosomal system in the abnormal accumulation of rimmed
vacuoles in s-IBM. Expressions of mannose 6-phosphate receptor (M6PR), clathrin
and hApg5 and hApg12 were analyzed in muscle biopsy specimens from patients
with
s-IBM, amyotrophic lateral sclerosis (ALS) or peripheral neuropathy and in
normal human muscle specimens by means of immunohistochemistry and reverse
transcriptase-polymerase chain reaction (RT-PCR). Most muscle fibers in control
specimens showed little or no immunoreactivity for clathrin and M6PR, which
are
involved in the receptor-mediated intracellular transport. Abnormal increases
in
both proteins were observed mainly in the sarcoplasm of atrophic fibers in all
diseased specimens. In s-IBM muscles in particular, clathrin and M6PR were often
observed inside rimmed vacuoles and in the sarcoplasm of vacuolated or
non-vacuolated fibers. mRNA levels of hApg5 and hApg12, which are involved in
autophagic vacuole formation, as well as of M6PR and clathrin were significantly
increased in s-IBM muscles in comparison to levels in normal and ALS/peripheral
neuropathy muscles. Our results suggest that the transport of newly synthesized
lysosomal enzymes from the secretory pathway via the trans-Golgi network of
the
Golgi apparatus and autophagic vacuole formation (i.e., autophagy) in the
lysosome system are activated in s-IBM muscles. Remarkable accumulation of
rimmed vacuoles is thought to occur because of abnormal lysosome function,
especially the formation or turnover of autolysosomes after the fusion of
autophagic vacuoles with the early endosomes or because of the increase in the
rate of muscle fiber breakdown.
PMID: 14513262 [PubMed - indexed for MEDLINE]
75: Lancet. 2003 Sep 20;362(9388):971-82.
Comment in:
Lancet. 2003 Nov 22;362(9397):1762-3; author reply 1763.
Polymyositis and dermatomyositis.
Dalakas MC, Hohlfeld R.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Bethesda, MD 20892-1382, USA.
dalakasm@ninds.nih.gov
The inflammatory myopathies, commonly described as idiopathic, are the largest
group of acquired and potentially treatable myopathies. On the basis of unique
clinical, histopathological, immunological, and demographic features, they can
be differentiated into three major and distinct subsets: dermatomyositis,
polymyositis, and inclusion-body myositis. Use of new diagnostic criteria is
essential to discriminate between them and to exclude other disorders.
Dermatomyositis is a microangiopathy affecting skin and muscle; activation and
deposition of complement causes lysis of endomysial capillaries and muscle
ischaemia. In polymyositis and inclusion-body myositis, clonally expanded
CD8-positive cytotoxic T cells invade muscle fibres that express MHC class I
antigens, which leads to fibre necrosis via the perforin pathway. In
inclusion-body myositis, vacuolar formation with amyloid deposits coexists with
the immunological features. The causative autoantigen has not yet been
identified. Upregulated vascular-cell adhesion molecule, intercellular adhesion
molecule, chemokines, and their receptors promote T-cell transgression, and
various cytokines increase the immunopathological process. Early initiation
of
therapy is essential, since both polymyositis and dermatomyositis respond to
immunotherapeutic agents. New immunomodulatory agents currently being tested
in
controlled trials may prove promising for difficult cases.
Publication Types:
Review
PMID: 14511932 [PubMed - indexed for MEDLINE]
76: Curr Opin Neurol. 2003 Oct;16(5):569-75.
Treatment of idiopathic inflammatory myopathies.
Amato AA, Griggs RC.
Department of Neurology, Brigham and Women's Hospital and Harvard Medical
School, Boston, Massachusetts 02115, USA. aamato@partners.org
PURPOSE OF REVIEW: This article reviews the results of recent therapeutic trials
in dermatomyositis, polymyositis, and inclusion body myositis and suggests an
approach to treating patients with inflammatory myopathy. RECENT FINDINGS: We
reviewed 10 double-blind, placebo-controlled therapeutic trials in patients
with
inflammatory myopathy. Only one, using intravenous immunoglobulin in refractory
dermatomyositis, indicated benefit. A brief trial of azathioprine in
polymyositis and eight studies using various treatments in inclusion body
myositis did not show benefit. SUMMARY: There have been no adequate
double-blind, placebo-controlled therapeutic trials of dermatomyositis and
polymyositis. It is generally accepted, however, that these disorders respond
to
immunosuppressive agents. Prednisone is usually the initial treatment. There
is
no agreement on how prednisone should be administered and even less agreement
about other agents. Inclusion body myositis, which now appears to be the most
common (in adults), is unresponsive to immunosuppressive and immunomodulating
therapies. There are candidate treatments for inclusion body myositis and a
need
for additional double-blind, placebo-controlled therapeutic trials in all
patients with inflammatory myopathy.
Publication Types:
Review
Review, Tutorial
PMID: 14501840 [PubMed - indexed for MEDLINE]
77: J Neuroimmunol. 2003 Aug;141(1-2):125-31.
Expression of IFN-gamma-inducible chemokines in inclusion body myositis.
Raju R, Vasconcelos O, Granger R, Dalakas MC.
National Institute of Neurological Disorders and Stroke, National Institutes
of
Health, Bethesda, MD 20892-1382, USA.
Because IFN-gamma-inducible chemokines, Mig (CXCL9), IP-10 (CXCL10), I-TAC
(CXCL11) and their receptor, CXCR3, are critical molecules in T cell trafficking
and generation of effector T cells, we examined their expression in the muscle
biopsies of patients with sporadic inclusion body myositis (s-IBM) and disease
controls. The functional role of these molecules was also studied by examining
the effect and time kinetics of IFN-gamma in inducing Mig and IP-10 expression
in human myotubes in vitro. We found significantly high levels of Mig and IP-10
mRNA expression in s-IBM muscles compared to controls. IFN-gamma upregulated
the
mRNA expression of Mig and IP-10 by human myotubes in a dose-dependent manner.
By double-label immunohistochemistry, Mig was expressed on a subset of CD8(+)
cells and the areas of the muscle fiber in contact or contiguous to the T cells;
CXCR3 was expressed only on a subset of the autoinvasive CD8(+) T cells but
not
the myofibers. IP-10 and I-TAC were not detected by immunocytochemistry. The
findings indicate that in s-IBM, IFN-gamma is involved in the upregulation and
in situ production of proinflammatory chemokines, which, in turn, participate
in
the recruitment of activated T cells and contribute to the self-sustaining
nature of endomysial inflammation.
PMID: 12965263 [PubMed - indexed for MEDLINE]
78: South Med J. 2003 Jul;96(7):721-3.
Inclusion body myositis associated with celiac sprue and idiopathic
thrombocytopenic purpura.
Williams SF, Mincey BA, Calamia KT.
Division of General Internal Medicine, Mayo Clinic Jacksonville, Jacksonville,
FL 32224, USA.
We report an unusual case of a 51-year-old woman with inclusion body myositis
associated with celiac sprue and idiopathic thrombocytopenic purpura. We propose
that the presence of all three disorders together suggests that they may share
an interrelated immune mechanism.
Publication Types:
Case Reports
PMID: 12940332 [PubMed - indexed for MEDLINE]
79: Am J Pathol. 2003 Sep;163(3):947-56.
Erratum in:
Am J Pathol. 2003 Dec;163(6):2645.
Expression of calcium-binding proteins MRP8 and MRP14 in inflammatory muscle
diseases.
Seeliger S, Vogl T, Engels IH, Schroder JM, Sorg C, Sunderkotter C, Roth J.
Institute of Experimental Dermatology, Department of Pediatrics, University
Hospital, Aachen, Germany.
The pathophysiological role of infiltrating macrophages and their subtypes
in
idiopathic inflammatory myopathies such as dermatomyositis, polymyositis, and
inclusion body myositis is not fully clear. Monocytes exhibit various phenotypes
with different functional properties such as release of pro- or
anti-inflammatory mediators. Expression of myeloid-related proteins MRP8 and
MRP14, two calcium-binding S100-proteins, characterizes a proinflammatory
subtype of macrophages. We immunohistochemically investigated expression of
MRP8
and MRP14 in muscle biopsies of 33 patients with dermatomyositis, polymyositis,
and inclusion body myositis. We found a clear association of expression of MRP8
and MRP14 by infiltrating macrophages with degeneration of myofibers. Because
MRP8 and MRP14 are secreted by activated macrophages we investigated if these
proteins would have direct extracellular effects on myocytes. We found that
the
purified MRP8/MRP14 complex inhibited proliferation and differentiation of C2C12
myoblasts and that it induced apoptosis via activation of caspase-3 in a time-
and dose-dependent manner. These results indicate that in the course of
inflammatory myopathies, activated macrophages can promote destruction and
impair regeneration of myocytes via secretion of MRP8/MRP14.
PMID: 12937135 [PubMed - indexed for MEDLINE]
80: FASEB J. 2003 Oct;17(13):1892-4. Epub 2003 Aug 15.
Human muscle cells express a B7-related molecule, B7-H1, with strong negative
immune regulatory potential: a novel mechanism of counterbalancing the immune
attack in idiopathic inflammatory myopathies.
Wiendl H, Mitsdoerffer M, Schneider D, Chen L, Lochmuller H, Melms A, Weller M.
Department of Neurology, University of Tubingen, Medical School, D-72076
Tubingen, Germany. heinz.wiendl@uni-tuebingen.de
B7-H1 is a novel B7 family protein attributed to costimulatory and immune
regulatory functions. Here we report that human myoblasts cultured from control
subjects and patients with inflammatory myopathies as well as TE671 muscle
rhabdomyosarcoma cells express high levels of B7-H1 after stimulation with the
inflammatory cytokine IFN-gamma. Coculture experiments of MHC class
I/II-positive myoblasts with CD4 and CD8 T cells in the presence of antigen
demonstrated the functional consequences of muscle-related B7-H1 expression:
production of inflammatory cytokines, IFN-gamma and IL-2, by CD4 as well CD8
T
cells was markedly enhanced in the presence of a neutralizing anti-B7-H1
antibody. This observation was paralleled by an augmented expression of the
T
cell activation markers CD25, ICOS, and CD69, thus showing B7-H1-mediated
inhibition of T cell activation. Further, we investigated 23 muscle biopsy
specimens from patients with polymyositis (PM), inclusion body myositis (IBM),
dermatomyositis (DM), and nonmyopathic controls for B7-H1 expression by
immunohistochemistry: B7-H1 was expressed in PM, IBM, and DM specimens but not
in noninflammatory and nonmyopathic controls. Staining was predominantly
localized to areas of strong inflammation and to muscle cells as well as
mononuclear cells. These data highlight the immune regulatory properties of
muscle cells and suggest that B7-H1 expression represents an inhibitory
mechanism induced upon inflammatory stimuli and aimed at protecting muscle
fibers from immune aggression.
PMID: 12923066 [PubMed - indexed for MEDLINE]
81: Neuromuscul Disord. 2003 Sep;13(7-8):559-67.
Clinical and genetic heterogeneity in chromosome 9p associated hereditary
inclusion body myopathy: exclusion of GNE and three other candidate genes.
Watts GD, Thorne M, Kovach MJ, Pestronk A, Kimonis VE.
Division of Genetics and Metabolism, Children's Hospital, Harvard Medical
School, 300 Longwood Avenue, Fegan 5, Boston, MA 02115, USA.
We have previously reported a new autosomal dominant inclusion body myopathy
clinically resembling limb girdle muscular dystrophy, associated with Paget
disease of bone in the majority and frontotemporal dementia in a third of
individuals. The critical locus for this unique disorder now termed IBMPFD is
9
p21.1-p12, spans 5.5 Mb and contains the gene responsible for the recessive
quadriceps-sparing inclusion body myopathy (IBM2). Mutation analysis of the
GNE
gene associated with IBM2 in affected individuals from four IBMPFD families
did
not identify any mutations, indicating that the two disorders are not allelic.
Expression studies indicate that GNE has a tissue-specific splice pattern, with
four splice variants. Mutation analysis in three other candidate genes
(beta-tropomyosin, NDUFB6 and SMU1) did not identify any mutations.
PMID: 12921793 [PubMed - indexed for MEDLINE]
82: J Rheumatol. 2003 Aug;30(8):1892.
Comment on:
J Rheumatol. 2002 Sep;29(9):1897-906.
Magnetic resonance imaging criteria to differentiate inclusion body myositis
from
polymyositis.
Hengstman GJ.
Publication Types:
Comment
Letter
PMID: 12913890 [PubMed - indexed for MEDLINE]
83: Neurology. 2003 Aug 12;61(3):322-6.
MAP kinase phosphatase-1 is induced in abnormal fibers in 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 investigate alterations in protein kinases and phosphatases that
regulate the activity of mitogen activated protein kinase (MAPK) in sporadic
inclusion body myositis (IBM). BACKGROUND: In vacuolated fibers in IBM, several
studies reported upregulation of the extracellular regulated kinase (ERK)
subclass of MAPK family. Whereas MAPK kinases (MKK) activate MAPK, MAPK
phosphatases (MKP) inactivate MAPK. MKP-1 is involved in muscle fiber
differentiation and it is downregulated during myotube formation. METHODS:
Immunolocalization of MKK1 through MKK4 and MKP-1 to MKP-3 was tested in muscle
specimens from 10 patients with IBM and controls. RESULTS: In IBM, strong and
focal deposits of MKP-1 were observed in vacuolated fibers. The MKP-1-positive
deposits were colocalized with ERK. MKP-2, MKP-3, and MKK were not associated
with vacuolated fibers. CONCLUSIONS: In IBM, MKP-1 is abnormally induced in
vacuolated fibers probably to inactivate ERK. Although direct activators other
than those tested in the current study might induce ERK, the absence of
activation of MKK suggests that the aggregation of ERK protein itself causes
the
seeming upregulation of the protein kinase in IBM. Like ERK and its nuclear
substrate, MKP-1 is an enzyme that forms aggregates in vacuolated fibers and
is
involved in myogenesis.
PMID: 12913191 [PubMed - indexed for MEDLINE]
84: Neurology. 2003 Aug 12;61(3):316-21.
Comment in:
Neurology. 2003 Aug 12;61(3):288-9.
Neurology. 2004 Jul 27;63(2):402-3; author reply 403.
Neurology. 2004 Jul 27;63(2):402; author reply 403.
Neurology. 2004 Jul 27;63(2):402; author reply 403.
Polymyositis: an overdiagnosed entity.
van der Meulen MF, Bronner IM, Hoogendijk JE, Burger H, van Venrooij WJ, Voskuyl
AE, Dinant HJ, Linssen WH, Wokke JH, de Visser M.
Rudolf Magnus Institute of Neuroscience, Department of Neurology, University
Medical Center, Utrecht, The Netherlands. M.F.G.vdMeulen@neuro.azu.nl
BACKGROUND: According to widely used criteria (Bohan and Peter criteria, 1975),
dermatomyositis (DM) is differentiated from polymyositis (PM) only by skin
changes. More recent criteria also include histopathologic characteristics
enabling the distinction between PM and DM and the differentiation of sporadic
inclusion body myositis (s-IBM) from PM. The authors investigated the
applicability of diagnostic features for diagnosing PM and DM. METHODS: The
authors performed a retrospective follow-up study of 165 patients with 1) a
previous diagnosis of myositis; 2) subacute onset of symmetric, proximal
weakness; and 3) an evaluation between 1977 and 1998 excluding other
neuromuscular disorders. RESULTS: The diagnoses at initial evaluation based
on
clinical, laboratory, and histopathologic criteria were PM, 9 (5%); DM, 59 (36%;
54 isolated, 3 with associated connective tissue disease [CTD], 2 with
associated malignancy); unspecified myositis (perimysial/perivascular
infiltrates, no PM or DM), 65 (39%; 38 isolated myositis, 26 with associated
CTD, 1 with malignancy); and possible myositis (necrotizing myopathy, no
inflammatory infiltrates), 32 (19%; 29 isolated myositis, 3 with associated
CTD). At follow-up evaluation, five of the nine patients with PM had typical
s-IBM features. None of the remaining four patients complied with the assumed
typical signs of PM. Ten of the 38 patients with isolated unspecified myositis
had been diagnosed with a CTD. CONCLUSIONS: Polymyositis is an overdiagnosed
entity. At evaluation, more than half the patients with autoimmune myositis
cannot be specifically diagnosed with polymyositis or dermatomyositis. A quarter
of patients with isolated unspecified myositis subsequently developed connective
tissue disease.
PMID: 12913190 [PubMed - indexed for MEDLINE]
85: Neurology. 2003 Aug 12;61(3):288-9.
Comment in:
Neurology. 2004 Jul 27;63(2):403-4; author reply 404.
Comment on:
Neurology. 2003 Aug 12;61(3):316-21.
Neurology. 2003 Aug 12;61(3):384-6.
Unicorns, dragons, polymyositis, and other mythological beasts.
Amato AA, Griggs RC.
Publication Types:
Comment
Editorial
PMID: 12913184 [PubMed - indexed for MEDLINE]
86: Semin Neurol. 2003 Jun;23(2):199-206.
Therapeutic approaches in patients with inflammatory myopathies.
Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Building 10, Room 4N248, 10 Center Drive,
MSC 1382, Bethesda, MD 20892-1382, USA.
Among the group of inflammatory myopathies, dermatomyositis (DM) remains the
most treatable subset responding, in the majority of the cases, to steroids,
intravenous immunoglobulin (IVIg), or immunosuppressants. Inclusion-body
myositis (IBM) remains the most difficult disease to treat; in uncontrolled
studies immunosuppressants and steroids have not helped, and controlled trials
with IVIg have been disappointing. Polymyositis (PM) is a very uncommon,
although still overdiagnosed, disorder and its rarity poses difficulties in
performing large-scale therapeutic studies; based on small series, however,
PM
seems to variably respond to immunotherapeutic interventions. The most
consistent problem in the treatment of inflammatory myopathies remains the
distinction of true PM from the difficult-to-treat cases of IBM, or from
necrotizing myopathies and dystrophic processes where secondary endomysial
inflammation may be prominent. The future in the management of PM, DM, and IBM
seems promising because of the availability of new agents directed at T-cell
activation molecules, cytokines, chemokines, and adhesion receptors. In IBM,
the
use of such immunomodulatory drugs may be combined with agents that block
cytokine-enhancing amyloid or with agents that inhibit the formation and
polymerization of amyloid fibrils.
Publication Types:
Review
Review, Tutorial
PMID: 12894385 [PubMed - indexed for MEDLINE]
87: Neurology. 2003 Jul 22;61(2):260-2.
Anti-T-lymphocyte globulin treatment in inclusion body myositis: a randomized
pilot study.
Lindberg C, Trysberg E, Tarkowski A, Oldfors A.
Department of Neurology, Sahlgrenska University Hospital/Molndal, Sahlgrenska
NeuroMuscular Center, Gothenburg, Sweden. christopher.lindberg@vgregion.se
The authors performed an open, randomized trial in patients with inclusion
body
myositis comparing 1) 12-month treatment with oral methotrexate 7.5 mg/week
alone (MTX group) with 2) 12-month MTX treatment preceded by 7 days of IV
anti-T-lymphocyte immunoglobulin treatment (ATG group). Eleven patients were
randomized; 10 patients completed 12 months follow-up. Myometry showed that
patients in the ATG group (n = 6) increased in mean muscle strength by 1.4%
compared with the MTX group (n = 5), whose muscle strength decreased by 11.1%
(p
= 0.021).
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 12874415 [PubMed - indexed for MEDLINE]
88: Neurology. 2003 Jul 22;61(2):257-60.
Transthyretin Val122Ile, accumulated Abeta, and inclusion-body myositis aspects
in cultured muscle.
Askanas V, Engel WK, McFerrin J, Vattemi G.
USC Neuromuscular Center, Department of Neurology, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, Los Angeles
90017-1912, USA. askanas@hsc.usc.edu
Cultured muscle fibers (CMF) from a patient with inclusion-body myositis (IBM)
and cardiac amyloidosis associated with the transthyretin (TTR) Val122Ile
mutation contained aspects of the IBM phenotype: vacuolation, congophilic
inclusions, and clusters of immunocolocalizing amyloid beta-peptide (Abeta)
and
TTR accumulations. These abnormalities are never present in normal human CMF.
These perturbations were greatly increased after Abeta precursor protein gene
transfer. The TTR mutation may be a genetic predisposition factor for the
patient's IBM.
Publication Types:
Case Reports
PMID: 12874414 [PubMed - indexed for MEDLINE]
89: Rheumatology (Oxford). 2003 Aug;42(8):1016-8.
Anti-PM-Scl antibodies in a patient with inclusion body myositis.
Selva-O'Callaghan A, Mijares-Boeckh-Behrens T, Labrador-Horrillos M,
Solans-Laque R, Ma Grau-Junyent J, Vilardell-Tarres M.
Publication Types:
Case Reports
Letter
Review
Review of Reported Cases
PMID: 12869677 [PubMed - indexed for MEDLINE]
90: Rheumatology (Oxford). 2003 Aug;42(8):1012-4.
Inclusion body myositis evolving in systemic lupus erythrematosus? A case
report.
Massawi G, Hickling P, Hilton D, Patterson C.
Publication Types:
Case Reports
Letter
Review
Review of Reported Cases
PMID: 12869675 [PubMed - indexed for MEDLINE]
91: Scand J Immunol. 2003 Aug;58(2):195-200.
Inclusion body myositis: clonal expansions of muscle-infiltrating T cells
persist over time.
Muntzing K, Lindberg C, Moslemi AR, Oldfors A.
Department of Pathology, Sahlgrenska University Hospital, SE-413 45 Goteborg,
Sweden.
Inclusion body myositis (IBM) is a chronic inflammatory myopathy. The muscle
histology is characterized by infiltration of T cells, which invade and
apparently destroy muscle fibres. This study was performed to investigate
whether predominant clones of muscle-infiltrating T cells are identical in
different muscles and whether they persist over time in IBM. By reverse
transcriptase-polymerase chain reaction, 25 T-cell receptor (TCR) variable beta
(Vbeta) chain families and the complementarity-determining region 3 (CDR3) of
the TCR were analysed in two different muscle biopsies of four patients with
IBM. In two of the patients, the muscle biopsies were obtained from different
muscles at one time point, whereas in two patients, the second biopsy was
obtained 9 years after the first biopsy. T cells expressing predominant Vbeta
families were analysed for clonality by fragment length analysis of the CDR3.
Predominant Vbeta families were analysed by DNA sequencing to identify identical
clones. Immunohistochemical staining of Vbeta families was performed to study
the distribution of T cells expressing identified predominant Vbeta families.
The muscle-infiltrating lymphocytes showed restricted expression of TCR Vbeta
families. DNA sequencing proved that clonally expanded T cells were identical
in
different muscles and persisted 9 years after the first biopsy.
Immunohistochemical analysis with Vbeta family-specific antibodies demonstrated
the endomysial localization of these T cells in inflammatory cell infiltrates.
Our results show that in IBM there is clonal restriction of TCR expression in
muscle-infiltrating lymphocytes. Identical T-cell clones predominate in
different muscles, and these clones persist for many years. These results
indicate an important, continuous, antigen-driven inflammatory reaction in IBM.
PMID: 12869141 [PubMed - indexed for MEDLINE]
92: Rheumatology (Oxford). 2004 Jan;43(1):49-54. Epub 2003 Jul 16.
International consensus outcome measures for patients with idiopathic
inflammatory myopathies. Development and initial validation of myositis activity
and damage indices in patients with adult onset disease.
Isenberg DA, Allen E, Farewell V, Ehrenstein MR, Hanna MG, Lundberg IE, Oddis
C,
Pilkington C, Plotz P, Scott D, Vencovsky J, Cooper R, Rider L, Miller F;
International Myositis and Clinical Studies Group (IMACS).
Center for Rheumatology, Department of Medicine, The Middlesex Hospital,
University College London, London, UK. d.isenberg@ucl.ac.uk
OBJECTIVE: To devise new tools to assess activity and damage in patients with
idiopathic myopathies (IIM). METHODS: An international multidisciplinary
consensus effort to standardize the conduct and reporting of the myositis
clinical trials has been established. Two tools, known as the myositis intention
to treat index (MITAX) and the myositis disease activity assessment visual
analogue scale (MYOACT), have been developed to capture activity in patients
with IIM. In addition, the myositis damage index (MDI) has been devised to
assess the extent and severity of damage developing in different organs and
systems. These measures have been reviewed by the myositis experts participating
in the International Myositis Assessment and Clinical Studies (IMACS) group
and
have been found to have good face validity and to be comprehensive. The
instruments were assessed in two real patient exercises involving patients with
adult dermatomyositis and inclusion body myositis. RESULTS: The reliability
of
MITAX, MYOACT and MDI, measured by the intraclass correlation coefficient among
the physicians, and the inter-rater reliability, as assessed by variation in
the
physicians' rating of patients, was fair to good for most aspects of the tools.
Reliability and inter-rater agreement improved at the second exercise after
the
participants had completed additional training. CONCLUSIONS: The MITAX, MYOACT
and MDI tools, which are now undergoing validity testing, should enhance the
consistency, comprehensiveness and reliability of disease activity and damage
assessment in patients with myositis.
Publication Types:
Consensus Development Conference
Multicenter Study
Review
PMID: 12867580 [PubMed - indexed for MEDLINE]
93: Neurology. 2003 Jul 8;61(1):145; author reply 145.
Comment on:
Neurology. 2002 Dec 10;59(11):1689-93.
Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body
myopathy.
Hinderlich S, Salama I, Eisenberg I, Mitrani-Rosenbaum S.
Publication Types:
Comment
Letter
PMID: 12847185 [PubMed - indexed for MEDLINE]
94: AIDS. 2003 May 23;17(8):1266-7.
Inclusion body myositis: another possible manifestation of
antiretroviral-associated mitochondrial toxicity.
Loutfy MR, Sheehan NL, Goodhew JE, Walmsley SL.
Publication Types:
Case Reports
Letter
PMID: 12819534 [PubMed - indexed for MEDLINE]
95: J Neurol. 2003 May;250(5):619-21.
Inclusion body myositis in a patient with a presumed diagnosis of post-polio
syndrome.
Parissis D, Karkavelas G, Taskos N, Milonas I.
Publication Types:
Case Reports
Letter
PMID: 12814114 [PubMed - indexed for MEDLINE]
96: Muscle Nerve. 2003 Jul;28(1):113-7.
Novel missense mutation and large deletion of GNE gene in autosomal-recessive
inclusion-body myopathy.
Del Bo R, Baron P, Prelle A, Serafini M, Moggio M, Fonzo AD, Castagni M,
Bresolin N, Comi GP.
Dipartimento di Scienze Neurologiche, Centro Dino Ferrari, Universita degli
Studi di Milano, IRCCS Ospedale Maggiore Policlinico, Via F Sforza 35, Milano
20122, Italy.
The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene
is
the causative gene for autosomal-recessive hereditary inclusion-body myopathy
(h-IBM). Two sisters affected with autosomal-recessive h-IBM were shown to be
compound heterozygous for two novel GNE mutations: a large deletion involving
exons 1-9, and a R162C amino acid change in the epimerase domain. This is the
first deletion event observed in a GNE allele and expands the molecular
pathogenesis of autosomal-recessive h-IBM. Copyright 2003 Wiley Periodicals,
Inc.
Publication Types:
Case Reports
PMID: 12811782 [PubMed - indexed for MEDLINE]
97: Acta Neurol Scand. 2003 Jul;108(1):22-7.
Inclusion body myositis--sensory dysfunction revealed with quantitative
determination of somatosensory thresholds.
Arnardottir S, Svanborg E, Borg K.
Department of Clinical Neuroscience, division of Neurology, Karolinska Hospital,
Stockholm, Sweden.
In order to evaluate sensory function in inclusion body myositis (IBM), nine
patients were subjected to sensibility screening and quantitative determination
of somatosensory thresholds. Data were compared with results from
electrophysiological examination and muscle biopsy. On sensibility screening
all
but one of the IBM patients had abnormal findings in hands and/or feet mostly
affecting thermal sensibility. Vibratory thresholds were abnormal in five and
thermal thresholds in four of the patients. Mean vibratory thresholds were
significantly (P < 0.05) higher in the IBM patients when compared with the
controls. Significantly increased heat pain thresholds were found in hands and
feet when compared with the controls while thermal thresholds were normal. Nerve
conduction velocities were decreased in three patients, EMG showed both
myopathic and neuropathic abnormalities in six patients. Eight patients had
neuropathic abnormalities on muscle biopsy. The sensory dysfunction found
suggests an affection of peripheral nerves in IBM mainly affecting large
diameter myelinated nerve fibres corroborating earlier findings of a peripheral
neuropathy in IBM.
PMID: 12807389 [PubMed - indexed for MEDLINE]
98: J Neurochem. 2003 Jun;85(6):1539-46.
Cystatin C colocalizes with amyloid-beta and coimmunoprecipitates with
amyloid-beta precursor protein in sporadic inclusion-body myositis muscles.
Vattemi G, 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,
California 90017-1912, USA.
Cystatin C (CC), an endogenous cysteine protease inhibitor, is accumulated
within amyloid-beta (A beta) amyloid deposits in Alzheimer's disease (AD) brain
and was proposed to play a role in the AD pathogenesis. Because the
chemo-morphologic muscle phenotype of sporadic inclusion-body myositis (s-IBM)
has several similarities with the phenotype of AD brain, including abnormal
accumulation of A beta deposits, we studied expression and localization of CC
in
muscle biopsies of 10 s-IBM, and 16 disease- and five normal-control muscle
biopsies. Physical interaction of CC with amyloid-beta precursor protein (A
beta
PP) was studied by a combined immunoprecipitation/immunoblotting technique in
the s-IBM muscle biopsies and in A beta PP-overexpressing cultured human muscle
fibers. In all s-IBM muscle biopsies, CC-immunoreactivity either colocalized
with, or was adjacent to, the A beta-immunoreactive inclusions in 80-90% of
the
vacuolated muscle fibers, mostly in non-vacuolated regions of their cytoplasm.
Ultrastructurally, CC immunoreactivity-colocalized with A beta on 6-10 nm
amyloid-like fibrils and floccular material. By immunoblotting, CC expression
was strongly increased in IBM muscle as compared to the controls. By
immunoprecipitation/immunoblotting experiments, CC coimmunoprecipitated with
A
beta PP, both in s-IBM muscle and in A beta PP-overexpressing cultured normal
human muscle fibers. Our studies (i) demonstrate for the first time that CC
physically associates with A beta PP, and (ii) suggest that CC may play a novel
role in the s-IBM pathogenesis, possibly by influencing A beta PP processing
and
A beta deposition.
PMID: 12787072 [PubMed - indexed for MEDLINE]
99: Neurology. 2003 May 13;60(9):1519-23.
Hereditary inclusion body myopathy: the Middle Eastern genetic cluster.
Argov Z, Eisenberg I, Grabov-Nardini G, Sadeh M, Wirguin I, Soffer D,
Mitrani-Rosenbaum S.
Department of Neurology and Agnes Ginges Center for Human Neurogenetics,
Hadassah University Hospital and Hebrew University-Hadassah Medical School,
Jerusalem. zargov@md2.huji.ac.il
BACKGROUND: Recessively inherited hereditary inclusion body myopathy (HIBM)
with
quadriceps sparing was initially described only in Jews originating from the
region of Persia. The recent identification of the gene responsible for this
myopathy and the common "Persian Jewish mutation" (M712T) enabled
the
re-evaluation of atypical phenotypes and the epidemiology of HIBM in various
communities in the Middle East. OBJECTIVE: To test for the M712T mutation in
the
DNA from HIBM patients in the Middle East. METHODS: DNA from all suspected HIBM
patients was tested for the M712T mutation. Unaffected members of families with
genetically proven HIBM were studied too. In the majority of families, haplotype
construction with markers spanning the 700-kb region of the HIBM gene was
performed. RESULTS: One hundred twenty-nine HIBM patients of 55 families (Middle
Eastern Jews, Karaites, and Arab Muslims of Palestinian and Bedouin origin)
were
homozygous for the M712T mutation, and all carried the same haplotype. Five
clinically unaffected subjects were also homozygous for the common mutation
and
haplotype, including two older adults (ages 50 and 68 years). Atypical features
with this same mutation were marked quadriceps weakness in five patients,
proximal weakness only in two patients, facial weakness in three patients, and
a
muscle biopsy showing perivascular inflammation in one patient. CONCLUSIONS:
The
phenotypic spectrum of recessive HIBM is wider than previously described, and
the diagnostic criteria for this myopathy must be changed. The Middle Eastern
cluster is the result of a founder mutation, with incomplete penetrance, that
is
approximately 1,300 years old and is not limited to Jews.
Publication Types:
Case Reports
Historical Article
PMID: 12743242 [PubMed - indexed for MEDLINE]
100: J Child Neurol. 2003 Mar;18(3):185-90.
Unfolding story of inclusion-body myositis and myopathies: role of misfolded
proteins, amyloid-beta, cholesterol, and aging.
Askanas V, Engel WK.
USC Neuromuscular Center, Department of Neurology, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA
90017-1912, USA. askanas@hsc.usc.edu
Sporadic inclusion-body myositis and hereditary inclusion-body myopathies are
progressive muscle diseases leading to severe disability. We briefly summarize
their clinical pictures and pathologic diagnostic criteria and discuss the
latest advances in illuminating their pathogenic mechanism(s). We emphasize
how
different etiologies might lead to the strikingly similar pathology and possibly
similar pathogenic cascade. On the basis of our research, several processes
seem
to be important in relation to the still speculative pathogenesis, including
(a)
increased transcription and accumulation of amyloid-beta precursor protein and
accumulation of its proteolytic fragment amyloid-beta; (b) abnormal accumulation
of components related to lipid metabolism, for example, cholesterol,
accumulation of which is possibly owing to its abnormal trafficking; (c)
oxidative stress; (d) accumulations of other Alzheimer's disease-related
proteins; and (e) a milieu of muscle cellular aging in which these changes
occur. We discuss a potentially very important role of unfolded and/or misfolded
proteins as a possible mechanism in the formations of the inclusion bodies and
other abnormalities.
Publication Types:
Lectures
PMID: 12731644 [PubMed - indexed for MEDLINE]
101: Neuropediatrics. 2003 Feb;34(1):40-4.
Congenital myopathy with abundant ring fibres, rimmed vacuoles and inclusion
body myositis-type inclusions.
Fidzianska A, Kaminska A.
Neuromuscular Unit, Medical Research Centre, Polish Academy of Sciences, Warsaw,
Poland.
We report a 17-year-old girl with an unusual neuromuscular disorder
characterised by slowly progressive proximal muscle weakness whose muscle biopsy
showed multiple ring fibres and numerous rimmed vacuoles as well as
intracytoplasmic and intranuclear inclusions of the inclusion body
myositis-type. The clinical features of the presented case, manifested by the
onset of the disease in early childhood, delayed motor development, short
stature, lordosis and joint contractures were suggestive of congenital myopathy.
The coexistence of ring fibres, rimmed vacuoles and inclusion-body myositis-type
inclusions in a child with congenital myopathy has not been previously reported.
Publication Types:
Case Reports
PMID: 12690567 [PubMed - indexed for MEDLINE]
102: Brain. 2003 May;126(Pt 5):1026-35.
Muscle fibres and cultured muscle cells express the B7.1/2-related inducible
co-stimulatory molecule, ICOSL: implications for the pathogenesis of
inflammatory myopathies.
Wiendl H, Mitsdoerffer M, Schneider D, Melms A, Lochmuller H, Hohlfeld R, Weller
M.
Department of Neurology, University of Tubingen, Medical School, Tubingen,
Germany. heinz.wiendl@uni-tuebingen.de
Inducible co-stimulator ligand (ICOSL), a member of the B7 family of
co-stimulatory molecules related to B7.1/2, regulates CD4 as well as CD8 T-cell
responses via interaction with its receptor ICOS on activated T cells. Here
we
examined the expression and the functional relevance of ICOSL in human muscle
cells in vivo and in vitro. We investigated 25 muscle biopsy specimens from
patients with polymyositis, dermatomyositis, inclusion body myositis, Duchenne
muscular dystrophy and non-myopathic controls for ICOSL expression by
immunohistochemistry. Normal muscle fibres constitutively express low levels
of
ICOSL. However, ICOSL expression is markedly increased in muscle fibres in
inflammatory myopathies. Cell surface staining was most prominent in the contact
areas between muscle fibres and inflammatory cells, which in turn show
expression of ICOS as a marker of T-cell activation. Muscle endothelial cells
show constitutive expression of ICOSL under normal and pathological conditions.
We also detected mRNA and cell surface protein expression of ICOSL on myoblasts
cultured from control subjects and patients as well as in TE671 muscle
rhabdomyosarcoma cells. ICOSL expression was upregulated by tumour necrosis
factor-alpha (TNF-alpha), whereas interferon-gamma (IFN-gamma) had no such
effect. Co-culture experiments of major histocompatibility complex (MHC) class
II-positive myoblasts with CD4 T cells together with superantigen demonstrated
that the expression of muscle-related ICOSL has functional consequences: the
production of Th1 (IFN-gamma) and Th2 cytokines [interleukin (IL)-4 and IL-10]
by CD4 T cells was markedly reduced in the presence of a neutralizing anti-ICOSL
monoclonal antibody (mAb HIL-131), thus showing the importance of ICOSL
co-stimulation for T-cell activation. Taken together, our results demonstrate
that human muscle cells express ICOSL, a functional co-stimulatory molecule
distinct from B7.1 and B7.2. ICOSL-ICOS interactions may play an important role
in inflammatory myopathies, providing further evidence for the
antigen-presenting capacity of muscle cells.
PMID: 12690043 [PubMed - indexed for MEDLINE]
103: Acta Neuropathol (Berl). 2003 Jul;106(1):1-7. Epub 2003 Apr 01.
Expression of the intermediate filament protein synemin in myofibrillar
myopathies and other muscle diseases.
Olive M, Goldfarb L, Dagvadorj A, Sambuughin N, Paulin D, Li Z, Goudeau B,
Vicart P, Ferrer I.
Institut de Neuropatologia, Ciutat Sanitaria i Universitaria de Bellvitge,
C/Feixa Llarga s/n masculine, 08907 Hospitalet de Llobregat, Spain.
25169mop@comb.es
Synemin is a member of the intermediate protein superfamily. Previous studies
in
avian and rodent skeletal and cardiac muscles have demonstrated that synemin
localises at the Z-band, where it associates with desmin and alpha-actinin.
In
the present study, the distribution of synemin was examined using
immunohistochemistry in muscle biopsy specimens from patients suffering from
myofibrillar myopathy (MM, n=6), dermatomyositis (DM, n=3), inclusion body
myositis (IBM, n=5), oculopharyngeal muscular dystrophy (OPD, n=3) and
denervation atrophy (DA, n=3), to investigate the possible participation of
this
protein in the pathogenesis of various muscular diseases. Of patients affected
by MM, two showed the presence of mutations in the desmin gene; none had
mutations in the alphaB-crystallin gene; and no mutations were identified in
synemin or syncoilin genes of three patients. Synemin immunohistochemistry
disclosed a faint staining corresponding to the Z-bands in the cytoplasm of
control muscle fibres; in contrast, focal aggregates of synemin were seen in
patients with MM. Increased synemin immunoreactivity was identified diffusely
or
in the subsarcolemmal space of scattered fibres in patients with DM, and in
vacuolated fibres of patients with IBM and OPD. Strong synemin immunoreactivity
was observed in target formations and atrophic fibres of patients with
denervating disorders, as well as in atrophic fibres, regardless of their
origin, in all patients studied. Synemin co-localised with desmin, as seen on
consecutive serial sections immunostained with anti-synemin or anti-desmin
antibodies. These observations demonstrate abnormal accumulations containing
both synemin and desmin in muscle fibres in patients with MM, IBM, DM, OPD and
DA. Considering the important role of synemin as one of intermediate filaments
of skeletal and cardiac muscle, its destruction and accumulation in the
intracellular debris suggest that synemin may participate in the pathogenesis
of
these disorders.
PMID: 12669240 [PubMed - indexed for MEDLINE]
104: Muscle Nerve. 2003 Apr;27(4):407-25.
Inflammatory myopathies: clinical, diagnostic and therapeutic aspects.
Mastaglia FL, Garlepp MJ, Phillips BA, Zilko PJ.
Centre for Neuromuscular and Neurological Disorders, University of Western
Australia, Queen Elizabeth II Medical Centre, Nedlands, Australia.
flmast@cyllene.uwa.edu.au
The three major forms of immune-mediated inflammatory myopathy are
dermatomyositis (DM), polymyositis (PM), and inclusion-body myositis (IBM).
They
each have distinctive clinical and histopathologic features that allow the
clinician to reach a specific diagnosis in most cases. Magnetic resonance
imaging is sometimes helpful, particularly if the diagnosis of IBM is suspected
but has not been formally evaluated. Myositis-specific antibodies are not
helpful diagnostically but may be of prognostic value; most antibodies have
low
sensitivity. Muscle biopsy is mandatory to confirm the diagnosis of an
inflammatory myopathy and to allow unusual varieties such as eosinophilic,
granulomatous, and parasitic myositis, and macrophagic myofasciitis, to be
recognized. The treatment of the inflammatory myopathies remains largely
empirical and relies upon the use of corticosteroids, immunosuppressive agents,
and intravenous immunoglobulin, all of which have nonselective effects on the
immune system. Further controlled clinical trials are required to evaluate the
relative efficacy of the available therapeutic modalities particularly in
combinations, and of newer immunosuppressive agents (mycophenolate mofetil and
tacrolimus) and cytokine-based therapies for the treatment of resistant cases
of
DM, PM, and IBM. Improved understanding of the molecular mechanisms of muscle
injury in the inflammatory myopathies should lead to the development of more
specific forms of immunotherapy for these conditions.
Publication Types:
Review
PMID: 12661042 [PubMed - indexed for MEDLINE]
105: Neurology. 2003 Mar 25;60(6):993-7.
Activation of nuclear factor-kappaB in inflammatory myopathies and Duchenne
muscular dystrophy.
Monici MC, Aguennouz M, Mazzeo A, Messina C, Vita G.
Department of Neurosciences, Psychiatry, and Anaesthesiology, University of
Messina, Italy.
OBJECTIVE: To investigate the immunolocalization and activation of nuclear
factor-kappaB (NF-kappaB) in polymyositis, dermatomyositis, and Duchenne
muscular dystrophy (DMD). BACKGROUND: NF-kappaB is a major transcription factor
modulating the cellular immune, inflammatory, and proliferative responses. In
skeletal muscle it was demonstrated to play a role in the expression of
inducible genes in response to oxidative stress and ischemia/reperfusion injury,
and also in myonuclear apoptosis and muscle catabolism. Some data suggest that
NF-kappaB may play a role in the pathogenesis of inclusion body myositis.
METHODS: Muscle samples from five patients each with polymyositis,
dermatomyositis, and DMD and 10 normal controls were studied by
immunocytochemistry and Western blot of nuclear extracts for the activated form
of NF-kappaB. NF-kappaB DNA binding activity was studied by electrophoretic
mobility shift assay (EMSA). RESULTS: Immunoreactivity for NF-kappaB was found
in the cytoplasm of all regenerating fibers and in 20 to 40% of necrotic fibers.
Western blot analysis of nuclear extracts showed a single band corresponding
to
65 kd in all patients. EMSA analysis confirmed activation of NF-kappaB pathway
in inflammatory myopathies and, to a lesser extent, also in DMD. CONCLUSIONS:
These data indicate that nuclear factor-kappaB pathway is activated in
polymyositis, dermatomyositis, and Duchenne muscular dystrophy. It may play
a
role in modulating the immune response and in regulating myogenesis and muscle
repair.
PMID: 12654966 [PubMed - indexed for MEDLINE]
106: Exp Neurol. 2003 Feb;179(2):150-8.
BACE1 and BACE2 in pathologic and normal human muscle.
Vattemi G, Engel WK, McFerrin J, Pastorino L, Buxbaum JD, Askanas V.
USC Neuromuscular Center, Department of Neurology, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, Los Angeles
90017-1912, USA.
BACE1 and BACE2 are recently discovered enzymes participating in processing
of
amyloid beta precursor protein (AbetaPP). Their discovery is contributing
importantly to understanding the mechanism of amyloid-beta generation, and hence
the pathogenesis of Alzheimer's disease (AD). Sporadic inclusion-body myositis
(s-IBM) and hereditary inclusion-body myopathy (h-IBM) are progressive muscle
diseases in which overproduction of AbetaPP and accumulation of its presumably
toxic proteolytic product amyloid-beta (Abeta) in abnormal muscle fibers appear
to play an important upstream role in the pathogenic cascade. In normal human
muscle AbetaPP was also shown to be present and presumably playing a role (a)
at
neuromuscular junctions and (b) during muscle development. To investigate
whether BACE1 and BACE2 play a role in normal and diseased human muscle, we
have
now studied them by immunocytochemistry and immunoblotting in 35 human muscle
biopsies, including: 5 s-IBM; 5 chromosome-9p1-linked quadriceps-sparing h-IBM;
and 25 control muscle biopsies. In addition, expression of BACE1 and BACE2 was
studied in normal cultured human muscle. Our studies demonstrate that BACE1
and
BACE2 (a) are expressed in normal adult muscle at the postsynaptic domain of
neuromuscular junctions, and in cultured human muscle; (b) are accumulated in
the form of plaque-like inclusions in both s-IBM and h-IBM vacuolated muscle
fibers; and (c) are immunoreactive in necrotizing muscle fibers. Accordingly,
BACE1 and BACE2 participate in normal and abnormal processes of human muscle,
suggesting that their functions are broader than previously thought.
PMID: 12618121 [PubMed - indexed for MEDLINE]
107: J Rehabil Med. 2003 Jan;35(1):31-5.
Sporadic inclusion body myositis: pilot study on the effects of a home exercise
program on muscle function, histopathology and inflammatory reaction.
Arnardottir S, Alexanderson H, Lundberg IE, Borg K.
Department of Clinical Neuroscience Division of Neurology, Karolinska Hospital,
SE-171 76 Stockholm, Sweden. snjolaug.arnardottir@ks.se
OBJECTIVE: To evaluate the safety and effect of a home training program on
muscle function in 7 patients with sporadic inclusion body myositis. DESIGN:
The
patients performed exercise 5 days a week over a 12-week period. METHODS: Safety
was assessed by clinical examination, repeated muscle biopsies and serum levels
of creatine kinase. Muscle strength was evaluated by clinical examination,
dynamic dynamometer and by a functional index in myositis. RESULTS: Strength
was
not significantly improved after the exercise, however none of the patients
deteriorated concerning muscle function. The histopathology was unchanged and
there were no signs of increased muscle inflammation or of expression of
cytokines and adhesion molecules in the muscle biopsies. Creatine kinase levels
were unchanged. A significant decrease was found in the areas that were
positively stained for EN-4 (a marker for endothelial cells) in the muscle
biopsies after training. CONCLUSION: The home exercise program was considered
as
not harmful to the muscles regarding muscle inflammation and function. Exercise
may prevent loss of muscle strength due to disease and/or inactivity.
Publication Types:
Evaluation Studies
PMID: 12610846 [PubMed - indexed for MEDLINE]
108: J Allergy Clin Immunol. 2003 Feb;111(2 Suppl):S659-68.
20. Immunologic neuromuscular disorders.
Chitnis T, Khoury SJ.
Center for Neurologic Disease, Brigham and Women's Hospital, Harvard Medical
School, 77 Louis Pasteur Avenue, LMRC 1st Floor, Boston, MA 02215, USA.
Immune-mediated disorders of each of the structural subdivisions of the nervous
and neuromuscular system have been described. Despite the immune privilege of
the central nervous system, and to a lesser extent the peripheral nervous
system, immune dysregulation is not uncommon. Environmental, genetic, and
immunologic factors have been postulated to be involved in the development of
these disorders. Major immune-mediated neurologic diseases of the central
nervous system include multiple sclerosis and acute disseminated
encephalomyelitis. Immune-mediated diseases of the peripheral nervous system
include myasthenia gravis, Guillain-Barre syndrome, chronic inflammatory
demyelinating polyneuropathy, idiopathic polymyositis, dermatomyositis, and
inclusion body myositis. Some of these disorders, such as myasthenia gravis
and
certain forms of acute inflammatory demyelinating polyneuropathy, are clearly
autoimmune in nature, whereas the immune system plays an important role in
pathogenesis in others. Understanding the immune mechanisms of disease and
uncovering potential therapeutic targets are essential for the design of new
treatments. The epidemiology, pathogenesis, diagnostic criteria, and current
therapeutic approaches to the major neuroimmunologic diseases are reviewed.
Publication Types:
Review
Review, Tutorial
PMID: 12592311 [PubMed - indexed for MEDLINE]
109: Rheum Dis Clin North Am. 2002 Nov;28(4):723-41.
Idiopathic inflammatory myopathies: epidemiology, classification, and diagnostic
criteria.
Mastaglia FL, Phillips BA.
Centre for Neuromuscular and Neurological Disorders, QEII Medical Centre,
Department of Medicine, University of Western Australia.
flmast@cyllene.uwa.edu.au
Epidemiologic studies have helped to define the prevalence and incidence of
PM,
DM, and IBM and have highlighted differences in risk between men and women and
in the age at onset for the different forms of myositis. Additionally, these
studies have shown that there is a substantially higher risk of PM and DM in
certain racial groups which is likely to be genetically determined. These
differences are all likely to be fundamental in terms of the pathogenesis of
these diseases but, as yet, their full significance remains uncertain. They
do,
however, suggest that the interplay between genetic and environmental initiating
factors is different in the three disorders. Additional population-based studies
in homogeneous racial groups, in parallel with studies of susceptibility genes
for autoimmune disease, such as those encoding the MHC and inflammatory
cytokines, are needed to throw further light on the role of genetic factors
in
the pathogenesis of the IIMs [47]. Because of the paucity of epidemiologic data
on IBM, further studies are required to determine the degree of variation in
prevalence in different populations and racial groups, as well as the
consistency of the male association and age spectrum of manifestations of the
disease. The particularly strong association with DR3 in this form of IIM [48]
clearly points to the importance of genetic factors in pathogenesis, but further
studies of DR3-associated genes in the MHC and of other candidate genes are
needed to define more precisely the genes that convey susceptibility to the
disease in different racial groups. Epidemiologic studies also have the
potential to identify environmental factors that may play a part in disease
initiation in genetically susceptible individuals. Seasonal patterns of disease
onset have been reported, particularly in patients with DM [49-51] as well as
seasonal variation in the frequency of relapses [52], pointing to the probable
involvement of intercurrent infections, ultraviolet light exposure, or other
environmental factors in disease initiation and reactivation. Further
prospective studies are required to determine the contribution of environmental
exposures and how they interact with genetic susceptibility factors to lead
to
myositis. One of the major limitations of a number of the previous epidemiologic
studies is the lack of precision in the diagnostic criteria used and the
classification of cases of IIM. The Bohan and Peter criteria [1] which were
used
in most studies after 1975, were introduced before IBM was recognized as an
entity distinct from PM; most of the published incidence and prevalence figures
for PM are therefore likely to be inaccurate. Multicentered, interdisciplinary,
prospective studies, incorporating comprehensive clinical, laboratory, and
pathologic information, are needed to develop and validate better diagnostic
and
classification criteria and to determine the true prevalence and incidence of
the many forms of IIM.
Publication Types:
Review
Review, Tutorial
PMID: 12510664 [PubMed - indexed for MEDLINE]
110: Rheum Dis Clin North Am. 2002 Nov;28(4):823-32.
Clinical presentation of the idiopathic inflammatory myopathies.
Yazici Y, Kagen LJ.
Hospital for Special Surgery, Weill Medical College of Cornell University,
535
East 70th Street, New York, NY 10021, USA. yaziciy@hss.edu
The hallmark of the inflammatory myopathies is muscle weakness. Although this
feature can lead to significant disability and impairment of activities of daily
living, its initial presentation may not be recognized early. Older individuals,
in particular, may feel that the changes caused by myositis reflect the effects
of aging rather than those of a disease process, and diagnosis, therefore, may
be delayed. This factor has negative impact on the response to therapy.
Inclusion body myositis, with its insidious onset in older people, and
laboratory findings which may not be markedly abnormal, presents a diagnostic
challenge. DM, with its characteristic symptomatic rash, is generally brought
to
medical attention more quickly. Another area of diagnostic concern occurs when
associated organ involvement precedes myopathy. This has been observed, for
example, with interstitial lung disease, and again represents a challenge to
physicians. In this connection, the antisynthetase syndrome presenting with
fevers, Raynaud's features, arthritis, or pulmonary involvement may not
initially be recognized as a manifestation of inflammatory muscle disease. Each
subgroup of IIM may present with a variety of extramuscular features that can
complicate diagnosis and alter therapy and prognosis. This is particularly true
for the pulmonary, GI, and cardiac manifestations and when cancer is associated
with myositis. For these reasons, such features of IIM should be carefully
evaluated, treated, and monitored over the course of the illness; in some cases
these may play a greater role in determining the outcome of patients with IIM
than the muscle involvement itself. It is hoped that in the future increased
familiarity with the manifestations of the inflammatory myopathies, together
with a better understanding of the underlying pathogenesis, will lead to more
rapid diagnosis and more effective treatments.
Publication Types:
Review
Review, Tutorial
PMID: 12506774 [PubMed - indexed for MEDLINE]
111: Rheum Dis Clin North Am. 2002 Nov;28(4):779-98, vi.
Muscle biopsy findings in inflammatory myopathies.
Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Building 10, Room 4N248, 10 Center Drive,
MSC 1382, Bethesda, MD 20892-1382, USA. dalakasm@ninds.nih.gov
The inflammatory myopathies encompass a heterogeneous group of acquired muscle
diseases characterized clinically, by muscle weakness, and histologically, by
inflammatory infiltrates within the skeletal muscles. The group of these
myopathies comprise three major and discrete subsets: polymyositis (PM),
dermatomyositis (DM), and inclusion body myositis (IBM). Each subset retains
its
characteristic clinical, immunopathologic, and morphologic features regardless
of whether it occurs separately or in connection with other systemic diseases.
Although the diagnosis of these disorders is based on the combination of
clinical examination, electromyographic data, serum muscle enzyme levels,
various autoantibodies, and the muscle biopsy findings, the muscle biopsy offers
the most definitive diagnostic information in the majority of the cases. This
article summarizes the main histologic features that characterize PM, DM, or
IBM
and emphasizes the main pitfalls associated with interpretation of the biopsies.
Publication Types:
Review
Review, Tutorial
PMID: 12506772 [PubMed - indexed for MEDLINE]
112: Hum Mutat. 2003 Jan;21(1):99.
Mutations spectrum of GNE in hereditary inclusion body myopathy sparing the
quadriceps.
Eisenberg I, Grabov-Nardini G, Hochner H, Korner M, Sadeh M, Bertorini T, Bushby
K, Castellan C, Felice K, Mendell J, Merlini L, Shilling C, Wirguin I, Argov
Z,
Mitrani-Rosenbaum S.
Molecular Biology Unit, Hadassah Hospital, The Hebrew University-Hadassah
Medical School, Jerusalem, Israel.
Hereditary Inclusion Body Myopathy (HIBM) is a unique group of neuromuscular
disorders characterized by adult onset and a typical muscle pathology. We have
recently identified the gene encoding for a bifunctional enzyme,
UDP-N-acetylglucosamine 2 epimerase/N-acetylmannosamine kinase (GNE), as the
mutated gene in the prototype form of the disease presenting quadriceps sparing,
particularly common in Middle Eastern Jews. Interestingly, we have identified
the homozygous M712T Middle Eastern Jewish mutation also in two unrelated Middle
Eastern Moslem families. We have also evaluated the involvement of GNE in
several families from worldwide non-Jewish ethnic origins presenting symptoms
similar to the Middle Eastern HIBM prototype. A total of 14 GNE mutations were
identified (one nonsense and 13 missense), of which six are novel: an homozygous
missense mutation in a consanguineous family from Italy and in a non
consanguineous family from USA, and distinct compound heterozygotes in families
from Germany, Italy, Ireland, Bahamas, USA and East India. This study brings
to
17 the number of reported GNE mutations in quadriceps sparing myopathy,
occurring either in the epimerase or the kinase domain of the enzyme. The
mechanism leading to this unique phenotype still remains to be elucidated.
Copyright 2002 Wiley-Liss, Inc.
PMID: 12497639 [PubMed - indexed for MEDLINE]
113: Neurology. 2002 Dec 10;59(11):1808-9.
Comment in:
Neurology. 2002 Dec 10;59(11):1674-6.
An Italian family with autosomal recessive inclusion-body myopathy and mutations
in the GNE gene.
Broccolini A, Pescatori M, D'Amico A, Sabino A, Silvestri G, Ricci E, Servidei
S, Tonali PA, Mirabella M.
Institute of Neurology, Catholic University, Rome, Italy. abroccolini@tiscali.it
Publication Types:
Case Reports
PMID: 12473780 [PubMed - indexed for MEDLINE]
114: Neurology. 2002 Dec 10;59(11):1776-9.
Comment in:
Neurology. 2002 Dec 10;59(11):1674-6.
GNE mutations in an American family with quadriceps-sparing IBM and lack of
mutations in s-IBM.
Vasconcelos OM, Raju R, Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Analysis for GNE mutations was performed in an American, non-Iranian Jewish,
family with quadriceps-sparing inclusion body myopathy (QS-IBM) and in 11
patients with sporadic IBM (s-IBM). Two novel nonallosteric site missense
mutations were found in the QS-IBM kinship. No mutations were identified in
s-IBM patients. After 8 years of follow-up and severe disease progression, the
quadriceps muscle in the QS-IBM patient remains strong despite subclinical
involvement documented with repeat MRI and muscle biopsy.
Publication Types:
Case Reports
PMID: 12473769 [PubMed - indexed for MEDLINE]
115: Neurology. 2002 Dec 10;59(11):1689-93.
Comment in:
Neurology. 2002 Dec 10;59(11):1674-6.
Neurology. 2003 Jul 8;61(1):145; author reply 145.
Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body
myopathy.
Nishino I, Noguchi S, Murayama K, Driss A, Sugie K, Oya Y, Nagata T, Chida
K,
Takahashi T, Takusa Y, Ohi T, Nishimiya J, Sunohara N, Ciafaloni E, Kawai M,
Aoki M, Nonaka I.
Department of Neuromuscular Research, National Institute of Neuroscience,
Kodaira, Tokyo, Japan. nishino@ncnp.go.jp
BACKGROUND: Distal myopathy with rimmed vacuoles (DMRV) is an
autosomal-recessive disorder with preferential involvement of the tibialis
anterior muscle that starts in young adulthood and spares quadriceps muscles.
The disease locus has been mapped to chromosome 9p1-q1, the same region as the
hereditary inclusion body myopathy (HIBM) locus. HIBM was originally described
as rimmed vacuole myopathy sparing the quadriceps; therefore, the two diseases
have been suspected to be allelic. Recently, HIBM was shown to be associated
with the mutations in the gene encoding the bifunctional enzyme,
UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). OBJECTIVE:
To determine whether DMRV and HIBM are allelic. METHODS: The GNE gene was
sequenced in 34 patients with DMRV. The epimerase activity in lymphocytes from
eight DMRV patients was also measured. RESULTS: The authors identified 27
unrelated DMRV patients with homozygous or compound-heterozygous mutations in
the GNE gene. DMRV patients had markedly decreased epimerase activity.
CONCLUSIONS: DMRV is allelic to HIBM. Various mutations are associated with
DMRV
in Japan. The loss-of-function mutations in the GNE gene appear to cause
DMRV/HIBM.
PMID: 12473753 [PubMed - indexed for MEDLINE]
116: Best Pract Res Clin Rheumatol. 2002 Dec;16(5):817-32.
Idiopathic inflammatory myopathies - myositis.
Dorph C, Lundberg IE.
Rheumatology Unit, Karolinska Hospital, SE- 171 76, Stockholm, Sweden.
Ingrid.Lundberg@medks.ki.se
The inflammatory myopathies - myositis - encompass a heterogeneous group of
chronic muscle disorders of unknown origin and with varying prognoses. New
clinical phenotypes of myositis have been identified since the most widely used
classification criteria were proposed in 1975. Based on clinical and
histopathological features, inclusion body myositis was identified. Furthermore,
the myositis-specific autoantibodies may also identify different clinical
phenotypes and serve as prognostic markers. The different classifications and
inclusion criteria that have been used in different studies make some
epidemiological data uncertain. In order to improve our knowledge of causative
factors, as well as of pathogenic mechanisms, there is a need for revision and
also for an international acceptance of the classification criteria. During
recent years, our knowledge has increased regarding the role of some genetic
and
environmental factors that could affect susceptibility for developing myositis
as well as the prognosis. Whether there is an association between myositis and
malignancies has been a subject of controversy for many years and recent
epidemiological data have brought some clarification on this issue.
Publication Types:
Review
Review, Tutorial
PMID: 12473276 [PubMed - indexed for MEDLINE]
117: J Clin Neurosci. 2003 Jan;10(1):99-101.
Inflammatory myopathies: how to treat the difficult cases.
Mastaglia FL, Zilko PJ.
Centre for Neuromuscular and Neurological Disorders, and Department of Medicine,
University of Western Australia, Nedlands, WA, Australia.
flmast@cyllene.uwa.edu.au
The initial approach to the treatment of patients with inflammatory myopathy
is
critical in determining the subsequent course and outcome. Prolonged
administration of high doses of corticosteroids should be avoided and a
second-line agent such as methotrexate or azathioprine should be introduced
earlier rather than later. Intravenous immunoglobulin therapy has an important
place if the myositis remains active, particularly in patients with
dermatomyositis, and is the treatment of choice in patients with
immunodeficiency who are not controlled by corticosteroids. In more resistant
cases of polymyositis or dermatomyositis it may be necessary to use
cyclophosphamide, cyclosporin or the promising newer immunosuppressive agents
mycophenolate mofetil or tacrolimus to achieve disease control. The treatment
of
inclusion body myositis remains unsatisfactory but a trial of prednisolone and
methotrexate is warranted in selected patients.
Publication Types:
Review
Review, Tutorial
PMID: 12464534 [PubMed - indexed for MEDLINE]
118: Med Hypotheses. 2003 Jan;60(1):94-101.
Magnesium may help patients with recessive hereditary inclusion body myopathy,
a
pathological review.
Darvish D.
HIBM Research Group, Encino, CA 91434, USA. dd@hibm.org
Recently, bi-allelic mutations in the gene coding for the bi-functional enzyme
UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK), symbol
GNE or GLCNE (MIM: 603824), were associated with the recessively inherited
phenotype of IBM2 (MIM: 600737). All patients tested so far have bi-allelic
missense mutation(s) of epimerase and/or kinase domains of GNE gene, which
clearly explains the recessive inheritance pattern of this phenotype. Single
allelic mutations of codons 263-266 of GNE have been implicated as the cause
of
French type sialuria (MIM: 269921). The dominantly inherited French type
sialuria seems to result from defective allosteric feedback inhibitory
regulation of GNE/MNK by cytidine monophosphate-N-acetylneuraminic acid
(CMP-NANA), resulting in overproduction of cytosolic N-acetylneuraminic acid,
and massive urinary excretion of free sialic acid. Because GNE is relatively
weakly expressed in skeletal muscle cells, and involvement of other organs are
not clinically evident in patients affected with IBM2, it is likely that the
missense mutation(s) found in these patients cause a partial reduction of the
efficiency of either the epimerase or the kinase activity of this enzyme.
Therapeutic dietary modifications are recommended including reduction of ethanol
consumption, avoidance of excess selenium, copper, and zinc, and dietary
promotion of magnesium (Mg(2+)), which is an essential co-factor for this
enzyme.
Publication Types:
Review
Review, Tutorial
PMID: 12450772 [PubMed - indexed for MEDLINE]
119: J Neuroimmunol. 2002 Dec;133(1-2):198-204.
Evidence for heterogeneity of T cell expansion in polymyositis and inclusion
body myositis.
van der Meulen MF, van Wichen DF, van Blokland WT, van den Berg LH, Wokke JH,
Hoogendijk JE, de Weger RA.
Department of Neurology, G03.228, Division of Neuromuscular Disorders,
University Medical Center Utrecht, P.O. Box 85500 3508 GA, Utrecht, The
Netherlands. M.F.G.vdMeulen@neuro.zau.nl
Vbeta usage of muscle-infiltrating T lymphocytes in polymyositis (PM) and
sporadic inclusion body myositis (s-IBM) was correlated with clinical and
histopathological features. Immunohistochemical analysis was combined with
complementarity-determining region 3 (CDR3) length analysis in nine muscle
biopsies of eight PM patients and six biopsies of five s-IBM patients. Vbeta
usage was heterogeneous in seven patients. Four of these patients had definite
PM with endomysial located T cell infiltrates, but T cells specifically
surrounding and invading individual non-necrotic fibers were not found. In two
s-IBM patients, Vbeta 2 usage was increased. In one of them, a repeat biopsy
showed a heterogeneous Vbeta usage. We conclude that clonal expansion of
muscle-infiltrating T cells could only be detected in part of the patients.
Explanations may be that clonal expansion does not take place in all disease
phases and that PM is a heterogeneous disease with respect to pathogenesis.
PMID: 12446023 [PubMed - indexed for MEDLINE]
120: J Vet Diagn Invest. 2002 Nov;14(6):501-3.
Inclusion body myositis in spring peepers (Pseudacris crucifer).
Raymond JT, Reichard T, Shellabarger W, Nordhausen R, Garner MM.
Northwest ZooPath, Snohomish, WA 98296-4815, USA.
In 2000, 2 adult captive spring peepers (Pseudacris crucifer) from the same
zoological park were humanely euthanized. Histologically, both frogs had
degeneration, atrophy, and necrosis of striated myofibers of the tongue admixed
with chronic lymphohistiocytic inflammation. One frog had similar lesions in
the
skeletal muscles of the body wall. Several degenerate and necrotic myofibers
contained single, eosinophilic, intranuclear inclusion bodies. Ultrastructural
examination of the inclusions revealed nonenveloped, icosahedral, virus-like
particles averaging 20-24 nm in diameter. This is the first reported case of
inclusion body myositis in frogs and is believed to be due to parvoviral
infection.
Publication Types:
Case Reports
PMID: 12423034 [PubMed - indexed for MEDLINE]
121: Curr Opin Rheumatol. 2002 Nov;14(6):653-7.
Inclusion body myositis.
Tawil R, Griggs RC.
Department of Neurology, University of Rochester, Rochester, New York 14642,
USA. Rabi_Tawil@urmc.rochester.edu
Inclusion body myositis (IBM) is an inflammatory myopathy with distinctive
clinicopathologic features. The etiology of IBM remains elusive. The
immune-mediated basis for this disease has been challenged by evidence
implicating a number of divergent etiologic factors. These factors include
mitochondrial deletions, nitric oxide induced oxidative stress, myonuclear
breakdown, and abnormal accumulation within muscle fibers of brain-specific
Alzheimer type proteins. The treatment of IBM with conventional
immunosuppressive agents has been disappointing. Therapeutic approaches
currently under study or consideration are beta-interferon and synthetic
anabolic hormones.
Publication Types:
Review
Review, Tutorial
PMID: 12410086 [PubMed - indexed for MEDLINE]
122: Mol Genet Metab. 2002 Nov;77(3):252-6.
Four novel mutations associated with autosomal recessive inclusion body myopathy
(MIM: 600737).
Darvish D, Vahedifar P, Huo Y.
HIBM Research Group, 16661 Ventura Blvd., #311, Encino, CA 91436, USA.
ddarvish@hibm.org
Recently, mutations in the gene encoding for the bi-functional enzyme
UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK), symbol
GNE or GLCNE (MIM: 603824) [EC 5.1.3.14], were associated with IBM2 (MIM:
600737). IBM2 is a recessively inherited vacuolar myopathy with a prevalence
rate of 1-2/1000 amongst people of Iranian-Jewish descent. Seven missense
mutations were previously described by Eisenberg et al. All families tested
from
Iranian and Middle Eastern Jewish ancestry have the same homozygous mutation
(bp2186t>c). Here we review the mutations in GNE associated with IBM2, and
we
describe additional four mutations found in individuals suffering from
clinically similar disorder who are not of Iranian or Jewish descent. These
findings further confirm that homozygous or compound heterozygous mutations
of
GNE/MNK gene associated with IBM2 are not confined to any single specific region
of the enzyme outside its negative feedback regulatory domain located at codons
249-275.
PMID: 12409274 [PubMed - indexed for MEDLINE]
123: Rev Neurol (Paris). 2002 Oct;158(10 Pt 1):948-58.
Understanding the immunopathogenesis of inclusion-body myositis: present and
future prospects.
Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Bethesda, USA.
Sporadic Inclusion Body Myositis (s-IBM) is the most common acquired
inflammatory myopathy. It has a stereotypic clinical presentation and a
predictably progressive course that leads to severe muscle weakness and
permanent disability. The combination of primary endomysial inflammation with
autoimmune features identical to those seen in Polymyositis, and degenerative
features with vacuolization of muscle fibers and deposits of tiny speckles of
amyloid, are characteristic for the disease. In this review, the immunopathology
of IBM is detailed. The inflammation which is prominent even late in the
disease, is characterized by activated, CD8+ cytotoxic T cells that secrete
perforin and invade MHC-I-expressing muscle fibers. The autoinvasive T cells
are
probably antigen driven because of specific rearrangement of their T Cell
Receptor profile, restriction of the CDR3 region, upregulation of co-stimulatory
molecules and their ligands on the muscle fibers, and activation of various
cytokines, chemokines and adhesion molecules. The disease can be seen in
association with HIV and HTLV-I infection, but viruses have not been amplified
from the muscle fibers and the antigen or the factors that trigger inflammation
are still unknown. The disease is mysteriously resistant to conventional
immunotherapies in spite of the immunopathologic similarities with PM. The cause
of the vacuolar formation in IBM is also unknown and the role, that the tiny
amyloid deposits play in the disease remain unclear. The treatment approaches
and the prospects for future immunotherapeutic interventions are discussed.
Publication Types:
Review
Review, Tutorial
PMID: 12407303 [PubMed - indexed for MEDLINE]
124: Neuromuscul Disord. 2002 Nov;12(9):853-7.
Inclusion body myositis: morphological clues to correct diagnosis.
Dahlbom K, Lindberg C, Oldfors A.
Department of Neurology and Clinical Neurophysiology, Orebro University
Hospital, S-701 85, Orebro, Sweden.
The aim of this study was to investigate variability of morphological changes
found in patients with sporadic inclusion body myositis, to assess the
diagnostic value of muscle biopsy. The study included all 43 definite inclusion
body myositis patients (86 biopsies) diagnosed at Sahlgrenska University
Hospital, Gothenburg, Sweden, between 1984 and 2000. Invasion of mononuclear
inflammatory cells in non-necrotic muscle fibres was found in 72 of 86
specimens, while all investigated biopsies showed up-regulation of major
histocompatibility complex class I. Cytochrome c oxidase-negative muscle fibres
were demonstrated in 84 of 86 biopsies. Rimmed vacuoles were present in all
specimens from the vastus lateralis and tibialis muscles, and in 43 of 51
biopsies from the deltoid muscle. In cases with clinical suspicion of inclusion
body myositis, where the muscle biopsy does not show inflammatory cell
infiltration and rimmed vacuoles, inclusion body myositis should still be
considered if there are cytochrome c oxidase-negative fibres and up-regulation
of major histocompatibility complex class I. In such cases repeat muscle biopsy
may be helpful.
PMID: 12398837 [PubMed - indexed for MEDLINE]
125: Neurology. 2002 Oct 22;59(8):1170-82.
Comment in:
Neurology. 2002 Oct 22;59(8):1128-9.
Molecular profiles of inflammatory myopathies.
Greenberg SA, Sanoudou D, Haslett JN, Kohane IS, Kunkel LM, Beggs AH, Amato AA.
Department of Neurology, Brigham and Women's Hospital, 75 Francis Street,
Boston, MA 02115, USA. sagreenberg@partners.org
OBJECTIVE: To describe the use of large-scale gene expression profiles to
distinguish broad categories of myopathy and subtypes of inflammatory myopathies
(IM) and to provide insight into the pathogenesis of inclusion body myositis
(IBM), polymyositis, and dermatomyositis. METHODS: Using Affymetrix GeneChip
microarrays, the authors measured the simultaneous expression of approximately
10,000 genes in muscle specimens from 45 patients in four major disease
categories (dystrophy, congenital myopathy, inflammatory myopathy, and normal).
The authors separately analyzed gene expression in 14 patients limited to the
three major subtypes of IM. Bioinformatics techniques were used to classify
specimens with similar expression profiles based on global patterns of gene
expression and to identify genes with significant differential gene expression
compared with normal. RESULTS: Ten of 11 patients with IM, all normals and
nemaline myopathies, and 10 of 12 patients with Duchenne muscular dystrophy
were
correctly classified by this approach. The various subtypes of inflammatory
myopathies have distinct gene expression signatures. Specific sets of
immune-related genes allow for molecular classification of patients with IBM,
polymyositis, and dermatomyositis. Analysis of differential gene expression
identifies as relevant to disease pathogenesis previously reported cytokines,
major histocompatibility complex class I and II molecules, granzymes, and
adhesion molecules, as well as newly identified members of these categories.
Increased expression of actin cytoskeleton genes is also identified.
CONCLUSIONS: The molecular profiles of muscle tissue in patients with
inflammatory myopathies are distinct and represent molecular signatures from
which diagnostic insight may follow. Large numbers of differentially expressed
genes are rapidly identified.
Publication Types:
Validation Studies
PMID: 12391344 [PubMed - indexed for MEDLINE]
126: Curr Opin Neurol. 2002 Oct;15(5):525-31.
Inclusion-body myositis and myopathies: different etiologies, possibly similar
pathogenic mechanisms.
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, USA. askanas@hsc.usc.edu
PURPOSE OF REVIEW: Sporadic inclusion-body myositis (s-IBM) and hereditary
inclusion body myopathies are progressive muscle diseases that lead to severe
disability. We discuss recent advances in illuminating their pathogenic
mechanism(s). RECENT FINDINGS: We emphasize how different etiologies might lead
to the strikingly similar pathology and possibly similar pathogenic cascade.
Our
basic hypothesis is that over-expression of amyloid-beta precursor protein
within aging muscle fibers is an early upstream event causing the subsequent
pathogenic cascade. On the basis of our research, several processes seem to
be
important in relation to the still speculative pathogenesis: (a) increased
transcription and accumulation of amyloid-beta precursor protein, and
accumulation of its proteolytic fragment Abeta; (b) accumulations of
phosphorylated tau and other Alzheimer-related proteins; (c) accumulation of
cholesterol and low-density lipoprotein receptors, the cholesterol accumulation
possibly due to its abnormal trafficking; (d) oxidative stress; and (e) a milieu
of muscle cellular aging in which these changes occur. We discuss unfolded
and/or misfolded proteins as a possible mechanism in formation of the inclusion
bodies and their consequences. The remarkable pathologic similarities between
s-IBM muscle and Alzheimer disease brain are discussed. SUMMARY: Unfolding
knowledge of the various pathogenetic aspects of the s-IBMs and hereditary
inclusion body myopathies may lead to new therapeutic avenues.
Publication Types:
Review
Review, Tutorial
PMID: 12351995 [PubMed - indexed for MEDLINE]
127: J Rheumatol. 2002 Sep;29(9):1897-906.
Comment in:
J Rheumatol. 2003 Aug;30(8):1892.
Magnetic resonance imaging criteria for distinguishing between inclusion body
myositis and polymyositis.
Dion E, Cherin P, Payan C, Fournet JC, Papo T, Maisonobe T, Auberton E, Chosidow
O, Godeau P, Piette JC, Herson S, Grenier P.
Department of Radiology, Institute of Myology, Paris, France.
elisabeth.dion@psl.ap-hop-paris.fr
OBJECTIVE: To develop diagnostic imaging criteria for polymyositis (PM) and
sporadic inclusion body myositis (sIBM). METHODS: We investigated 220 patients
with suspected inflammatory myopathies by magnetic resonance imaging (MRI).
Findings were compared with the results of clinical and biological examinations
and muscle biopsy. PM and IBM were diagnosed in 25 patients each. Quantitative
and qualitative MRI analysis of the 3 muscle groups of the 2 thighs included
fatty infiltration, atrophy, inflammation, and the type and distribution of
the
lesions. RESULTS: MRI was abnormal in all patients. Fatty infiltration and
atrophy were more frequent in patients with sIBM (p < 0.05). Inflammation
as the
sole abnormality was preferentially encountered in PM (p = 0.05). Widespread
abnormalities were more frequent in sIBM (p < 0.01). Abnormalities in PM
tended
to be distributed along the fascia. Involvement of the anterior group, an
asymmetrical distribution, and a distal predominance were all more frequent
in
sIBM (p < 0.001). CONCLUSION: Despite some overlap in MRI findings between
the 2
diseases, MRI was useful for distinguishing PM from sIBM.
PMID: 12233884 [PubMed - indexed for MEDLINE]
128: Curr Rheumatol Rep. 2002 Oct;4(5):427-33.
Newest pathogenetic considerations in inclusion-body myositis: possible role
of
amyloid-beta, cholesterol, relation to aging and to Alzheimer's disease.
Askanas V, Engel WK.
University of Southern California Neuromuscular Center, Good Samaritan Hospital,
637 South Lucas Avenue, Los Angeles, CA 90017-1912, USA. askanas@hsc.usc.edu
This report summarizes clinical features and diagnostic criteria, and the newest
advances related to seeking the pathogenic mechanism(s) of sporadic
inclusion-body myositis. On the basis of the authors' research, several
processes seem to be important in relation to the still-speculative
pathogenesis: increased transcription and accumulation of amyloid-b precursor
protein and accumulation of its proteolytic fragment amyloid-b; abnormal
accumulation of components related to lipid metabolism (eg, low-density
lipoprotein receptors and cholesterol; accumulation of cholesterol is possibly
caused by its abnormal trafficking); oxidative stress; accumulations of other
Alzheimer-related proteins including phosphorylated tau; a milieu of muscle
cellular aging in which these changes occur. The authors' basic hypothesis is
that overexpression of amyloid-b precursor protein within the aging muscle
fibers is an early upstream event causing the subsequent pathogenic cascade.
The
remarkable pathologic similarities between inclusion-body myositis muscle and
Alzheimer's disease brain are discussed.
Publication Types:
Review
Review, Tutorial
PMID: 12217248 [PubMed - indexed for MEDLINE]
129: Curr Rheumatol Rep. 2002 Oct;4(5):415-26.
Malignancy in patients with inflammatory myopathy.
Buchbinder R, Hill CL.
Cabrini Medical Centre, Suite 41, 183 Wattletree Road, Malvern, Victoria 3144,
Australia. rachelle.buchbinder@med.monash.edu.au
The most recent evidence from population-based cohort studies confirms the
association between malignancy and dermatomyositis and polymyositis. These
studies show an even stronger association between polymyositis and malignancy
than previous studies, suggesting less misclassification. This is particularly
true of one study that used pathologic criteria to distinguish between myositis
subtypes. Recent data also confirm that the association for dermatomyositis
and
polymyositis is not purely caused by diagnostic suspicion or surveillance bias.
More data are still required to determine individual cancer risks, although
it
appears that ovarian and lung cancer are associated with dermatomyositis while
lung cancer and non-Hodgkin's lymphoma are associated with polymyositis. An
association between malignant disease and inclusion body myositis has also been
verified for the first time. Of interest, too, is the increasing number of
reports documenting cases in which the clinical course of the myositis mirrors
that of the cancer, supporting the notion that in some instances, myositis is
a
paraneoplastic disorder.
Publication Types:
Review
Review, Tutorial
PMID: 12217247 [PubMed - indexed for MEDLINE]
130: Neurology. 2002 Aug 13;59(3):451-4.
Comment in:
Neurology. 2002 Dec 10;59(11):1674-6.
Distal myopathy with rimmed vacuoles: novel mutations in the GNE gene.
Tomimitsu H, Ishikawa K, Shimizu J, Ohkoshi N, Kanazawa I, Mizusawa H.
Department of Neurology and Neurological Science, Graduate School, Tokyo Medical
and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
The authors present three novel missense mutations in the
UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene, the
causative gene for hereditary inclusion body myopathy, in Japanese patients
with
distal myopathy with rimmed vacuoles. Seven out of nine patients had homozygous
V572L mutation, one was a compound heterozygote with C303V and V572L mutations,
and the remaining patient bore homozygous A631V mutation.
PMID: 12177386 [PubMed - indexed for MEDLINE]
131: Acta Neuropathol (Berl). 2002 Sep;104(3):297-304. Epub 2002 Jun 08.
Expression, localization and functional divergence of alphaB-crystallin and
heat
shock protein 27 in core myopathies and neurogenic atrophy.
Fischer D, Matten J, Reimann J, Bonnemann C, Schroder R.
Department of Neurology, University Hospital Bonn, Rheinische
Friedrich-Wilhelms-Universitat, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
AlphaB-crystallin (alphaBC) and heat shock protein 27 (hsp 27) are members
of
the family of small heat shock proteins (shsps), which exert a role as molecular
chaperones by binding unfolded or denatured proteins, thereby suppressing
irreversible protein aggregation and consecutive cell damage. The essential
role
of shsps in human neuromuscular disorders is highlighted by the observation
that
a mutation of the human alphaBC gene causes an autosomal dominant "myofibrillar
myopathy" characterized by alphaBC and desmin accumulation. Furthermore,
an
aberrant immunostaining of alphaBC was recently reported in sporadic inclusion
body myositis. In the present study we analyzed the expression and localization
of alphaB-crystallin and hsp 27 in various congenital myopathies by means of
indirect immunofluorescence, immunogold electron microscopy and Western
blotting. We demonstrate an increased immunoreactivity of alphaBC and hsp 27
in
central and minicore lesions as well as in target fibers, which renders both
shsps as reliable, but nonspecific, markers for core and target structures.
In
contrast, Western blotting demonstrated a normal expression level of alphaBC
and
hsp 27, which indicates that the increased immunostaining is not the result
of
an enhanced protein expression. Furthermore, thiocyanate-induced degradation
of
actin filaments led to a dramatic decrease of hsp 27 immunostaining in core
and
target lesions, whereas the increased alphaBC and desmin immunostaining was
found to be even more enhanced. The latter findings imply a functional diversity
of both shsps with a preferential association of hsp 27 with the actin
microfilament system and alphaBC with the intermyofibrillar desmin cytoskeleton
in human skeletal muscle.
PMID: 12172916 [PubMed - indexed for MEDLINE]
132: Semin Neurol. 2002 Mar;22(1):41-51.
Misunderstandings, misperceptions, and mistakes in the management of the
inflammatory myopathies.
Kissel JT.
Department of Neurology, Ohio State University, Columbus, Ohio 43210-1250, USA.
Many misconceptions persist concerning fundamental issues related to the
idiopathic inflammatory myopathies. Such misconceptions can lead to frank
mistakes in the diagnosis and management of these disorders. In some cases,
these misperceptions have resulted from overreliance on out-of-date information
and "classic" articles that are no longer classic! In other instances,
misperceptions persist because of the many voids in our understanding of these
diseases. This review uses case presentations to highlight important caveats
in
diagnosing and managing the common idiopathic inflammatory myopathies.
Publication Types:
Case Reports
Review
Review, Tutorial
PMID: 12170392 [PubMed - indexed for MEDLINE]
133: Neurology. 2002 Jun 25;58(12):1779-85.
Differential expression of chemokines in inflammatory myopathies.
De Bleecker JL, De Paepe B, Vanwalleghem IE, Schroder JM.
Department of Neurology, University Hospital, Gent, Belgium.
jan.debleecker@rug.ac.be
BACKGROUND: Chemokines represent a family of small-molecular-weight cytokines
that recruit and activate inflammatory cells in response to inflammation.
Invasion of cytotoxic memory T cells and macrophages in nonnecrotic muscle
fibers characterizes polymyositis and sporadic inclusion body myositis.
Dermatomyositis is a complement-mediated endotheliopathy. Elucidation of the
mechanisms guiding lymphocyte diapedesis and trafficking could lead to selective
therapeutic interventions. METHODS: Immunoblots and multistep immunofluorescence
studies with non-cross-reactive antibodies recognizing interleukin-8, monocyte
chemoattractant protein-1 (MCP-1), MCP-3, TARC (thymus and activation regulated
cytokine), and RANTES (regulated upon activation, normal T-cell expressed and
secreted), using appropriate positive and negative controls. In situ
hybridization was used to localize MCP-1 mRNA. RESULTS: MCP-1 protein was
strongly expressed on T cells and a subset of macrophages actively invading
a
proportion of the nonnecrotic muscle fibers in polymyositis and inclusion body
myositis alike. Capillaries and arterioles in the vicinity of endomysial
inflammatory foci were immunoreactive for MCP-1, with faint or no expression
in
unaffected parts of the tissue. By contrast, widespread and strong endothelial
MCP-1 expression occurred on perifascicular and perimysial endothelia in
dermatomyositis, also at sites remote from inflammatory infiltrates. In some
control specimens, a subset of capillaries also expressed MCP-1, possibly
reflecting a role of this chemokine in normal immune surveillance. MCP-1 mRNA
was detected in scattered macrophages in each inflammatory myopathy. All other
chemokines were absent. CONCLUSION: Chemokines are differentially expressed
in
the symptomatic stage of inflammatory myopathies. MCP-1 plays a major role in
the myocytotoxicity in polymyositis and inclusion body myositis. MCP-1 may be
induced by membranolytic attack complex binding to endothelial cells in
dermatomyositis.
PMID: 12084877 [PubMed - indexed for MEDLINE]
134: Acta Neurol Scand. 2002 May;105(5):403-7.
Expression of Bcl-2 in inclusion body myositis.
Fyhr IM, Lindberg C, Oldfors A.
Department of Pathology, Sahlgrenska University Hospital, Goteborg University,
S-413 45 Goteborg, Sweden. ingmarie.fyhr@path.gu.se
OBJECTIVES: On the background of the possible role of the anti-apoptotic protein
Bcl-2 to inhibit apoptosis induced by the Fas/Fas ligand system in inflammatory
myopathies we investigated the expression of Bcl-2 in inclusion body myositis
(IBM). MATERIAL AND METHODS: We examined muscle tissue from seven IBM patients
and controls by immunocytochemistry using antibodies against Bcl-2, Fas (a
member of the tumor necrosis factor receptor family) and the regeneration
marker, neural cell adhesion molecule (N-CAM). We also investigated the
occurrence of DNA fragmentation by the terminal deoxynucleotidyl transferase
(TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labeling
(TUNEL)-method. RESULTS: Both Bcl-2 and Fas were up-regulated in muscle fibers
in IBM and disease controls. Bcl-2 was expressed by regenerating muscle fibers
while Fas was expressed by non-regenerating muscle fibers associated with
inflammatory cell infiltrates. Bcl-2 and Fas were also expressed by inflammatory
cells. There were scattered TUNEL positive nuclei and most of these appeared
to
be inflammatory cells. CONCLUSION: The low occurrence of apoptotic myonuclei
is
not related to Bcl-2 expression, which is confined to regenerating muscle cells
in IBM and other myopathies.
PMID: 11982494 [PubMed - indexed for MEDLINE]
135: Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6334-9. Epub 2002 Apr 23.
Inclusion body myositis-like phenotype induced by transgenic overexpression
of
beta APP in skeletal muscle.
Sugarman MC, Yamasaki TR, Oddo S, Echegoyen JC, Murphy MP, Golde TE, Jannatipour
M, Leissring MA, LaFerla FM.
Department of Neurobiology and Behavior, University of California, Irvine,
CA
92697, USA.
Inclusion body myositis (IBM), the most common age-related muscle disease in
the
elderly population, is an incurable disorder leading to severe disability.
Sporadic IBM has an unknown etiology, although affected muscle fibers are
characterized by many of the pathobiochemical alterations traditionally
associated with neurodegenerative brain disorders such as Alzheimer's disease.
Accumulation of the amyloid-beta peptide, which is derived from proteolysis
of
the larger amyloid-beta precursor protein (betaAPP), seems to be an early
pathological event in Alzheimer's disease and also in IBM, where in the latter,
it predominantly occurs intracellularly within affected myofibers. To elucidate
the possible role of betaAPP mismetabolism in the pathogenesis of IBM,
transgenic mice were derived in which we selectively targeted betaAPP
overexpression to skeletal muscle by using the muscle creatine kinase promoter.
Here we report that older (>10 months) transgenic mice exhibit intracellular
immunoreactivity to betaAPP and its proteolytic derivatives in skeletal muscle.
In this transgenic model, selective overexpression of betaAPP leads to the
development of a subset of other histopathological and clinical features
characteristic of IBM, including centric nuclei, inflammation, and deficiencies
in motor performance. These results are consistent with a pathogenic role for
betaAPP mismetabolism in human IBM.
PMID: 11972038 [PubMed - indexed for MEDLINE]
136: J Neurol Neurosurg Psychiatry. 2002 May;72(5):650-2.
Human T cell leukaemia virus type I associated neuromuscular disease causing
respiratory failure.
Littleton ET, Man WD, Holton JL, Landon DN, Hanna MG, Polkey MI, Taylor GP.
The National Hospital for Neurology and Neurosurgery, University College London
Hospitals NHS Trust, Queen Square, London, UK.
Polymyositis and inclusion body myositis have rarely been described in
association with human T cell leukaemia virus type I (HTLV-I) infection. Most
of
such patients have coexisting HTLV-I associated myelopathy (HAM). Two patients
with HTLV-I infection, myopathy, and respiratory failure are described. The
muscle biopsy specimen of the first patient bore the histological features of
inclusion body myositis and there was no evidence of concurrent myelopathy.
The
second patient had HAM, and her muscle biopsy showed non-specific myopathic
and
neuropathic changes. Both patients developed respiratory muscle weakness over
eight years after diagnosis of myopathy, leading to hypercapnic respiratory
failure requiring mechanical ventilatory support. Respiratory failure as a
complication of HTLV-I associated myopathy has not previously been described.
Publication Types:
Case Reports
PMID: 11971056 [PubMed - indexed for MEDLINE]
137: Rheumatology (Oxford). 2002 Apr;41(4):440-4.
Primary Sjogren's syndrome associated with inclusion body myositis.
Kanellopoulos P, Baltoyiannis C, Tzioufas AG.
Department of Pathophysiology, School of Medicine, University of Athens, Greece.
OBJECTIVE: To describe three new patients with inclusion body myositis (IBM)
associated with primary Sjogren's syndrome (pSS) and summarize the clinical
and
serological picture for all six patients reported so far. PATIENTS AND METHODS:
Three out of 518 (0.6%) pSS patients followed in our department over a period
of
15 yr (1985-2000) also presented IBM. The diagnosis was based on histological
criteria. Previous reports described four more patients with IBM associated
with
pSS. Five out of six were females; the mean age of IBM onset was 53.3+/-14.0
yr
and the disease duration 8.0+5.8 yr. RESULTS: Four out of six patients presented
IBM several years after the onset of pSS. Four out of six patients presented
extraglandular manifestations, such as arthralgias, vitamin B12 deficiency,
interstitial kidney disease and biliary cirrhosis. The serological picture did
not differ significantly from that observed in pSS alone. CONCLUSION: Although
rare, IBM may be seen in patients with pSS and it affects predominantly women.
The clinical and pathological pictures do not differ from those observed in
idiopathic IBM. A common autoimmune pathway in these two diseases, but no
definite conclusions can be drawn.
Publication Types:
Case Reports
PMID: 11961175 [PubMed - indexed for MEDLINE]
138: J Neurol. 2002 Jan;249(1):69-75.
Clinical and serological characteristics of 125 Dutch myositis patients.
Myositis specific autoantibodies aid in the differential diagnosis of the
idiopathic inflammatory myopathies.
Hengstman GJ, Brouwer R, Egberts WT, Seelig HP, Jongen PJ, van Venrooij WJ,
van
Engelen BG.
Neuromuscular Centre Nijmegen, Institute of Neurology, University Medical Centre
Nijmegen, The Netherlands. g.hengstman@czzoneu.azn.nl
The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of
systemic diseases that include the familiar disease entities of dermatomyositis
(DM), polymyositis (PM), and inclusion body myositis (IBM). A subset of patients
has unique autoantibodies which are specific for IIM (myositis specific
autoantibodies; MSAs). We studied the clinical and serological characteristics
of IIM in 125 Dutch patients. Sera were analysed by immunoblotting,
enzyme-linked immunosorbent assay, and immunoprecipitation. The most frequently
encountered MSA was the anti-Jo-1 autoantibody (20%), followed by anti-tRNAHis
(6%), anti-Mi-2 (6%), and anti-SRP (4%). The presence of certain MSAs was
clearly associated with specific clinical characteristics. Anti-Jo-1 and
anti-tRNAHis were associated with the anti-synthetase syndrome, anti-SRP with
PM
with severe myalgia and arthralgia and a moderate response to immunosuppressive
treatment. A novel finding was the presence of anti-Mi-2, not only in DM, but
also in PM. MSAs were frequently present in DM/PM sera, but were hardly ever
detected in the sera of IBM patients. The few IBM patients with MSAs
demonstrated a significant response to immunosuppressive treatment. It can be
concluded that MSAs define specific clinical syndromes within the spectrum of
IIM and that they can assist in the differential diagnosis and treatment plan
of
these enigmatic disorders by virtually excluding IBM by their presence, and
by
potentially identifying a subgroup of steroid-responsive IBM patients.
PMID: 11954871 [PubMed - indexed for MEDLINE]
139: J Rheumatol. 2002 Apr;29(4):717-25.
Subclinical myositis is common in primary Sjogren's syndrome and is not related
to muscle pain.
Lindvall B, Bengtsson A, Ernerudh J, Eriksson P.
Department of Clinical Neurosciences and Locomotion, University Hospital,
Linkoping, Sweden. Bjorn.Lindvall@lio.se
OBJECTIVE: Although muscle pain is common in primary Sjogren's syndrome (SS),
the underlying mechanisms are mainly unknown. We studied all patients with SS
at
our rheumatology unit with respect to muscle pain in general and to fibromyalgia
(FM), and correlated clinical data to muscle biopsy findings. METHODS: We
investigated 48 patients with SS according to the modified European diagnostic
criteria. The ACR criteria for FM were used to subgroup the patients. Muscle
biopsy was performed in 36 patients. Light microscope morphology and
immunohistochemical expression of MHC class I, MHC class II, and membrane attack
complex (MAC) were studied. RESULTS: We found 44% of patients complained of
muscle pain; 27% fulfilled the ACR criteria for FM, whereas 17% had other forms
of myalgia. Muscle pain could not be related to histopathological findings.
Signs of inflammation were found in 26 of 36 biopsies (72%), and inflammation
combined with degeneration/regeneration (i.e., histological signs of
polymyositis) in 17 biopsies (47%). However, only 5 patients (14%) had clinical
as well as histological signs of polymyositis. Eight muscle biopsies (22%)
showed histological features of inclusion body myositis (IBM). However, no
patient had clinical symptoms suggestive of this disease. Abnormal expression
of
MHC class I, MHC class II, and MAC was found in 18 (50%), 16 (44%), and 27 (75%)
patients, respectively. CONCLUSION: Muscle pain, especially FM, is common in
SS.
Histopathological signs of myositis are very common in SS. However, muscle
symptoms are not related to histological signs of muscle inflammation. IBM-like
findings may represent vacuolar myopathic degeneration due to previous
subclinical muscle inflammation rather than a specific clinical entity.
PMID: 11950012 [PubMed - indexed for MEDLINE]
140: Neurology. 2002 Apr 9;58(7):1081-7.
A pilot randomized trial of oxandrolone in inclusion body myositis.
Rutkove SB, Parker RA, Nardin RA, Connolly CE, Felice KJ, Raynor EM.
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical
School, Boston, MA 02215, USA. srutkove@caregroup.harvard.edu
BACKGROUND: Inclusion body myositis (IBM) remains without effective therapy.
As
anabolic steroids have myotrophic properties, the authors studied whether a
synthetic androgen, oxandrolone, would have efficacy in IBM. METHODS: A
double-blind, placebo-controlled, crossover design was used. Patients received
oxandrolone or placebo for 12 weeks followed by a minimum 2-month washout
period, followed by 12 weeks of the alternative treatment. Maximal voluntary
isometric contraction testing (MVICT), manual muscle testing (MMT), and
functional performance testing were obtained before and after each treatment
period, with the whole-body MVICT score as the primary outcome measure. RESULTS:
Of 19 patients enrolled, 16 (14 men, 2 women; median age 68.5 years) had
complete data for at least the first treatment period, with 13 completing the
entire study. Whole-body MVICT improved by a median of 15.5 kg with drug and
4.1
kg with placebo (p = 0.06), whereas MMT demonstrated a median increase of 2.0
Medical Research Council points with drug and 0.9 point with placebo (p = 0.33).
Upper-extremity MVICT demonstrated a significant treatment effect, with strength
increasing a median 6.3 kg with drug vs 2.5 kg with placebo (p = 0.006). Stair
climbing also increased a median of 1 step on average with drug versus no change
with placebo (p < 0.001). Minimal adverse effects occurred. CONCLUSIONS:
Oxandrolone had a borderline significant effect in improving whole-body strength
and a significant effect in improving upper-extremity strength as measured by
MVICT. Given these findings, further study of this drug, possibly in combination
with an immunomodulating agent, is warranted.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 11940697 [PubMed - indexed for MEDLINE]
141: Acta Neurol Scand. 2002 Apr;105(4):309-13.
Matrix metalloproteinases in inflammatory myopathies: enhanced immunoreactivity
near atrophic myofibers.
Schoser BG, Blottner D, Stuerenburg HJ.
Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximillians
University Munich, Munich, Germany. benedikt.schoser@fbs.med.uni-muenchen.de
OBJECTIVES: To further examine the role of proteolytic enzyme expression of
matrix metalloproteinases (MMP) and T-cell markers in inflammatory myopathies
and controls. MATERIAL AND METHODS: We studied the expression of MMP-2, MMP-7,
and MMP-9 in 19 cases of inflammatory myopathies and controls using
immunocytochemistry. RESULTS: Inflammatory myopathies showed distinct patterns
of up-regulation of MMP. MMP-9 was strongly expressed in atrophic myofibers
in
all inflammatory myopathies. MMP-2 immunoreactivity was similar in its
distribution, however, to a weaker intensity. In dermatomyositis the
perifascicular atrophy showed pronounced MMP-9 immunoreactivity, probably
reflecting denervated patterns of myofibers. Moreover, MMP-7 strongly
immunolabeled invaded myofibers in polymyositis cases only. CONCLUSION: These
patterns confirm, that MMP-7 up-regulation is prominent in PM, while MMP-2
immunoreactivity is only slightly elevated in inflamed muscle. In general, MMP-9
up-regulation appears to be an important additional molecular event in the
multistep process of all inflammatory myopathies.
PMID: 11939944 [PubMed - indexed for MEDLINE]
142: Pediatr Dev Pathol. 2002 Mar-Apr;5(2):151-8.
Aluminum phagocytosis in quadriceps muscle following vaccination in children:
relationship to macrophagic myofasciitis.
Lacson AG, D'Cruz CA, Gilbert-Barness E, Sharer L, Jacinto S, Cuenca R.
Departments of Pediatrics and Pathology, University of South Florida at All
Children's Hospital, 801 Sixth Street South 7020, St. Petersburg, FL 33731,
USA.
Macrophagic myofasciitis (MMF) is a rare, seemingly emerging entity among adult
patients in France. We encountered two children with the first two cases of
MMF
in North America. A 5-year-old male with chronic intestinal pseudo-obstruction
required nighttime parenteral nutrition. Abnormal pupillary reflexes and urinary
retention suggested a diffuse dysautonomia, which prompted a neurological
diagnostic work-up. A 3-year-old child had developmental delay and hypotonia.
Both children received age-appropriate immunizations. Quadriceps muscle biopsy
from each child showed the typical patchy, cohesive centripetal infiltration
of
alpha-1-antitrypsin+, alpha-1-antichymotrypsin+, CD68+, PAS+, CD1a-, S-100-,
factor XIII- granular macrophages with adjacent myofiber atrophy, dilated blood
vessels, and mild endomysial and perimysial fibrosis. No myonecrosis was
observed and no discrete granulomas were seen. A single aluminum peak was
demonstrated on energy dispersive X-ray microanalysis. The etiology of the
clinical symptoms in these cases and in cases reported as MMF remains
intriguing. Despite numerous stains to demonstrate organisms, most infectious
causes leading to macrophage activation were ruled out. These cases are being
reported to increase awareness of this condition and to encourage a systematic
epidemiologic and clinicopathologic study in North America.
Publication Types:
Case Reports
PMID: 11910509 [PubMed - indexed for MEDLINE]
143: Ann Neurol. 2002 Mar;51(3):369-72.
Comparison of weakness progression in inclusion body myositis during treatment
with methotrexate or placebo.
Badrising UA, Maat-Schieman ML, Ferrari MD, Zwinderman AH, Wessels JA, Breedveld
FC, van Doorn PA, van Engelen BG, Hoogendijk JE, Howeler CJ, de Jager AE,
Jennekens FG, Koehler PJ, de Visser M, Viddeleer A, Verschuuren JJ, Wintzen
AR.
Department of Neurology, Leiden University Medical Center, The Netherlands.
ubadrising@lumc.nl
We investigated whether 5 to 20mg per week oral methotrexate could slow down
disease progression in 44 patients with inclusion body myositis in a randomized
double-blind placebo-controlled study over 48 weeks. Mean change of quantitative
muscle strength testing sum scores was the primary study outcome measure.
Quantitative muscle strength testing sum scores declined in both treatment
groups, -0.2% for methotrexate and -3.4% for placebo (95% confidence interval
=
-2.5% to +9.1% for difference). There were also no differences in manual muscle
testing sum scores, activity scale scores and patients' own assessments after
48
weeks of treatment. Serum creatine kinase activity decreased significantly in
the methotrexate group. We conclude that oral methotrexate did not slow down
progression of muscle weakness but decreased serum creatine kinase activity.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 11891832 [PubMed - indexed for MEDLINE]
144: Neurology. 2002 Mar 12;58(5):780-6.
Myosin heavy chain IIa gene mutation E706K is pathogenic and its expression
increases with age.
Tajsharghi H, Thornell LE, Darin N, Martinsson T, Kyllerman M, Wahlstrom J,
Oldfors A.
Department of Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden.
BACKGROUND: The authors recently described a new autosomal dominant myopathy
(OMIM 605637 inclusion body myopathy 3) associated with a missense mutation
in
the myosin heavy chain (MyHC) IIa gene (MyHC IIa, Human Gene Map [HGM] locus
MYH2). Young patients showed minor changes in their muscle biopsies, although
dystrophic alterations and rimmed vacuoles with 15- to 20-nm tubulofilaments
identical to those in sporadic inclusion body myositis (s-IBM) were observed
in
some of the adult (especially older) patients. The current study was undertaken
to investigate the relation between expression of the mutant MyHC IIa and
pathologic changes in muscle. METHODS: The expression of MyHC IIa in nine muscle
specimens from six individuals carrying the mutation was analyzed by
immunohistochemistry, sodium dodecyl sulfate-polyacrylamide gel electrophoresis,
and a new reverse transcriptase--PCR method to measure the relative abundance
of
the various MyHC transcripts. RESULTS: Young patients with muscle weakness and
minor pathologic changes in muscle expressed MyHC IIa at undetectable levels.
MyHC IIa was expressed at high levels in adults with a progressive clinical
course and dystrophic muscle changes. In these cases, a large number of muscle
fibers were hybrids with expression of more than one MyHC isoform. Both MyHC
IIa
alleles were equally expressed. The relative level of MyHC IIa transcripts
exceeded that of the corresponding protein, indicating an increased turnover
of
mutated protein. MyHC IIa expression was a consistent finding in muscle fibers
with rimmed vacuoles. CONCLUSIONS: The clear correlation between pathologic
changes and expression of MyHC IIa indicates that defects in MyHC may lead not
only to muscle weakness but also to muscle degeneration. The consistent
expression of MyHC IIa in muscle fibers with rimmed vacuoles indicates that
the
breakdown of sarcomeric proteins is a key element in the pathogenesis of rimmed
vacuoles of s-IBM type.
PMID: 11889243 [PubMed - indexed for MEDLINE]
145: Muscle Nerve. 2002 Mar;25(3):390-7.
Localized bioimpedance analysis in the evaluation of neuromuscular disease.
Rutkove SB, Aaron R, Shiffman CA.
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical
School, 330 Brookline Avenue, TCC-810, Boston, Massachusetts 02215, USA.
Localized bioimpedance analysis is a novel, noninvasive technique with potential
application to neuromuscular disease. In this procedure, high-frequency
alternating current is passed through muscle, and parameters related to the
consequent voltage pattern are evaluated. Currents flowing perpendicular to
muscle fibers encounter many more cell membranes than do currents flowing
parallel to them, producing surface voltage patterns that are altered by
disease. Using this technique, 45 normal subjects and 25 patients with various
neuromuscular diseases were studied, including 4 with amyotrophic lateral
sclerosis, 4 with inflammatory myopathy, and 11 with inclusion-body myositis.
Two parameters, the spatially averaged phase and the effective longitudinal
resistivity, were altered in patients with neuromuscular disease. Reductions
in
phase correlated to disease progression, whereas normalization of phase
correlated with disease remission. In patients with inclusion-body myositis,
a
unique pattern of reduced phase and elevated resistivity was identified. These
findings suggest that localized bioimpedance analysis has the potential of
playing a substantial role in the diagnostic and therapeutic evaluation of
neuromuscular disease. Copyright 2002 Wiley Periodicals, Inc.
PMID: 11870716 [PubMed - indexed for MEDLINE]
146: Neurology. 2002 Feb 12;58(3):438-45.
Three lipoprotein receptors and cholesterol in inclusion-body myositis muscle.
Jaworska-Wilczynska M, Wilczynski GM, Engel WK, Strickland DK, Weisgraber KH,
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.
BACKGROUND: An important aspect of inclusion-body myositis (IBM) vacuolated
muscle fibers (VMF) is abnormal accumulation of amyloid-beta precursor protein
(AbetaPP) epitopes and its product, amyloid-beta (Abeta), and of phosphorylated
tau (p-tau) in the form of paired helical filaments. Lipoprotein receptors and
cholesterol are known to play an important role in AbetaPP processing, Abeta
production, and tau phosphorylation. METHODS: In 10 IBM and 22 control muscle
biopsies the authors immunolocalized low-density lipoprotein receptor (LDLR),
very low-density lipoprotein receptor (VLDLR), and low-density lipoprotein
receptor-related protein (LRP), and colocalized them with Abeta, p-tau, APOE,
and free cholesterol. RESULTS: In each biopsy, virtually all IBM VMF had strong
LDLR-immunoreactive inclusions, which colocalized with Abeta, APOE, p-tau, and
free cholesterol. VLDLR was increased mainly diffusely, but in approximately
50%
of the VMF it was also accumulated in the form of inclusions colocalizing with
Abeta, APOE, and free cholesterol, but not with p-tau. LRP inclusions were
present in a few VMF. In all myopathies, a subset of regenerating and
necrotizing muscle fibers had prominent diffuse accumulation of both LDLR and
free cholesterol. At normal neuromuscular junctions (NMJ) postsynaptically,
LDLR
and VLDLR, but not LRP, were immunoreactive. CONCLUSIONS: 1) Abnormal
accumulation of LDLR, VLDLR, LRP, and cholesterol within IBM vacuolated muscle
fibers suggests novel roles for them in the IBM pathogenesis. 2) Expression
of
LDLR and VLDLR at normal NMJ suggests physiologic roles for them in
transsynaptic signaling pathways, increased internalization of lipoproteins
there, or both. 3) Increased LDLR and free cholesterol in some regenerating
and
necrotizing muscle fibers suggest a role for them in human muscle fiber growth
and repair and necrotic death.
PMID: 11839845 [PubMed - indexed for MEDLINE]
147: Acta Neuropathol (Berl). 2002 Jan;103(1):59-65.
Increased expression of manganese superoxide dismutase is associated with that
of nitrotyrosine in myopathies with rimmed vacuoles.
Tsuruta Y, Furuta A, Taniguchi N, Yamada T, Kira J, Iwaki T.
Department of Neuropathology, Neurological Institute, Graduate School of Medical
Sciences, Kyushu University, Fukuoka, Japan.
Oxidative stress has been suggested as one of the pathogenetic mechanisms of
inclusion body myositis (IBM). To study the role of antioxidant enzymes in
myopathies with rimmed vacuoles, we examined expressions of copper, zinc
superoxide dismutase (Cu, Zn-SOD) and manganese superoxide dismutase (Mn-SOD),
and the relationship between SODs and other proteins localized in rimmed
vacuoles in muscle biopsy specimens from three cases of sporadic IBM and two
of
distal myopathy with rimmed vacuoles (DMRV) as well as eight control cases of
myopathies without rimmed vacuoles. Immunoblot analysis showed distinct protein
bands of both SODs in IBM and DMRV using subtype-specific antibodies.
Intensities of immunoreactive bands for Mn-SOD in IBM and DMRV were stronger
than those in the control cases. Immunohistochemistry disclosed accumulation
of
both SODs in vacuolated muscle fibers in all cases of IBM and DMRV.
Immunoreactivity for Mn-SOD was often colocalized with that of nitrotyrosine,
cytochrome oxidase, tau, and lysosome-associated membrane proteins 2 (LAMP-2)
in
vacuolated fibers. Some of the Cu, Zn-SOD-positive vacuolated fibers were
associated with ubiquitin. The two SODs may have different roles for cell
protection, and the expression of Mn-SOD is associated with nitric oxide-induced
oxidative damage in myopathies with rimmed vacuoles.
PMID: 11837748 [PubMed - indexed for MEDLINE]
148: Acta Paediatr Taiwan. 2001 Nov-Dec;42(6):367-9.
Stiff-Baby--an unusual manifestation of cytoplasmic body myopathy: report of
one
case.
Chen YD, Chen CH, Mak SC, Chi CS.
Department of Pediatrics, Taichung Veterans General Hospital, Taiwan.
A 2-month-old male baby was admitted to our hospital with episodic cyanosis
and
respiratory failure which required mechanical ventilation. He was found to have
upper limb flexion rigidity and poor weight gain since one month old.
Progressive muscle stiffness over the abdomen, chest wall, back and four limbs
were also noted. He could not be weaned from the ventilator smoothly due to
recurrent CO2 retention. Laboratory tests revealed a high serum creatine kinase
level. Cytoplasmic body myopathy was confirmed by muscle biopsy. The unusual
initial presentations of generalized stiffness and early onset of respiratory
failure were quite different from those of patients reported in the literature,
who had floppiness, muscular atrophy and weakness. Prednisolone and Vigabatrin
were given and the patient showed slight improvement in muscle stiffness and
spontaneous movement.
Publication Types:
Case Reports
PMID: 11811228 [PubMed - indexed for MEDLINE]
149: Neurology. 2002 Jan 22;58(2):326.
Intravenous immunoglobulin for dysphagia of inclusion body myositis.
Cherin P, Pelletier S, Teixeira A, Laforet P, Simon A, Herson S, Eymard B.
Service de Medecine Interne I, Hopital Salpetriere, Paris, France.
patrick.cherin@psl.ap-hop-paris.fr
Publication Types:
Case Reports
PMID: 11805271 [PubMed - indexed for MEDLINE]
150: Arch Pathol Lab Med. 2002 Jan;126(1):105-6.
Pathologic quiz case: male with chronic progressive painless muscle weakness.
Ciliberti EF, Prayson RA.
Department of Neurology, Cleveland Clinic Florida, Fort Lauderdale, USA.
Publication Types:
Case Reports
PMID: 11800662 [PubMed - indexed for MEDLINE]
151: J Neurol Neurosurg Psychiatry. 2002 Feb;72(2):203-10.
An expanded cortical representation for hand movement after peripheral motor
denervation.
Reddy H, Bendahan D, Lee MA, Johansen-Berg H, Donaghy M, Hilton-Jones D,
Matthews PM.
Centre for Functional Magnetic Resonance Imaging of the Brain (fMRIB),
Department of Clinical Neurology, University of Oxford, Oxford, UK.
OBJECTIVES: Functional reorganisation of the motor or sensory cortex has been
demonstrated in animals after section of mixed peripheral nerves. Here
functional changes in the motor cortex specifically after peripheral motor
denervation in humans are investigated. METHODS: Functional MRI (fMRI) was used
to study brain activation during a finger flexion-extension task in patients
with a late onset, acquired pure motor neuropathy (n=6), contrasting results
with those from patients with pure sensory neuropathies (n=4) or healthy
controls (n=7). RESULTS: Increases in the extent of activation in the motor
cortex both ipsilateral and contralateral to the hand moved were found in the
patients with motor neuropathy. The neuroanatomical localisation of the mixed
contralateral sensorimotor cortex activation volume was more posterior for the
patients with motor neuropathy than for the healthy controls (mean difference,
12 mm, p<0.05). The pure sensory neuropathy group by contrast showed no change
in the extent of activation relative to healthy controls and a trend for more
anterior primary sensorimotor cortex activation (p<0.06). To test whether
the
increased activation volumes found in patients with motor neuropathy were a
result simply of factors such as increased effort with movement rather than
the
motor denervation, patients with hand weakness from inclusion body myositis
(n=4) were studied while making similar hand movements. No differences in either
the numbers of significantly activated voxels or in their localisation were
found relative to healthy controls (n=10). CONCLUSIONS: These results provide
a
novel demonstration that peripheral denervation (as distinguished from factors
related to weakness) leads to functional reorganisation of the sensorimotor
cortex in the adult brain. This suggests that adaptive responses to motor
denervation involve the central as well as the peripheral nervous system.
PMID: 11796770 [PubMed - indexed for MEDLINE]
152: Rheumatology (Oxford). 2002 Jan;41(1):22-6.
Outcome in patients with idiopathic inflammatory myositis: morbidity and
mortality.
Sultan SM, Ioannou Y, Moss K, Isenberg DA.
Centre for Rheumatology, Department of Medicine, University College Hospital,
London W1P 9PG, UK.
OBJECTIVE: To assess the long-term outcome of a cohort of 46 patients with
idiopathic myositis by assessing both health status, as measured by the SF-36,
and cumulative survival probability over a 20-yr follow-up period at a single
rheumatology centre. Methods and results. Forty-six patients under long-term
follow-up from 1978 to 1999 were identified from our database. All patients
fulfilled three out of four of the Bohan and Peter criteria for myositis. We
excluded those with malignancy-associated disease and those with inclusion body
myositis. Twenty-three patients (50%) had adult-onset polymyositis, 14 (30.4%)
had adult-onset dermatomyositis, one had childhood-onset dermatomyositis and
eight (17.4%) had an overlap syndrome (associated with either systemic lupus
erythematosus or rheumatoid arthritis). During the course of the disease, seven
patients (15.2%) went into full remission, eight (17.4%) had monophasic illness,
nine (19.6%) had a relapsing-remitting course, 16 (34.8%) had chronic
progressive illness and six (13.04%) died. All patients had significantly lower
SF-36 scores in all aspects of health compared with the general population (P<
or =0.001). Patients with chronic progressive illness had significantly greater
bodily pain (P< or =0.05, t-test) than those with a relapsing-remitting illness,
but did not differ in other aspects of health. There was no significant
difference in the scores in the different domains of the SF-36 between the
patients with active disease and those with inactive disease (0.05<P<0.1).
Six
of the 46 patients died. Cumulative survival probability was calculated. The
five-year survival rate was 95% and the 10-yr survival rate 83.8%. CONCLUSION:
Patients with myositis report significantly poorer health compared with the
general population. Health status and disease activity are important outcome
measures in the assessment of patients with myositis.
PMID: 11792875 [PubMed - indexed for MEDLINE]
153: Fukuoka Igaku Zasshi. 2001 Nov;92(11):370-6.
Inclusion body myositis associated with hepatitis C virus infection.
Tsuruta Y, Yamada T, Yoshimura T, Satake M, Ogata K, Yamamoto T, Furuya H,
Kira
J.
Department of Neurology, Neurological Institute, Graduate School of Medical
Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582,
Japan.
Inclusion body myositis (IBM) is a chronic progressive inflammatory myopathy
in
elders. Three patients with chronic hepatitis C developed IBM. Their muscle
biopsies were examined by polymerase chain reaction (PCR) for two patients and
immunohistochemistry for three patients. The hepatitis C virus (HCV)-RNA genome
was detected in one of the two patients. The degenerated and atrophic muscle
fibers were immunoreactive for an anti-HCV antibody in all three patients.
Immunoreactivity for an anti-HCV antibody was not apparent in the muscle
specimen from an IBM patient without HCV infection. Our findings suggest that
HCV infection is related to the pathogenesis in some cases of IBM.
PMID: 11774706 [PubMed - indexed for MEDLINE]
154: Expert Opin Investig Drugs. 2001 Jul;10(7):1265-77.
Recent advances in the management of adult myositis.
Fam AG.
Division of Rheumatology, Sunnybrook and Women's College Health Sciences Centre,
University of Toronto, Toronto, Ontario, Canada. adel.fam.@swchsc.on.ca
Standard drug therapy of adult polymyositis, dermatomyositis and inclusion
body
myositis includes high-dose corticosteroids and cytotoxic drugs (methotrexate,
azathioprine (AZA) and cyclophosphamide). Recent data are in favour of the early
introduction of a cytotoxic or immunomodulating drug in addition to
corticosteroid therapy. In patients with corticosteroid- and cytotoxic-resistant
myositis, promising novel approaches to management include: iv. megadose pulse
methylprednisolone combined with cytotoxic drugs, combination therapy with both
methotrexate and AZA, cyclosporin, tacrolimus, fludarabine and iv.
immunoglobulin (IVIG). Recent advances in the understanding of the role of
cytokines and complement, in the pathogenesis of myositis, have led to
preliminary therapeutic trials of three biological agents: etanercept,
infliximab and anti-C5 monoclonal antibody.
Publication Types:
Review
Review, Tutorial
PMID: 11772250 [PubMed - indexed for MEDLINE]
155: Mol Genet Metab. 2001 Dec;74(4):458-75.
Clinical delineation and localization to chromosome 9p13.3-p12 of a unique
dominant disorder in four families: hereditary inclusion body myopathy, Paget
disease of bone, and frontotemporal dementia.
Kovach MJ, Waggoner B, Leal SM, Gelber D, Khardori R, Levenstien MA, Shanks
CA,
Gregg G, Al-Lozi MT, Miller T, Rakowicz W, Lopate G, Florence J, Glosser G,
Simmons Z, Morris JC, Whyte MP, Pestronk A, Kimonis VE.
Division of Genetics and Metabolism, Department of Pediatrics, Southern Illinois
University-School of Medicine, Springfield, Illinois, USA.
Autosomal dominant myopathy, Paget disease of bone, and dementia constitute
a
unique disorder (MIM 605382). Here we describe the clinical, biochemical,
radiological, and pathological characteristics of 49 affected (23 male, 26
female) individuals from four unrelated United States families. Among these
affected individuals 90% have myopathy, 43% have Paget disease of bone, and
37%
have premature frontotemporal dementia. EMG shows myopathic changes and muscle
biopsy reveals nonspecific myopathic changes or blue-rimmed vacuoles. After
candidate loci were excluded, a genome-wide screen in the large Illinois family
showed linkage to chromosome 9 (maximum LOD score 3.64 with marker D9S301).
Linkage analysis with a high density of chromosome 9 markers generated a maximum
two-point LOD score of 9.29 for D9S1791, with a maximum multipoint LOD score
of
12.24 between D9S304 and D9S1788. Subsequent evaluation of three additional
families demonstrating similar clinical characteristics confirmed this locus,
refined the critical region, and further delineated clinical features of this
unique disorder. Hence, autosomal dominant inclusion body myopathy (HIBM), Paget
disease of bone (PDB), and frontotemporal dementia (FTD) localizes to a
1.08-6.46 cM critical interval on 9p13.3-12 in the region of autosomal recessive
IBM2. Copyright 2001 Elsevier Science.
PMID: 11749051 [PubMed - indexed for MEDLINE]
156: Microsc Res Tech. 2001 Nov 15;55(4):249-58.
Oxides and apoptosis in inflammatory myopathies.
Stangel M, Mix E, Zettl UK, Gold R.
Department of Neurology, Universitatsklinikum Benjamin Franklin, Free University
Berlin, D-12200 Berlin, Germany.
Reactive oxygen intermediates (ROI) and nitric oxide (NO(.)) are produced in
abundance in the inflammatory muscle diseases of autoimmune origin polymyositis
(PM), dermatomyositis (DM), and inclusion body myositis (IBM). However, their
role in the pathogenesis of these diseases is so far not clear. In contrast
to
demyelinating neuropathies, there is no convincing evidence for oxide-induced
apoptosis either in myocytes or in lymphocytes and phagocytes in inflammatory
myopathies. On the contrary, NO(.) released at low concentrations at target
sites may even have cell-protective effects. A major mechanism of protection
from apoptosis in both myocytes and inflammatory cells seems to be the
upregulation of anti-apoptotic proteins like Bcl-2. Caution is warranted to
apply antioxidative and anti-apoptotic agents to patients with inflammatory
myopathies as long as the pathogenic role of oxides and apoptosis in the
individual case is not resolved. Copyright 2001 Wiley-Liss, Inc.
Publication Types:
Review
Review, Tutorial
PMID: 11748863 [PubMed - indexed for MEDLINE]
157: Lancet. 2001 Dec 8;358(9297):1962-4.
Presence of BACE1 and BACE2 in muscle fibres of patients with sporadic
inclusion-body myositis.
Vattemi G, Engel WK, McFerrin J, Buxbaum JD, Pastorino L, Askanas V.
Sporadic inclusion-body myositis (IBM) is the most common, progressive muscle
disease of older individuals. We investigated the presence of BACE1 and
BACE2-two beta secretases that cleave amyloid-beta-precursor protein-in
muscle-biopsy samples from patients with IBM and from controls. On
immunofluorescence, BACE1 and BACE2 co-localised with amyloid beta in IBM
vacuolated muscle fibres, but were not found in controls. Immunoblotting showed
increased BACE2 but not BACE1 in patients with IBM compared with controls. Our
study suggests that both of these proteases might participate in processing
of
amyloid-beta-precursor protein in IBM muscle fibres.
Publication Types:
Letter
PMID: 11747923 [PubMed - indexed for MEDLINE]
158: Muscle Nerve. 2001 Nov;24(11):1526-34.
Patterns of muscle involvement in inclusion body myositis: clinical and magnetic
resonance imaging study.
Phillips BA, Cala LA, Thickbroom GW, Melsom A, Zilko PJ, Mastaglia FL.
Centre for Neuromuscular and Neurological Disorders, Australian Neuromuscular
Research Institute, University of Western Australia, Perth, Western Australia,
Australia. b.phillips@unimelb.edu.au
The differential patterns of muscle involvement in the upper and lower limbs
in
sporadic inclusion body myositis (sIBM) were examined in 18 patients using both
quantitative and manual muscle testing as well as magnetic resonance imaging
(MRI) in 9 patients. Weakness of the quadriceps femoris and the forearm flexors
was present in most patients, but there was considerable variability in the
patterns and severity of muscle involvement. MRI disclosed preferential patterns
of muscle involvement within functional groups such as the quadriceps femoris,
in which there was severe involvement of the vasti with relative sparing of
the
rectus femoris, and the triceps surae, in which selective involvement of the
medial gastrocnemius was common. Involvement of flexor digitorum profundus on
MRI was found in only one third of patients. The results emphasize the
variability in the clinical phenotype and differential susceptibility of muscles
to the disease process in sIBM. Copyright 2001 John Wiley & Sons, Inc.
PMID: 11745956 [PubMed - indexed for MEDLINE]
159: Neurochem Int. 2002 Jan;40(1):85-103.
Transglutaminases in disease.
Kim SY, Jeitner TM, Steinert PM.
Laboratory of Skin Biology, NIAMS, NIH, MD, USA. sykim@burke.org
Transglutaminases (TGases) are enzymes that are widely used in many biological
systems for generic tissue stabilization purposes. Mutations resulting in lost
activity underlie several serious disorders. In addition, new evidence documents
that they may also be aberrantly activated in tissues and cells and contribute
to a variety of diseases, including neurodegenerative diseases such as
Alzheimer's and Huntington's diseases. In these cases, the TGases appear to
be a
factor in the formation of inappropriate proteinaceous aggregates that may be
cytotoxic. In other cases such as celiac disease, however, TGases are involved
in the generation of autoantibodies. Further, in diseases such as progressive
supranuclear palsy, Huntington's, Alzheimer's and Parkinson's diseases, the
aberrant activation of TGases may be caused by oxidative stress and
inflammation. This review will examine the role and activation of TGases in
a
variety of diseases.
Publication Types:
Review
Review, Tutorial
PMID: 11738475 [PubMed - indexed for MEDLINE]
160: Rheumatol Int. 2001 Oct;21(2):75-7.
Association of inclusion body myositis with subacute cutaneous lupus
erythematosus.
Wenzel J, Uerlich M, Gerdsen R, Bieber T, Boehm I.
Department of Dermatology, University of Bonn, Germany.
joerg.wenzel@ukb.uni-bonn.de
We present the case of a 71-year-old man with inclusion body myositis combined
with subacute cutaneous lupus erythematosus and dysphagia. Although inclusion
body myositis is usually resistant to immunosuppressive therapy, this patient
improved under treatment with corticosteroids. The presented case is discussed
in the context of earlier reports of inclusion body myositis and lupus
erythematosus.
Publication Types:
Case Reports
Review
Review of Reported Cases
PMID: 11732863 [PubMed - indexed for MEDLINE]
161: Dysphagia. 2001 Fall;16(4):244-8.
Cricopharyngeal muscle hypertrophy associated with florid myositis.
Bachmann G, Streppel M, Krug B, Neuen-Jacob E.
Klinik und Poliklinik fur Hals-Nasen-Ohrenheilkunde, Universitat zu Koln,
Germany. gregor.bachmann@rito.no
Hypertrophy of the cricopharyngeal muscle is a serious clinical condition that
can cause severe dysphagic symptoms, including prolonged deglutition and
postdeglutitive aspiration. Although the therapeutical concepts are well
established, the pathogenic mechanism of cricopharyngeal hypertrophy remains
unclear. We present a patient with a ten-year history of progressive dysphagia.
The neurological and MRI findings were normal. However, videocineradiography
showed severe hypertrophy of the cricopharyngeal muscle. This condition was
first treated by injections of botulinum toxin, which did not alleviate the
symptoms. Next, myotomy and muscle biopsy were performed. Histological
evaluation disclosed lymphoplasmacellular florid myositis, single-fiber atrophy,
and muscle fiber necrosis with phagocytosis. There were no signs of inclusion
body myositis or oculopharyngeal muscular dystrophy. Our finding of severe
cricopharyngeal muscle hypertrophy associated with myositis has been published
previously (n = 34). The study presented here shows cricopharyngeal dysphagia
associated with various systemic diseases, including motor neuron disease,
general granulomatous disease, dermatomyositis, or inclusion body myositis.
Isolated changes of the cricopharyngeal muscle were described in 65% of the
cases.
Publication Types:
Case Reports
Review
Review of Reported Cases
PMID: 11720399 [PubMed - indexed for MEDLINE]
162: Curr Opin Pharmacol. 2001 Jun;1(3):300-6.
The molecular and cellular pathology of inflammatory muscle diseases.
Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders,
National Institutes of Health, Bethesda, MD 20892-1382, USA.
dalakasm@ninds.nih.gov
The inflammatory muscle diseases dermatomyositis, polymyositis and inclusion
body myositis are of unknown cause, but immune mechanisms are strongly
implicated. Progress in the past two years has led to an improved understanding
of the main molecular events involved in the immunological synapse between
muscle and autoinvasive T cells. In particular, we now have a better
understanding of TCR gene rearrangement in endomysial T cells, regulation of
MHC
expression, activity of co-stimulatory molecules, and the signalling cascades
activated by cytokines, chemokines and metalloproteinases. Recent reports of
an
upregulation of strong anti-apoptotic molecules on the surface of muscle fibers
identifies the end result of these disease processes, loss of muscle cells,
as
through necrosis, and not apoptosis. Such progress in molecular immunopathology
has generated the interest to apply semispecific immunotherapies with the hope
of halting disease progression or improving the strength of patients
unresponsive to currently available non-specific immunotherapeutic
interventions.
Publication Types:
Review
Review, Tutorial
PMID: 11712755 [PubMed - indexed for MEDLINE]
163: Neurology. 2001 Nov 13;57(9):1566-70.
Erratum in:
Neurology 2002 Jan 22;58(2):334.
Randomized pilot trial of betaINF1a (Avonex) in patients with inclusion body
myositis.
Muscle Study Group.
Neuromuscular Disease Center, Rochester, NY 14642, USA.
BACKGROUND: Inclusion body myositis (IBM) is the most common acquired disease
of
muscle in adults over the age of 50 years. Although there is compelling evidence
for the importance of immunologic abnormalities in its pathogenesis, the cause
of the disease is not known, and it is considered to be resistant to treatment
with corticosteroids and other conventional immunosuppressive agents.
beta-Interferon (betaIFN), an immunomodulatory cytokine, is a candidate
therapeutic agent for IBM. METHOD: A 24-week, multicenter, randomized,
placebo-controlled, parallel-group clinical trial of 30 microg of
beta-interferon-1a (betaINF1a) administered IM once a week in 30 patients with
IBM was conducted. The primary goal was to establish the safety and tolerability
of betaINF1a in IBM. A secondary goal was to obtain preliminary data on the
efficacy of betaINF1a by measuring changes from baseline in muscle strength
and
muscle mass. RESULTS: Twenty-nine of the 30 subjects enrolled completed the
study. Two subjects (one in the placebo group, one in the betaINF1a group)
experienced severe adverse events. One subject, randomized to receive betaINF1a,
died from an ischemic bowel after resection of a colonic mass. No subjects
required dosage reductions, and the adverse event profile was similar for the
placebo and betaINF1a groups. There were no significant differences in the
changes in muscle strength and muscle mass between the placebo and betaINF1a
groups at 6 months. CONCLUSIONS: betaINF1a at a dose of 30 microg/week IM is
well tolerated in IBM. Further studies are needed to establish its therapeutic
usefulness in this inflammatory myopathy.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 11706093 [PubMed - indexed for MEDLINE]
164: Neurology. 2001 Nov 13;57(9):1561-5.
Production of IL-6 by human myoblasts stimulated with Abeta: relevance in the
pathogenesis of IBM.
Baron P, Galimberti D, Meda L, Scarpini E, Conti G, Cogiamanian F, Scarlato G.
Department of Neurological Sciences, Centro Dino Ferrari, University of Milan
School of Medicine, IRCCS Ospedale Maggiore, Milan, Italy.
neuromil@mailserver.unimi.it
OBJECTIVE: To determine whether amyloid-beta protein (Abeta) can induce the
production of proinflammatory cytokines by cultured normal muscle cells.
BACKGROUND: Sporadic inclusion body myositis (IBM) is characterized by the
presence of rimmed vacuoles and fibrillary inclusions of Abeta in muscle fibers,
and often inflammatory cells. Endomysial expression of proinflammatory molecules
has suggested an ongoing immune process, but the site of sensitization and the
mechanisms that trigger an inflammatory reaction is unknown. METHOD: The authors
used Northern blot analysis and specific immunoassays to study the expression
and secretion in cell-free supernatants of tumor necrosis factor-alpha
(TNFalpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) by purified
human myoblasts and C2C12 mouse skeletal muscle cells incubated with Abeta[1-42]
or Abeta[25-35] peptides. RESULTS: Nonstimulated muscle cells produced
detectable IL-6, whereas secretion of IL-1beta and TNFalpha was absent.
Incubation with Abeta peptides increased IL-6 production, whereas TNFalpha and
IL-1beta levels remained undetectable. Northern blot analysis of
Abeta-stimulated human myoblasts revealed an increase in IL-6 mRNA expression.
CONCLUSIONS: Cultured muscle cells increase the constitutive production of IL-6
in response to local deposition of Abeta in sporadic IBM. IL-6 could be a CD8(+)
proliferation and differentiation agent, an autocrine proteolysis-inducing
factor of damaged myotubes, and a proliferation-stimulating agent for satellite
cells to replace the destroyed myofibers in IBM.
PMID: 11706091 [PubMed - indexed for MEDLINE]
165: Curr Opin Rheumatol. 2001 Nov;13(6):469-75.
Inclusion body myositis: genetic factors, aberrant protein expression, and
autoimmunity.
Oldfors A, Fyhr IM.
Goteborg Neuromuscular Center, Department of Pathology, Sahlgrenska University
Hospital, Goteborg, Sweden. anders.oldfors@path.gu.se
Sporadic inclusion body myositis (s-IBM) is an inflammatory myopathy mainly
affecting elderly individuals. It has a chronic progressive course leading to
severe disability. Immunosuppressive treatment is in most instances ineffective.
S-IBM is morphologically characterized by mononuclear cell infiltrates and
vacuolated muscle fibers with pathologic accumulation of a large number of
different proteins. Recent research has focused on the expression of various
factors that may contribute to the inflammatory reaction and the typical
inclusions. This review summarizes the new information on genetic factors,
abnormal protein expression and inflammation, which provides a basis for linking
the different typical morphologic features of s-IBM to a cascade of pathogenic
events.
Publication Types:
Review
Review, Tutorial
PMID: 11698722 [PubMed - indexed for MEDLINE]
166: Acta Neuropathol (Berl). 2001 Oct;102(4):385-92.
CCR2A and CCR2B, the two isoforms of the monocyte chemoattractant protein-1
receptor are up-regulated and expressed by different cell subsets in idiopathic
inflammatory myopathies.
Bartoli C, Civatte M, Pellissier JF, Figarella-Branger D.
Laboratoire de Biopathologie Nerveuse et Musculaire, Faculte de medecine, IBDM
Marseille, France.
The idiopathic inflammatory myopathies (IIM), including dermatomyositis (DM),
polymyosititis (PM) and inclusion body myositis (IBM), are a group of autoimmune
diseases characterized by chronic lymphocytic and macrophagic infiltration in
muscle. The mechanism for recruitment of these cells probably involves
chemokines. We have previously reported that monocyte chemoattractant protein-1
(MCP-1), a beta chemokine, seems to play a major role in mononuclear cell
recruitment especially in DM. Here we have investigated the distribution of
the
main MCP-1 receptors CCR2A and CCR2B in IIM by polymerase chain reaction (PCR),
immunohistochemistry and in situ hybridization. We have shown by reverse
transcription-PCR that both CCR2A and CCR2B were expressed at low level in
normal muscle and that CCR2A was up-regulated in IIM (P=0.02) and was higher
in
PM and IBM than in DM (P=0.04). By immunohistochemistry and in situ
hybridization we have observed that CCR2 isoforms were expressed by different
cell subsets in both normal and IIM muscle. CCR2A was expressed in vessel walls
and by some mononuclear cells, especially in cells involved in partial invasion
in PM and IBM. CCR2B expression was observed in all satellite cells, in the
muscular domain of neuromuscular junctions and in some regenerative fibers of
IIM, but not in inflammatory exudates. In conclusion, the present study
highlights the major role played by MCP-1 and its counter-receptor CCR2 in the
pathophysiology of IIM, and shows that the CCR2 receptors are cell specific.
The
variation of the total amount of CCR2A and its local distribution according
to
the type of IIM might be a new path towards the understanding of the
constitution of mononuclear infiltrates in IIM.
PMID: 11603815 [PubMed - indexed for MEDLINE]
167: Liver. 2001 Oct;21(5):357-60.
Inclusion body myositis associated with hepatitis C virus infection.
Kase S, Shiota G, Fujii Y, Okamoto K, Oyama K, Nakano T, Nomura T, Suou T,
Nakashima K, Ito H, Kawasaki H.
Second Department of Internal Medicine, Faculty of Medicine, Tottori University,
Yonago, Japan. kaseron@grape.med.tottori-u.ac.jp
The case of a 77-year-old woman with hepatitis C virus infection with a 5-year
history of muscle weakness and mild disturbance of gait is reported. Steroid
therapy did not improve her symptoms. She developed HCV-related liver cirrhosis
and hepatocellular carcinoma, and muscle biopsy revealed inclusion body
myositis. Immunohistochemistry showed that the nonstructural region of HCV and
8-hydroxy-2'-deoxyguanosine, a marker of DNA damage by reactive oxygen species,
were present in striated muscle cells of this patient.
Publication Types:
Case Reports
PMID: 11589773 [PubMed - indexed for MEDLINE]
168: Intern Med. 2001 Sep;40(9):940-4.
Severe inclusion body myositis with interstitial pneumonia.
Mori S, Hamada H, Yokoyama A, Kohno N, Kondo K, Hara Y, Kawata H, Hiwada K.
Second Department of Internal Medicine, Ehime University School of Medicine,
Onsen-gun.
We report a patient with a severe inclusion body myositis (IBM). His illness
was
unusual in terms of a rapid progression, high creatine kinase levels, and
complication with interstitial pneumonia. He responded well to immunosuppressive
agents such as corticosteroids, cyclosporin A, cyclophosphamide, and
immunoglobulin. The present patient indicates the wide range of the disease,
and
that immunosuppressive agents may be useful for treatment of IBM.
Publication Types:
Case Reports
PMID: 11579961 [PubMed - indexed for MEDLINE]
169: Neuropediatrics. 2001 Aug;32(4):196-205.
Reducing body myopathy with cytoplasmic bodies and rigid spine syndrome: a
mixed
congenital myopathy.
Goebel HH, Halbig LE, Goldfarb L, Schober R, Albani M, Neuen-Jacob E, Voit T.
Department of Neuropathology, Medical Center, Johannes Gutenberg University,
Mainz, Germany. goebel@neuropatho.klinik.uni-mainz.de
At the age of five years a male child started to develop a progressive rigid
spine, torsion scoliosis, and flexion contractures of his elbows, knees, hips,
and ankles owing to severe proximal and distal muscle weakness. He had three
muscle biopsies from three different muscles at ages 7, 11, and 14 years,
respectively. Myopathologically, these muscle tissues contained numerous
inclusions which, at the ultrastructural level, turned out to be reducing bodies
and cytoplasmic bodies, often in close spatial proximity. Similar histological
inclusions, although not further identified by histochemistry and electron
microscopy, were seen in his maternal grandmother's biopsied muscle tissue who
had developed weakness of the legs and hands after the age of 50 years. The
patient's parents were healthy, but the mother's quadriceps muscle showed an
increased spectrum of muscle fibre diameters. Our patient, thus, had a
neuromuscular disorder, perhaps familial, presenting as a mixed congenital
myopathy, i.e., reducing body myopathy with cytoplasmic bodies, of which the
morphological lesions could be consistently documented over several years in
his
different limb muscles. While other mixed congenital myopathies had shown cores
and rods, both related to sarcomeres and thus possibly morphogenetically
related, cytoplasmic bodies thought to be related to Z-bands and reducing bodies
dissimilar to any muscle fibre constituent do not share any common denominator.
Therefore, we suggest that this neuromuscular disorder may be a unique mixed
congenital myopathy, either sporadic or genetic. In the latter case, the
transmission pattern suggested X-linked recessive inheritance, but an
autosomal-dominant transmission with variable penetrance could not be ruled
out.
Publication Types:
Case Reports
Review
Review of Reported Cases
PMID: 11571700 [PubMed - indexed for MEDLINE]
170: Arch Pathol Lab Med. 2001 Oct;125(10):1326-30.
Bcl-2, Bcl-x, and Bax expression by immunohistochemistry in inclusion body
myositis: a study of 27 cases.
Prayson RA, Yu AC.
Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio
44195, USA.
CONTEXT: Bcl-2, Bcl-x, and Bax are among the variety of proteins that have
been
described as being involved in the regulation of apoptotic cell death. Bcl-2
and
Bcl-x(L) inhibit apoptosis, and Bax is proapoptotic. OBJECTIVE: To evaluate
the
expression of Bcl-2, Bcl-x, and Bax in inclusion body myositis (IBM).Design.-We
examined muscle specimens from 27 patients (17 men, 10 women) with IBM to
evaluate Bcl-2, Bcl-x, and Bax expression by immunohistochemistry. RESULTS:
Patient ages ranged from 29 to 80 years (mean 62.2 years). All biopsies were
marked by endomysial chronic inflammation, muscle fiber necrosis, and
regeneration. Rimmed (autophagic) vacuoles were present in all cases. Ragged
red
fibers were noted in 4 biopsies (15%), and cytochrome oxidase-deficient fibers
were found in 10 biopsies (37%). Ultrastructural evidence of intranuclear or
cytoplasmic tubulofilamentous inclusions, confirming the diagnosis of IBM, were
noted in all cases. Paracrystalline mitochondrial inclusions were seen in 5
biopsies (18.5%). Inflammatory cells stained positively with Bcl-2 in all
biopsies, Bax in 26 biopsies (96%), and Bcl-x in 8 biopsies (30%). Degenerating
muscle fibers were highlighted with Bax in 24 biopsies (89%), Bcl-2 in 2
biopsies (7%), and Bcl-x in 3 biopsies (11%). Regenerative muscle fibers were
noted to stain with Bax in 24 muscles (89%), Bcl-2 in 21 muscles (78%), and
Bcl-x in 4 muscles (15%). Rimmed vacuoles were highlighted by Bax in 24 biopsies
(89%) and only rarely by Bcl-2 (n = 2, 7%) and Bcl-x (n = 3, 11%). A
subsarcolemmal staining pattern was observed in 21 biopsies (78%) with Bax,
6
biopsies (22%) with Bcl-2, and only 1 biopsy (4%) with Bcl-x. CONCLUSIONS: (1)
Bax (proapoptotic) immunostaining highlighted most autophagic vacuoles; (2)
subsarcolemmal Bax and Bcl-2 immunoreactivity may be associated with
mitochondrial defects that are commonly noted in IBM; (3) Bcl-2 and Bax
immunoreactivity were not confined to degenerating muscle fibers and in fact
appeared to be expressed more commonly in regenerating fibers, suggesting that
their expression may be independent of apoptosis in the setting of IBM.
PMID: 11570908 [PubMed - indexed for MEDLINE]
171: Curr Opin Neurol. 2001 Oct;14(5):591-6.
Inflammatory muscle diseases.
Hilton-Jones D.
Muscular Dystrophy Campaign Muscle and Nerve Centre, Department of Clinical
Neurology, Radcliffe infirmary, Oxford OX2 6HE, UK.
david.hilton-jones@cineuro.ox.ac.uk
Dermatomyositis and polymyositis are treatable disorders of skeletal muscle.
Despite their clinical similarities, they appear to have fundamentally different
autoimmune origins. Inclusion body myositis, from its origins 30 years ago,
has
emerged as the commonest acquired myopathy of the elderly. Despite inflammatory
changes, it is unclear whether it should be considered a primary inflammatory
myopathy, and it generally responds poorly to the same treatments that are
effective in other inflammatory myopathies.
Publication Types:
Review
PMID: 11562570 [PubMed - indexed for MEDLINE]
172: Medicine (Baltimore). 2001 Sep;80(5):320-7.
Inclusion body myositis in Connecticut: observations in 35 patients during
an
8-year period.
Felice KJ, North WA.
Department of Neurology, University of Connecticut School of Medicine,
Farmington, Connecticut 06030-1840, USA. felice@nso.uchc.edu
PMID: 11552086 [PubMed - indexed for MEDLINE]
173: Nat Genet. 2001 Sep;29(1):83-7.
The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is
mutated in recessive hereditary inclusion body myopathy.
Eisenberg I, Avidan N, Potikha T, Hochner H, Chen M, Olender T, Barash M,
Shemesh M, Sadeh M, Grabov-Nardini G, Shmilevich I, Friedmann A, Karpati G,
Bradley WG, Baumbach L, Lancet D, Asher EB, Beckmann JS, Argov Z,
Mitrani-Rosenbaum S.
Unit for Molecular Biology, Hadassah, Hospital, The Hebrew University-Hadassah
Medical School, Jerusalem, Israel.
Hereditary inclusion body myopathy (HIBM; OMIM 600737) is a unique group of
neuromuscular disorders characterized by adult onset, slowly progressive distal
and proximal weakness and a typical muscle pathology including rimmed vacuoles
and filamentous inclusions. The autosomal recessive form described in Jews of
Persian descent is the HIBM prototype. This myopathy affects mainly leg muscles,
but with an unusual distribution that spares the quadriceps. This particular
pattern of weakness distribution, termed quadriceps-sparing myopathy (QSM),
was
later found in Jews originating from other Middle Eastern countries as well
as
in non-Jews. We previously localized the gene causing HIBM in Middle Eastern
Jews on chromosome 9p12-13 (ref. 5) within a genomic interval of about 700 kb
(ref. 6). Haplotype analysis around the HIBM gene region of 104 affected people
from 47 Middle Eastern families indicates one unique ancestral founder
chromosome in this community. By contrast, single non-Jewish families from
India, Georgia (USA) and the Bahamas, with QSM and linkage to the same 9p12-13
region, show three distinct haplotypes. After excluding other potential
candidate genes, we eventually identified mutations in the
UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene in
the
HIBM families: all patients from Middle Eastern descent shared a single
homozygous missense mutation, whereas distinct compound heterozygotes were
identified in affected individuals of families of other ethnic origins. Our
findings indicate that GNE is the gene responsible for recessive HIBM.
PMID: 11528398 [PubMed - indexed for MEDLINE]
174: Arch Neurol. 2001 Aug;58(8):1253-6.
Inclusion body myositis mimicking motor neuron disease.
Dabby R, Lange DJ, Trojaborg W, Hays AP, Lovelace RE, Brannagan TH, Rowland LP.
Neurological Institute, Columbia-Presbyterian Medical Center, Box 150, 710
W
168th St, New York, NY 10032, USA.
OBJECTIVE: To describe the clinical and electrophysiologic features of patients
with inclusion body myositis that was misinterpreted as motor neuron disease.
PATIENTS AND METHODS: We retrospectively retrieved the medical records of 70
patients with a pathologic diagnosis of inclusion body myositis. From this
group, we selected those who had been first diagnosed as having motor neuron
disease or amyotrophic lateral sclerosis. We reviewed the clinical,
electrophysiologic, laboratory, and morphologic studies. RESULTS: Nine (13%)
of
70 patients with inclusion body myositis had been diagnosed as having motor
neuron disease. Six of the 9 patients had asymmetric weakness; in 4 the distal
arm muscles were affected. Eight patients had finger flexor weakness. Tendon
reflexes were preserved in weak limbs in 6, hyperactive in 2, and absent in
1.
Four patients had dysphagia. Fasciculation was seen in 2 patients. None had
definite upper motor neuron signs or muscle cramps. Routine electromyographic
studies showed fibrillation potentials and positive sharp waves in all 9.
Fasciculation potentials were seen in 7 and long-duration polyphasic motor unit
potentials were seen in 8. There was no evidence of a myogenic disorder in these
9 patients. Muscle biopsy was done because of slow progression or prominent
weakness of the finger flexors and was diagnostic of inclusion body myositis.
A
quantitative electromyogram was myopathic in 4 of the 5 patients studied.
CONCLUSIONS: Inclusion body myositis may mimic motor neuron disease. Muscle
biopsy and quantitative electromyographic analysis are indicated in patients
with atypical motor neuron disease, especially those with slow progression or
early and disproportionate weakness of the finger flexors.
PMID: 11493165 [PubMed - indexed for MEDLINE]
175: Acta Neuropathol (Berl). 2001 Jun;101(6):579-84.
Expression of the lysosome-associated membrane proteins in myopathies with
rimmed vacuoles.
Tsuruta Y, Furuta A, Furuta K, Yamada T, Kira J, Iwaki T.
Department of Neuropathology, Neurological Institute, Graduate School of Medical
Sciences, Kyushu University, Fukuoka, Japan.
Lysosome-associated membrane proteins (LAMPs) are structural glycoproteins
located on the lysosomal membrane and are thought to have an important role
in
protein degradation. Increased lysosomal activity is associated with the
formation of rimmed vacuoles, which are observed in various muscle disorders
such as inclusion body myositis (IBM) and distal myopathy with rimmed vacuole
(DMRV). In the present study, we examined LAMP-1 and LAMP-2 in biopsied muscle
specimens from four cases of sporadic IBM and two of DMRV, as well as six of
myopathies without rimmed vacuoles. In all cases of IBM and DMRV,
immunohistochemistry showed accumulation of LAMPs in the rimmed vacuoles and
the
subsarcolemmal portion of the vacuolated fibers. Immunoreactivities of LAMPs
in
the vacuolated fibers were often associated with those of cathepsin D; however,
cathepsin D was not expressed on some LAMP-positive fibers. Further, atrophic
muscle fibers were sometimes positive for LAMPs expression. These findings were
more prominent in LAMP-2 than in LAMP-1. Thus, LAMP-2 may play an important
role
in the increased protein degradation in diseased muscle fibers. The increased
expression of LAMPs in the vacuolated muscle fibers may be associated with the
formation of rimmed vacuoles in IBM and DMRV.
PMID: 11515786 [PubMed - indexed for MEDLINE]
176: Acta Neuropathol (Berl). 2001 Jun;101(6):572-8.
Immunolocalization of FAS and FAS ligand in inflammatory myopathies.
De Bleecker JL, Meire VI, Van Walleghem IE, Groessens IM, Schroder JM.
Ghent University Hospital, Department of Neurology, Belgium.
jan.debleecker@rug.ac.be
Fas/Fas ligand (FasL) interaction can induce apoptosis, have a costimulatory
role or act as a mechanism by which cytotoxic T cells produce target cell lysis.
We used several commercially available antibodies to study Fas and FasL
expression in polymyositis (PM), inclusion body myositis (IBM), dermatomyositis
(DM) and normal controls. A strong Fas signal occurred on the sarcolemma, and
to
a lesser extent in the sarcoplasm of neural cell adhesion molecule
(NCAM)-positive or developmental myosin heavy chain-positive regenerating muscle
fibers and of injured fibers with presumed abortive regenerative activity,
including some nonnecrotic invaded fibers in PM and IBM and some of the atrophic
perifascicular fibers in DM. Most fibers within groups of atrophic fibers in
IBM
were strongly Fas-positive, and statistically more muscle fibers were
Fas-positive in IBM compared to PM. A subset of the actively invading CD8+ T
cells in nonnecrotic muscle fibers in PM and IBM, and scattered CD4+ cells in
each inflammatory myopathy, had up-regulated Fas expression, probably reflecting
costimulation. No FasL antibody consistently labeled the positive control tissue
(testis) or intramuscular elements in control or inflammatory myopathy
specimens. Our study identifies regenerating muscle fibers as the main site
of
Fas immunoreactivity in inflammatory myopathies, and Fas expression may be part
of an activated or reactivated developmental program of new gene expression
in
regenerating or denervated muscle fibers. Our data plead against a specific
role
of Fas/FasL interaction in the immunopathogenesis of the inflammatory
myopathies.
PMID: 11515785 [PubMed - indexed for MEDLINE]
177: Neurology. 2001 Aug 14;57(3):548-50.
A prospective natural history study of inclusion body myositis: implications
for
clinical trials.
Rose MR, McDermott MP, Thornton CA, Palenski C, Martens WB, Griggs RC.
Department of Neurology, King's Neurosciences Centre, King's College Hospital,
London, UK. m.r.rose@kcl.ac.uk
Eleven patients with untreated inclusion body myositis (IBM) were prospectively
studied during a 6-month period that included muscle strength, lean body mass,
and muscle mass measurements. There was an overall quantifiable mean decline
in
percent of predicted normal muscle strength of 4% from baseline in a 6-month
period, but one third of patients showed no change or slight improvements in
strength. Short-term treatment trials in IBM will require large numbers of
patients to detect slowing, arrest, or even slight improvement in muscle
strength.
PMID: 11502935 [PubMed - indexed for MEDLINE]
178: Curr Rheumatol Rep. 2001 Aug;3(4):334-45.
Utility of magnetic resonance imaging in the evaluation of patients with
inflammatory myopathies.
Park JH, Olsen NJ.
Department of Radiology, Vanderbilt University Medical School, MCN-CCC-1121,
Nashville, TN 37232-2675, USA. Jane.Park@mcmail.vanderbilt.edu
Magnetic resonance imaging (MRI) and P-31 magnetic resonance spectroscopy (P-31
MRS) provide unique, quantitative data that cannot be obtained from routine
laboratory tests. MRI is the method of choice for imaging of muscle
abnormalities. It is also a very sensitive technique for localizing
nonhomogeneous inflammation in inflammatory myopathies such as dermatomyositis,
juvenile dermatomyositis, amyopathic dermatomyositis, polymyositis, and
inclusion body myositis. During treatment of inflammatory myopathies, the extent
and severity of inflammation may decrease at varying rates, but weakness and
fatigue remain serious clinical problems. The metabolic abnormalities detected
with P-31 MRS are more persistent and can be used for objective patient
evaluation after the disappearance of inflammation and normalization of serum
levels of muscle enzymes. With P-31 MRS, biochemical defects are quantitated,
including low levels of ATP and phosphocreatine (PCr) and elevated
concentrations of ADP and inorganic phosphate (Pi), which may all be related
to
weakness and fatigue. Thus, MRI and P-31 MRS are useful in assessing the status
of patients with inflammatory myopathies during treatment with prednisone and
immunosuppressive drugs.
Publication Types:
Review
Review, Tutorial
PMID: 11470053 [PubMed - indexed for MEDLINE]
179: Curr Rheumatol Rep. 2001 Aug;3(4):317-24.
The benefits and limitations of a physical training program in patients with
inflammatory myositis.
Lawson Mahowald M.
Minneapolis VA Medical Center, Rheumatology Office (111R), One Veterans Drive,
Minneapolis, MN 55417, USA. Mahow001@umn.edu
The clinical features of inflammatory myositis are determined by the severity
and extent of muscle weakness and systemic manifestations. The benefits and
limitations of physical training programs and rehabilitation strategies depend
on the clinical phase of the disease and analysis of underlying impairments
responsible for functional limitations in the patient. Patients with early stage
disease and severe weakness will be treated differently than patients who have
responded to medication and are improving. Not all patients will respond to
medications; their therapy programs will have different requirements. This
article reviews available data on the physiologic responses to exercise in
patients with inflammatory muscle diseases. New data support more aggressive
approaches to progressive strengthening exercises for patients with inflammatory
myositis.
Publication Types:
Review
Review, Tutorial
PMID: 11470051 [PubMed - indexed for MEDLINE]
180: Neurology. 2001 Jul 24;57(2):368.
Comment on:
Neurology. 2000 Oct 24;55(8):1235.
Prion codon 129 homozygosity and sporadic inclusion body myositis.
Lampe J, Gossrau G, Reichmann H, Walter MC, Mendel B, Lochmuller H.
Publication Types:
Comment
Letter
PMID: 11468340 [PubMed - indexed for MEDLINE]
181: Eur J Hum Genet. 2001 Jul;9(7):501-9.
Physical and transcriptional map of the hereditary inclusion body myopathy
locus
on chromosome 9p12-p13.
Eisenberg I, Hochner H, Shemesh M, Levi T, Potikha T, Sadeh M, Argov Z, Jackson
CL, Mitrani-Rosenbaum S.
The Unit for Development of Molecular Biology and Genetic Engineering, Hadassah
Hospital, The Hebrew University-Hadassah Medical School, Jerusalem 91240,
Israel.
Hereditary inclusion body myopathy (HIBM) is a group of neuromuscular disorders
characterised by adult-onset, slowly progressive distal and proximal muscle
weakness and typical muscle pathology. Previously, we have mapped the gene
responsible for a recessive form of HIBM to chromosome 9p1 and narrowed the
interval to one single YAC clone of 1 Mb in size. As a further step towards
the
identification of the HIBM gene, we have constructed a detailed physical and
transcriptional map of this region. A high resolution BAC contig that includes
the HIBM critical region, flanked by marker 327GT4 and D9S1859, was constructed.
This contig allowed the precise localisation of 25 genes and ESTs to the
proximal region of chromosome 9. The expression pattern of those mapped genes
and ESTs was established by Northern blot analysis. In the process of refining
the HIBM interval, 13 new polymorphic markers were identified, of which 11 are
CA-repeats, and two are single nucleotide polymorphisms. Certainly, this map
provides an important integration of physical and transcriptional information
corresponding to chromosome 9p12-p13, which is expected to facilitate the
cloning and identification not only of the HIBM gene, but also other disease
genes which map to this region.
PMID: 11464241 [PubMed - indexed for MEDLINE]
182: Neuroreport. 2001 Jul 3;12(9):1809-14.
Novel cytoplasmic immunolocalization of RNA polymerase II in inclusion-body
myositis muscle.
Wilczynski GM, Engel WK, Askanas V.
USC Neuromuscular Center, Department of Neurology, University of Southern
California, Keck School of Medicine, Good Samaritan Hospital, 637 South Lucas
Ave, Los Angeles, CA 90017-1912, USA.
Sporadic inclusion-body myositis (IBM) is a progressive degenerative muscle
disease of older persons. Abnormalities of gene-expression and RNA metabolism
have recently been proposed to contribute to the IBM pathogenic cascade. We
now
demonstrate, using well characterized, epitope-specific antibodies, that the
largest subunit of RNA polymerase II is abnormally accumulated in the cytoplasm
of IBM muscle fibers, where it is co-localized with phosphorylated tau on IBM
paired helical filaments. Since RNA polymerase II is a crucial nuclear factor
involved in both transcription and mRNA processing, our results support the
hypothesis that abnormality of either or both of those processes might be
caused, in part, by pathological trafficking of RNA polymerase II, and that
abnormal trafficking might be an important factor in the IBM pathogenic cascade.
PMID: 11435903 [PubMed - indexed for MEDLINE]
183: Surg Today. 2001;31(6):553-6.
Fournier's gangrene: report of six cases.
Ochiai T, Ohta K, Takahashi M, Yamazaki S, Iwai T.
Department of Surgery, Ohta Nishinouchi General Hospital, Koriyama, Fukushima,
Japan.
Fournier's gangrene (FG) is a fatal infectious disease with necrotic fasciitis
of the external genitalia. This disease persists to this day in spite of recent
advances in antibiotics. Although fewer than 100 cases have been reported in
Japan, we have treated six cases in the last 4 years. The patients consisted
of
five men and one woman, with an average age of 47.5 years. All patients received
surgical treatment including incisions, aggressive debridement, drainage,
irrigation, and antibiotic therapy. Two patients, who suffered from underlying
diseases of diabetic nephropathy and inclusion body myositis, died. These
findings confirm the fact that FG requires a prompt diagnosis and immediate
surgical treatment.
Publication Types:
Case Reports
PMID: 11428614 [PubMed - indexed for MEDLINE]
184: Ann Intern Med. 2001 Jun 19;134(12):1156.
Long-lasting effectiveness of intravenous immunoglobulin in a patient with
inclusion-body myositis.
Mukunda BN, Dileep Kumar P, Smith HR.
Publication Types:
Case Reports
Letter
PMID: 11412071 [PubMed - indexed for MEDLINE]
185: Ann Intern Med. 2001 Jun 19;134(12):1087-95.
Incidence of malignant disease in biopsy-proven inflammatory myopathy. A
population-based cohort study.
Buchbinder R, Forbes A, Hall S, Dennett X, Giles G.
Department of Clinical Epidemiology, Suite 41, Cabrini Medical Centre, 183
Wattletree Road, Malvern, Victoria, Australia 3144.
rachelle.buchbinder@med.monash.edu.au
BACKGROUND: The validity and magnitude of an association between myositis and
malignant disease continue to be debated. Such issues as the legitimacy of a
myositis diagnosis and distinction among myositis subgroups in previous
population-based studies remain unresolved. OBJECTIVE: To determine the risk
for
malignant disease in patients with biopsy-proven inflammatory myopathies.
DESIGN: Population-based, retrospective cohort study. SETTING: Victoria,
Australia. PATIENTS: 537 patients in whom a biopsy-positive idiopathic
inflammatory myopathy was first diagnosed from 1981 through 1995. MEASUREMENTS:
Standardized incidence ratios were calculated to compare the incidence of
malignant disease in patients with inflammatory myopathy and the general
population. RESULTS: A total of 116 cases of malignant disease were found in
104
patients. Seventy-four cases were identified concurrently with (within 7 days)
or after diagnosis of myositis. The highest risk for malignant disease was
associated with dermatomyositis (standardized incidence ratio, 6.2 [95% CI,
3.9
to 10.0]). The risk was also increased in polymyositis (standardized incidence
ratio, 2.0 [CI, 1.4 to 2.7]), although the relative risk for malignant disease
in dermatomyositis compared with polymyositis was 2.4 (CI, 1.3 to 4.2). An
increased risk for malignant disease was also found in inclusion-body myositis
(standardized incidence ratio, 2.4 [CI, 1.2 to 4.9]). The excess risk for
malignant disease diminished with time (standardized incidence ratio, 4.4 [CI,
2.7 to 7.1] in the first year; 3.4 [CI, 2.3 to 5.1] between 1 and 3 years; 2.2
[CI, 1.3 to 3.9] between 3 and 5 years; and 1.6 [CI, 1.0 to 2.6] beyond 5 years
[ P for trend, 0.002]). CONCLUSION: The risk for malignant disease is increased
in biopsy-proven dermatomyositis and polymyositis and also appears to be
increased in inclusion-body myositis.
PMID: 11412048 [PubMed - indexed for MEDLINE]
186: Fukuoka Igaku Zasshi. 2001 Apr;92(4):99-104.
High-dose vitamin C therapy for inclusion body myositis.
Yamada T, Minohara M, Imaiso Y, Sakae N, Hara H, Tanaka K, Yamamoto T, Taniwaki
T, Furuya H, Kira J.
Department of Neurology, Neurological Institute, Graduate School of Medical
Sciences, Kyushu University, Fukuoka 812-8582, Japan.
yamada@neuro.med.kyushu-u.ac.jp
OBJECTIVES: The efficiency of high-dose vitamin C therapy for inclusion body
myositis (IBM) was assessed. SUBJECTS & METHODS: The subjects were five
patients
with IBM confirmed pathologically. After the intravenous administration of 40
mg/kg vitamin C five times/week for four weeks, muscle weakness was found to
improve in three cases. The average muscle score improved from 8.1 to 8.8, from
7.0 to 8.1 and from 6.2 to 6.8. Magnetic resonance imaging (MRI) demonstrated
a
reduction in the size of T2 high lesions and gadolinium enhancement in the thigh
muscles in one case. Based on our findings, high-dose vitamin C therapy is
considered to be effective in some cases of IBM.
Publication Types:
Evaluation Studies
PMID: 11411094 [PubMed - indexed for MEDLINE]
187: Neuromuscul Disord. 2001 Jul;11(5):452-7.
Macrophagic myofasciitis associated with inclusion body myositis: a report
of
three cases.
Cherin P, Menard D, Mouton P, Viallard JF, Le Hello C, Authier FJ, Gherardi
RK,
Coquet M, Herson S, Leroi JP.
Medecine Interne I, CHU Pitie-Salpetriere, 47 Boulevard de l'Hopital, 75013,
Paris, France. patrick.cherin@psl.ap-hop-paris.fr
We describe three patients with macrophagic myofasciitis and inclusion body
myositis. All patients fulfilled diagnostic criteria for inclusion body myositis
and myopathologic criteria for macrophagic myofasciitis. In the three cases
macrophagic myofasciitis complicated the evolution of a known and painless
inclusion body myositis and was diagnosed in a repeated deltoid biopsy because
of the appearance of myalgia during the course of inclusion body myositis in
all
cases. The unexpected appearance of myalgia during the course of painless
inclusion body myositis must arouse the suspicion of an association of another
inflammatory muscle disease, macrophagic myofasciitis.
Publication Types:
Case Reports
PMID: 11404116 [PubMed - indexed for MEDLINE]
188: Neuromuscul Disord. 2001 Jul;11(5):447-51.
Rimmed vacuoles and the added value of SMI-31 staining in diagnosing sporadic
inclusion body myositis.
van der Meulen MF, Hoogendijk JE, Moons KG, Veldman H, Badrising UA, Wokke JH.
Department of Neurology, G 03.228, Division of Neuromuscular Disorders,
University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX, The, Utrecht,
Netherlands. m.f.g.vdmeulen@neuro.azu.nl
Problems in diagnosing sporadic inclusion body myositis may arise if all
clinical features fit a diagnosis of polymyositis, but the muscle biopsy shows
some rimmed vacuoles. Recently, immunohistochemistry with an antibody directed
against phosphorylated neurofilament (SMI-31) has been advocated as a diagnostic
test for sporadic inclusion body myositis. The aims of the present study were
to
define a quantitative criterion to differentiate sporadic inclusion body
myositis from polymyositis based on the detection of rimmed vacuoles in the
haematoxylin-eosin staining and to evaluate the additional diagnostic value
of
the SMI-31 staining. Based on clinical criteria and creatine kinase levels in
patients with endomysial infiltrates, 18 patients complied with the diagnosis
of
sporadic inclusion body myositis, and 17 with the diagnosis of polymyositis.
A
blinded observer counted the abnormal fibres in haematoxylin-eosin-stained
sections and in SMI-31-stained sections. The optimal cut-off in the
haematoxylin-eosin test was 0.3% vacuolated fibres. Adding the SMI-31 staining
significantly increased the positive predictive value from 87 to 100%, but
increased the negative predictive value only to small extent. We conclude that
(1) patients with clinical and laboratory features of polymyositis, including
response to treatment, may show rimmed vacuoles in their muscle biopsy and that
(2) adding the SMI-31 stain can be helpful in differentiating patients who
respond to treatment from patients who do not.
PMID: 11404115 [PubMed - indexed for MEDLINE]
189: Adv Exp Med Biol. 2001;487:219-28.
Neurodegeneration-associated proteins and inflammation in sporadic
inclusion-body myositis.
Lampe JB, Walter MC, Reichmann H.
Department of Neurology, Technical University of Dresden, Germany.
PMID: 11403162 [PubMed - indexed for MEDLINE]
190: Mol Cell Neurosci. 2001 May;17(5):793-810.
Beta-amyloid peptide expression is sufficient for myotube death: implications
for human inclusion body myopathy.
Querfurth HW, Suhara T, Rosen KM, McPhie DL, Fujio Y, Tejada G, Neve RL, Adelman
LS, Walsh K.
Division of Neurology, St. Elizabeth's Medical Center, Boston, MA 02135, USA.
hquerfur@opal.tufts.edu
Inclusion body myositis (sIBM) is the most common disorder of skeletal muscle
in
aged humans. It shares biochemical features with Alzheimer's disease, including
congophilic deposits, which are immunoreactive for beta-amyloid peptide (Abeta)
and C'-terminal betaAPP epitopes. However, the etiology of myofiber loss and
the
role of intracellular Abeta in IBM is unknown. Here we report correlative
evidence for apoptotic cell death in myofibers of IBM patients that exhibit
pronounced Abeta deposition. HSV-1-mediated gene transfer of Abeta(42) into
cultured C2C12 myotubes resulted in a 12.6-fold increase in dUTP-labeled and
condensed nuclei over nonexpressing myotubes (P < 0.05). The C'-terminal
betaAPP
domain C99 also induced myotube apoptosis, but to a significantly lesser extent
than Abeta. Apoptosis specific to Abeta-expressing myotubes was also
demonstrated through DNA fragmentation, decreased mitochondrial function and
the
loss of membrane phospholipid polarity. Myotubes laden with Abeta(42), but not
other transgene products, developed cytoplasmic inclusions consisting of
fibrillar material. Furthermore, injection of normal mouse gastrocnemius muscle
with HSV-encoding Abeta cDNA resulted in TUNEL-positive myofibers with pyknotic
nuclei. We conclude that Abeta is sufficient to induce apoptosis in myofibers
both in vivo and in vitro and suggest it may contribute to myofiber loss and
muscle dysfunction in patients with IBM. Copyright 2001 Academic Press.
PMID: 11358479 [PubMed - indexed for MEDLINE]
191: J Neurol Neurosurg Psychiatry. 2001 May;70(5):706.
Anti-Jo-1 positive inclusion body myositis with a marked and sustained clinical
improvement after oral prednisone.
Hengstman GJ, Ter Laak HJ, van Engelen BG, van Venrooij BG.
Publication Types:
Case Reports
Letter
PMID: 11336039 [PubMed - indexed for MEDLINE]
192: J Neurol Sci. 2001 Apr 1;185(2):119-22.
Mycophenolate (CellCept) treatment of myasthenia gravis, chronic inflammatory
polyneuropathy and inclusion body myositis.
Mowzoon N, Sussman A, Bradley WG.
Department of Neurology, University of Miami School of Medicine (M712), PO
Box
016960, Miami, FL 33101, USA.
We report favorable results of the long term use of mycophenolate in the
treatment of three patients with myasthenia gravis (MG), two patients with
chronic inflammatory demyelinating polyneuropathy (CIDP), one patient with
secondary polymyositis (PM), and one patient with inclusion body myositis (IBM).
Side effects were mild. Mycophenolate appears to be a useful addition to the
armamentarium of immunosuppressants for treatment of chronic immunologically
mediated neuromuscular diseases.
Publication Types:
Clinical Trial
PMID: 11311292 [PubMed - indexed for MEDLINE]
193: Brain Pathol. 2001 Apr;11(2):182-9.
Increased expression of the normal cellular isoform of prion protein in
inclusion-body myositis, inflammatory myopathies and denervation atrophy.
Zanusso G, Vattemi G, Ferrari S, Tabaton M, Pecini E, Cavallaro T, Tomelleri
G,
Filosto M, Tonin P, Nardelli E, Rizzuto N, Monaco S.
Department of Neurological and Visual Sciences, University of Verona, Italy.
The cellular isoform of the prion protein (PrPc) is a
glycosylphosphatidylinositol-anchored glycoprotein, normally expressed in neural
and non-neural tissues, including skeletal muscle. In transmissible spongiform
encephalopathies, or prion diseases, PrPc, which is soluble in nondenaturing
detergent and sensitive to proteinase K (PK)-treatment, represents the molecular
substrate for the production of a detergent-insoluble and PK-resistant isoform,
termed PrP(Sc). In human prion diseases, PrP(Sc) accumulation occurs only in
brain tissues, with the exception of new variant Creutzfeldt-Jakob disease,
where PrP(Sc) is also detected in lymphoid tissues. Increased amounts of prion
protein expression and deposition have been described in pathological muscle
fibers of two human muscle disorders, called sporadic inclusion-body myositis
(s-IBM) and hereditary inclusion-body myopathy, but it is unknown whether
accumulated prion protein reflects normal PrPc or PrP(Sc). We investigated the
biochemical characteristics of prion protein in normal human muscle, s-IBM,
other inflammatory myopathies and denervation atrophy. We report that 1) both
the glycoform profile and size of the normal muscle PrPc are different from
those of human brain PrPc; 2) in addition to s-IBM, increased PrPc expression
is
seen in polymyositis, dermatomyositis and neurogenic muscle atrophy, but PrPc
glycoforms are unchanged; 3) only the normal PrPc isoform, and not PrP(Sc),
is
detected in s-IBM. The present results exclude that s-IBM is a prion disease.
PMID: 11303793 [PubMed - indexed for MEDLINE]
194: Acta Neurol Scand. 2001 Feb;103(2):131-5.
Report of a patient with inclusion body myositis and CD8+ chronic lymphocytic
leukaemia--post-mortem analysis of muscle and brain.
Arnardottir S, Ansved T, Nennesmo I, Borg K.
Department of Clinical Neuroscience, Karolinska Hospital, Karolinska Institutet,
Stockholm, Sweden.
We report a 73-year-old woman with sporadic inclusion body myositis (s-IBM)
and
a T-cell chronic lymphocytic leukaemia (T-CLL). The s-IBM diagnosis was based
on
clinical symptoms and muscle biopsy showing inflammatory infiltrates and rimmed
vacuoles with 15 18 nm diameter tubulofilamentous inclusions on ultrastructural
examination. The inflammatory infiltrates consisted of CD8+ T-lymphocytes and
macrophages. The diagnosis of a CD8+ T-CLL was based on peripheral blood samples
and bone marrow aspiration. The postmortem analysis of skeletal muscle showed
fascicular atrophy, which may support a neurogenic component in s-IBM and the
analysis of the brain showed only a few diffuse plaques in different cortical
regions and occasionally neuritic plaques. A pathophysiological analogy between
s-IBM and Alzheimer's has been suggested on the basis of similarities in protein
accumulation in muscle of s-IBM patients and brain of Alzheimer's patients.
However, we were unable to detect any changes suggestive of Alzheimer's disease
in the brain of the s-IBM patient presented here.
Publication Types:
Case Reports
PMID: 11227133 [PubMed - indexed for MEDLINE]
195: J Neuropathol Exp Neurol. 2001 Jan;60(1):1-14.
Inclusion-body myositis: newest concepts of pathogenesis and relation to aging
and Alzheimer disease.
Askanas V, Engel WK.
USC Neuromuscular Center, Department of Neurology, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, Los Angeles
90017-1912, USA.
We review the newest advances related to seeking the pathogenic mechanism(s)
of
sporadic inclusion-body myositis (s-IBM) and present the pathologic diagnostic
criteria of s-IBM. We discuss the possible pathogenic role of several themes,
such as 1) increased amyloid-beta precursor protein (AbetaPP) and of its
fragment Abeta; 2) phosphorylation of tau protein; 3) oxidative stress; 4)
abnormal a) signal-transduction, b) transcription, and c) RNA accumulation;
5)
"junctionalization" and myogenous" denervation; and 6) lymphocytic
inflammation.
Evidence is provided supporting our hypothesis that overexpression of AbetaPP
within the aging muscle fibers is an early upstream event causing the subsequent
pathogenic cascade. The remarkable pathologic similarities between s-IBM muscle
and Alzheimer disease (AD) brain are discussed, and the possible cause and
significance are addressed.
Publication Types:
Review
Review, Tutorial
PMID: 11202170 [PubMed - indexed for MEDLINE]
196: Hosp Med. 2000 Nov;61(11):767-71.
Pitfalls in the diagnosis of motor neurone disease.
Hardiman O.
Department of Neurology, Beaumont Hospital, Dublin 9, Ireland.
Motor neurone disease is characterized by progressive degeneration of upper
and
lower motor neurones with preservation of cognition. Recognition of classical
motor neurone disease is not difficult, but during the early stages both false
positive and false negative diagnoses are common. Careful examination, frequent
follow-up and ancillary tests are necessary to avoid erroneous diagnoses.
Publication Types:
Review
Review, Tutorial
PMID: 11198744 [PubMed - indexed for MEDLINE]
197: Neurology. 2001 Feb 13;56(3):323-7.
A controlled study of intravenous immunoglobulin combined with prednisone in
the
treatment of IBM.
Dalakas MC, Koffman B, Fujii M, Spector S, Sivakumar K, Cupler E.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Bethesda, MD, USA.
OBJECTIVE: To investigate whether the combination of intravenous immunoglobulin
(IVIg) with prednisone improves muscle strength and alters endomysial
inflammation in patients with sporadic inclusion body myositis (s-IBM).
BACKGROUND: In a previous controlled trial in s-IBM, IVIg did not significantly
improve strength in spite of modest benefits in some muscle groups. The
possibility that prednisone may have a synergistic effect with IVIg prompted
another controlled trial. METHODS: Thirty-six patients with biopsy-proven IBM
were randomized to receive IVIg or placebo monthly for 3 months. Before
infusions, all patients were started on high-dose prednisone for 3 months.
Primary outcome measures were differences in the 1) Quantitative Muscle Strength
(QMT) testing; and 2) modified Medical Research Council (MRC) scores, between
the patients randomized to IVIg + prednisone compared with those randomized
to
placebo + prednisone. Repeated open muscle biopsies were performed at random
in
24 patients to determine changes in the number of autoinvasive T cells and
necrotic muscle fibers. RESULTS: Nineteen patients were randomized to IVIg +
prednisone and 17 to placebo + prednisone. No significant change was noted in
muscle strength, assessed by QMT and MRC, from baseline to the 2nd, 3rd, or
4th
month after treatment between the two groups. The number of necrotic fibers
was
reduced in the IVIg randomized group (p < 0.01), and the mean number of CD2+
cells was significantly decreased in both groups (p < 0.0001), denoting a
steroid effect. CONCLUSION: IVIg combined with prednisone for a 3-month period
was not effective in IBM. Endomysial inflammation was significantly reduced
after treatment, but the reduction was not of clinical significance.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 11171896 [PubMed - indexed for MEDLINE]
198: Clin Infect Dis. 2001 Feb 1;32(3):510-4. Epub 2001 Jan 24.
Sporadic inclusion body myositis in a patient with human T cell leukemia virus
type 1-associated myelopathy.
Ozden S, Gessain A, Gout O, Mikol J.
Unite d'Oncologie Virale, Institut Pasteur, Paris, France.
Sporadic inclusion body myositis is a disease of unknown pathogenesis in which
a
viral etiology has long been suspected. We report a case that occurred in a
patient with human T cell leukemia virus type 1-associated myelopathy. The
diagnosis was confirmed by histopathological studies of the deltoid muscle.
Nucleic acids amplification and in situ hybridization indicated the presence
of
integrated proviral DNA and viral mRNA transcripts in the lesions.
Publication Types:
Case Reports
PMID: 11170963 [PubMed - indexed for MEDLINE]
199: Neuromuscul Disord. 2001 Jan;11(1):88-92.
64th ENMC International Workshop: therapeutic approaches to dermatomyositis,
polymyositis, and inclusion body myositis29-31 January 1999, Naarden, The
Netherlands.
Muller-Felber W, Pongratz D, Reimers C.
Friedrich-Baur-Institut, Ludwig Maximilians University, Munich, Germany.
Publication Types:
Congresses
PMID: 11166170 [PubMed - indexed for MEDLINE]
200: Brain. 2001 Feb;124(Pt 2):341-51.
Expression of specific matrix metalloproteinases in inflammatory myopathies.
Kieseier BC, Schneider C, Clements JM, Gearing AJ, Gold R, Toyka KV, Hartung HP.
Department of Neurology, Karl Franzens University, Graz, Austria.
bc.kieseier@kfunigraz.ac.at
The family of matrix metalloproteinases (MMPs) comprises endopeptidases that
are
capable of degrading all extracellular matrix components. Given these actions,
it is conceivable that MMPs may play a pathogenic role in inflammatory
myopathies. These immune-mediated disorders are characterized by the invasion
of
mononuclear phagocytes and T lymphocytes and the loss of muscle fibres. We
examined whether specific MMPs and their natural inhibitors (tissue inhibitors
of metalloproteinases; TIMPs) are expressed in muscle during acute inflammatory
attacks by studying muscle biopsies obtained from patients diagnosed as having
polymyositis, dermatomyositis, sporadic inclusion body myositis and, for
comparison, from cases of various muscular dystrophies. Quantitative polymerase
chain reaction analysis revealed significantly elevated mRNA expression of
interstitial collagenase (MMP-1) and gelatinase B (MMP-9) in polymyositis and
dermatomyositis and to a lesser extent in inclusion body myositis, whereas the
level of expression of TIMPs remained unchanged in comparison with controls.
Increased mRNA levels were associated with enhanced enzyme expression, as
determined by immunoblotting, gelatin zymography and in situ zymography.
Immunohistochemically, MMP-1 could be localized around the sarcolemma of
diseased muscle fibres and to cells resembling fibroblasts, whereas MMP-9 seemed
to be expressed primarily by invading T lymphocytes. Raised levels of MMPs could
not be detected in the sera of affected patients, emphasizing the crucial action
of MMPs in the inflamed muscle. Our results imply a pathogenic role for specific
MMPs in the genesis of inflammatory myopathies, and open new strategies for
therapeutic intervention.
Publication Types:
Clinical Trial
Controlled Clinical Trial
PMID: 11157561 [PubMed - indexed for MEDLINE]
201: Ann Rheum Dis. 2001 Feb;60(2):116-23.
Comment in:
Ann Rheum Dis. 2001 Aug;60(8):810.
Autoantibody profiles in the sera of European patients with myositis.
Brouwer R, Hengstman GJ, Vree Egberts W, Ehrfeld H, Bozic B, Ghirardello A,
Grondal G, Hietarinta M, Isenberg D, Kalden JR, Lundberg I, Moutsopoulos H,
Roux-Lombard P, Vencovsky J, Wikman A, Seelig HP, van Engelen BG, van Venrooij
WJ.
Department of Biochemistry, University of Nijmegen, Nijmegen, The Netherlands.
OBJECTIVE: To determine the prevalence of myositis specific autoantibodies
(MSAs) and several myositis associated autoantibodies (MAAs) in a large group
of
patients with myositis. METHODS: A total of 417 patients with myositis from
11
European countries (198 patients with polymyositis (PM), 181 with
dermatomyositis (DM), and 38 with inclusion body myositis (IBM)) were
serologically analysed by immunoblot, enzyme linked immunosorbent assay (ELISA)
and/or immunoprecipitation. RESULTS: Autoantibodies were found in 232 sera
(56%), including 157 samples (38%) which contained MSAs. The most commonly
detected MSA was anti-Jo-1 (18%). Other anti-synthetase, anti-Mi-2, and anti-SRP
autoantibodies were found in 3%, 14%, and 5% of the sera, respectively. A
relatively high number of anti-Mi-2 positive PM sera were found (9% of PM sera).
The most commonly detected MAA was anti-Ro52 (25%). Anti-PM/Scl-100,
anti-PM/Scl-75, anti-Mas, anti-Ro60, anti-La, and anti-U1 snRNP autoantibodies
were present in 6%, 3%, 2%, 4%, 5%, and 6% of the sera, respectively. Remarkable
associations were noticed between anti-Ro52 and anti-Jo-1 autoantibodies and,
in
a few sera, also between anti-Jo-1 and anti-SRP or anti-Mi-2 autoantibodies.
CONCLUSIONS: The incidence of most of the tested autoantibody activities in
this
large group of European patients is in agreement with similar studies of
Japanese and American patients. The relatively high number of PM sera with
anti-Mi-2 reactivity may be explained by the use of multiple recombinant
fragments spanning the complete antigen. Furthermore, our data show that some
sera may contain more than one type of MSA and confirm the strong association
of
anti-Ro52 with anti-Jo-1 reactivity.
PMID: 11156543 [PubMed - indexed for MEDLINE]
202: J Neurol. 2000 Nov;247(11):882-4.
Familial inclusion body myositis with histologically confirmed sensorimotor
axonal neuropathy.
Hengstman GJ, van Engelen BG, ter Laak HJ, Gabreels-Festen AA.
Publication Types:
Case Reports
Letter
PMID: 11151424 [PubMed - indexed for MEDLINE]
203: Neurology. 2001 Jan 9;56(1):87-93.
Inclusion body myositis: expression of extracellular signal-regulated kinase
and
its substrate.
Nakano S, Shinde A, Kawashima S, Nakamura S, Akiguchi I, Kimura J.
Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto,
Japan. snakano@isola.kuhp.kyoto-u.ac.jp
OBJECTIVE: To assess abnormal intracellular signal transduction in inclusion
body myositis (IBM). BACKGROUND: Mitogen-activated protein kinases (MAPKs) play
pivotal roles in intracellular signal transduction and regulate cell growth
and
differentiation. Upon their activation, MAPKs translocate from the cytoplasm
into the nucleus. DESIGN/METHODS: The authors investigated the localization
of
several forms of the MAPK family-extracellular signal-regulated kinase (ERK),
c-Jun N-terminal protein kinase (JNK), and p38 MAPK (p38)-in 10 patients with
sporadic IBM and in 52 control subjects. The relationship between the
localization of immunopositive deposits and nuclei was tested with
bis-benzimide. RESULTS: Vacuolated fibers in IBM displayed very strong focal
immunoreactivity of ERK, but not of JNK or p38. The ERK-positive deposits in
these vacuolated fibers colocalized with the nuclear substrate of ERK, Elk-1.
ERK- and Elk-1-positive deposits were located frequently on the surface of the
nuclei in vacuolated fibers in IBM. Similar findings to those of sporadic IBM
were observed in three patients with distal myopathy with rimmed vacuoles, but
not in eight normal or the other 41 disease controls. CONCLUSION: There is
evidence for impaired molecular transport to the nucleus from the cytoplasm
in
the vacuolated fibers in IBM. This could be due to cytoplasmic aggregation of
ERK and Elk-1 or to abnormal nuclear pore machinery involved in the transport
of
ERK and its substrate upon ERK activation.
PMID: 11148241 [PubMed - indexed for MEDLINE]
204: Curr Rheumatol Rep. 2000 Jun;2(3):216-24.
The role of cytokines, chemokines, and adhesion molecules in the pathogenesis
of
idiopathic inflammatory myopathies.
Lundberg IE.
Department of Rheumatology, Karolinska Hospital, S-171 76 Stockholm, Sweden.
Ingrid.Lundberg@medks.ki.se
Cytokines, chemokines, and adhesion molecules are important mediators in chronic
inflammation and in immune regulation. In idiopathic inflammatory myopathies
(IIM), increased expression of proinflammatory cytokines particularly
interleukin (IL)-1alpha and IL-1beta, tumor necrosis factor (TNF)-alpha and
macrophage inflammatory proteins (MIP)-1alpha, as well as of the inhibitory
cytokines transforming growth factor (TGF)-beta was observed in muscle. There
was no difference in cytokine and chemokine pattern between polymyositis,
dermatomyositis, and inclusion body myositis, which could indicate that similar
pathogenetic mechanisms are involved in these subsets of myositis. A prominent
finding of IL-1alpha expression in endothelial cells, both in patients with
active inflammation and in patients with chronic persisting muscle weakness
without inflammation, makes this an interesting molecule in understanding the
mechanisms for the pathogenesis of muscle weakness. Involvement of the blood
vessels in the pathogenesis of myositis was further supported by increased
expression of adhesion molecules and by a phenotypical expression of endothelial
cells, resembling high endothelium venules in all three subsets of IIM. The
molecular studies to date indicate a role of the microvessels in the
pathogenesis of IIM not only in DM, as was previously suggested, but also in
PM
and IBM. The studies also indicate that IL-1alpha could be a target molecule
for
new therapeutical interventions.
Publication Types:
Review
Review, Tutorial
PMID: 11123062 [PubMed - indexed for MEDLINE]
205: Curr Treat Options Neurol. 2000 Jan;2(1):7-12.
Inclusion Body Myositis.
Barohn RJ, Amato AA.
Department of Neurology, University of Texas Southwestern Medical Center, 5323
Harry Hines Blvd., Dallas, TX 75235-8897, USA.
Inclusion body myositis (IBM) is usually refractory to immunosuppressive
therapy; however, a few reports suggest that a minority of patients with IBM
may
have a partial, transient response or that therapy may slow progression.
Therefore, although we generally discourage the use of immunosuppressive therapy
for IBM, if the patient is willing to accept the potential side effects of
therapy, a 3- to 6-month trial of oral prednisone can be attempted: 100 mg/d
for
2 to 4 weeks, then 100 mg every other day for 2 to 3 months. If prednisone alone
produces no improvement after 3 months, oral methotrexate can be added: 10 to
15
mg/wk for 6 to 12 months. If there is no objective clinical improvement in
strength after a trial of prednisone alone or prednisone plus methotrexate over
the course of 6 to 12 months, we discontinue pharmacologic therapy. Because
of
the great expense, relative lack of availability, and minimal evidence of
benefit of intravenous immunoglobulin (IVIG), we do not recommend this form
of
immunomodulating therapy for IBM.
PMID: 11096732 [PubMed - as supplied by publisher]
206: Curr Treat Options Neurol. 1999 Jul;1(3):263-272.
Inflammatory Myopathy.
Mastaglia FL, Phillips BA, Zilko PJ.
Departments of Medicine, Neurology, and Clinical Immunology, Australian
Neuromuscular Research Institute, 4th Floor, G Block, Queen Elizabeth II Medical
Centre, Perth, Australia 6009.
Patients with polymyositis or dermatomyositis should be treated with prednisone
(approximately 1 mg/kg/d) for an initial period of 4 to 6 weeks. Once
improvement occurs, the dose should be tapered and converted to an alternate-day
regimen, which should be continued for at least 12 months. Methotrexate or
azathioprine should be administered concomitantly to patients in whom there
is
inadequate control. The early introduction of one of these drugs allows more
rapid reduction in the dose of prednisone and helps to avert serious side
effects. Intravenous immunoglobulin therapy is indicated for patients who have
immunodeficiency, who are unable to tolerate immu-nosuppressive drugs, whose
conditions are deteriorating, or who have severe relapses. Cyclosporine or
cyclophosphamide may be effective for resistant disease. Patients with inclusion
body myositis should undergo a 3- to 6-month trial of prednisone, alone or in
combination with methotrexate or azathioprine. Maintenance doses of these drugs
should be continued if the patient's condition improves or stabilizes.
PMID: 11096714 [PubMed - as supplied by publisher]
207: Curr Opin Rheumatol. 2000 Nov;12(6):482-91.
Update on the genetics of the idiopathic inflammatory myopathies.
Shamim EA, Rider LG, Miller FW.
Division of Monoclonal Antibodies, Center for Biologics Evaluation and Research,
Food and Drug Administration, Bethesda, Maryland 20892, USA. shamim@cber.fda.gov
A number of lines of investigation suggest that, as is likely the case for
other
autoimmune diseases, the idiopathic inflammatory myopathies (IIM) develop as
a
result of specific environmental exposures in genetically susceptible
individuals. Current data imply that multiple genes are involved in the etiology
of these complex disorders. Targeted gene studies and whole genome approaches
have begun to identify several genetic risk factors for autoimmune diseases,
but
the rarity and heterogeneity of the IIM have limited our knowledge of their
associated genes. Current findings suggest that human leukocyte antigen (HLA)
genes on chromosome 6, particularly HLA DRB1*0301 and the linked allele
DQA1*0501, have the strongest associations with all clinical forms of IIM in
white patients. Different HLA alleles, however, may confer risk or protection
for myositis in distinct ethnic, serologic, and environmental exposure groups.
Non-HLA genetic risk factors, which have been documented for other autoimmune
diseases, are now being identified for the IIM. These include polymorphic genes
encoding immunoglobulin heavy chains (defined by serologic markers known as
Gm
allotypes), cytokines and their receptors, and certain proteins that accumulate
in the myocyte vacuoles of inclusion body myositis patients. Selected allelic
polymorphisms of interleukin-1 receptor antagonist variable number tandem
repeats and genes for tumor necrosis factor alpha and interleukin-1 alpha also
have recently been associated with IIM. The pathogenic bases for the differences
among the many clinically, pathologically and immunologically defined syndromes
known as the IIM will be elucidated through a better understanding of the
multiple genes that define risks for their development, as well as through
investigations of gene-gene and gene-environment interactions.
Publication Types:
Review
Review, Tutorial
PMID: 11092196 [PubMed - indexed for MEDLINE]
208: Neurology. 2000 Nov 14;55(9):1385-7.
Epidemiology of inclusion body myositis in the Netherlands: a nationwide study.
Badrising UA, Maat-Schieman M, van Duinen SG, Breedveld F, van Doorn P, van
Engelen B, van den Hoogen F, Hoogendijk J, Howeler C, de Jager A, Jennekens
F,
Koehler P, van der Leeuw H, de Visser M, Verschuuren JJ, Wintzen AR.
Department of Neurology, Leiden University Medical Center, The Netherlands.
ubadrising@neurology.azl.nl
Epidemiologic data on inclusion body myositis (IBM) are scarce, and possibly
biased, because they are derived from larger neuromuscular centers. The present
nationwide collaborative cross-sectional study, which culminated on July 1,
1999, resulted in identification of 76 patients with IBM and the establishment
of a prevalence of 4.9 patients with IBM per million inhabitants in the
Netherlands. Several discrepancies suggest that this may be an underestimation.
The most frequently identified pitfall in diagnosing IBM was an erroneous
diagnosis of polymyositis or motor neuron disease.
PMID: 11087787 [PubMed - indexed for MEDLINE]
209: Arch Neurol. 2000 Nov;57(11):1561-5.
Apolipoprotein E and neuromuscular disease: a critical review of the literature.
Bedlack RS, Strittmatter WJ, Morgenlander JC.
PO Box 3403, Duke University Medical Center, Durham, NC 27710, USA.
bedla001@mc.duke.edu
Molecular mechanisms that alter the incidence and rate of neuromuscular disease
progression are, in many cases, only partially understood. Several recent
studies have asked whether apolipoprotein E (apoE for the protein, APOE for
the
gene) influences these aspects of specific neuromuscular disorders, as it does
in central nervous system disorders such as Alzheimer disease. Although these
studies are open to methodological criticism, several interesting trends have
emerged. First, the APOE4 allele seems to be associated with an increased risk
for developing certain neuromuscular diseases, including diabetic neuropathy
and
human immunodeficiency viral neuropathy. Second, this allele appears to be
associated with faster progression of some neuromuscular diseases, including
diabetic neuropathy and possibly motor neuron disease. Third, the APOE2 allele
seems to confer protection against developing certain neuromuscular diseases,
including the amyotrophic lateral sclerosis (ALS)/parkinsonism/dementia complex
of Guam. Finally, this allele is associated with a better prognosis in
neuromuscular diseases such as motor neuron disease. The effect of various APOE
alleles on neuromuscular diseases therefore parallels their influence on central
nervous system diseases. Arch Neurol. 2000;57:1561-1565
Publication Types:
Review
Review, Tutorial
PMID: 11074787 [PubMed - indexed for MEDLINE]
210: Neurology. 2000 Oct 24;55(8):1235.
Comment in:
Neurology. 2001 Jul 24;57(2):368.
Sporadic inclusion body myositis not linked to prion protein codon 129 methionine
homozygosity.
Orth M, Tabrizi SJ, Schapira AH.
University Department of Clinical Neurosciences, Royal Free and University
College Medical School, London, UK.
PMID: 11071511 [PubMed - indexed for MEDLINE]
211: Neurosci Lett. 2000 Oct 20;293(1):33-6.
Cyclin-dependent kinase 5 colocalizes with phosphorylated tau in human
inclusion-body myositis paired-helical filaments and may play a role in tau
phosphorylation.
Wilczynski GM, Engel WK, Askanas V.
USC Neuromuscular Center, Department of Neurology, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, Los Angeles
90017-1912, USA.
To investigate the possible role of cyclin-dependent kinase 5 (cdk5) in the
formation of paired helical filaments (PHFs) in muscle of patients with
inclusion-body myositis (IBM), we immunolocalized cdk5, by light- and electron-
microscopy, in muscle biopsies of six IBM patients. Approximately 80-90% of
IBM
vacuolated muscle fibers, and 10-15% of nonvacuolated fibers, contained well
defined cdk5-immunoreactive inclusions that colocalized with phosphorylated
tau
in 70-80% of those fibers. Immunoelectronmicroscopy revealed the association
of
cdk5 with tau-immunoreactive PHFs. In all biopsies that contained them,
regenerating muscle fibers had diffuse, moderate to strong cdk5
immunoreactivity. At all neuromuscular junctions, there was strong cdk5
immunoreactivity postsynaptically. Our study suggests that cdk5: (1) plays a
role in IBM pathogenesis, possibly mediating phosphorylation of PHF-related
tau;
(2) is involved in muscle regeneration; and (3) has a novel function at normal
neuromuscular junctions.
PMID: 11065131 [PubMed - indexed for MEDLINE]
212: J Neuroimmunol. 2000 Nov 1;111(1-2):146-51.
T-cell anti-apoptotic mechanisms in inflammatory myopathies.
Vattemi G, Tonin P, Filosto M, Spagnolo M, Rizzuto N, Tomelleri G.
Department of Neurological Sciences and Vision, University of Verona, Verona,
Italy.
Recent studies have shown an up-regulation of the Fas/Fas ligand system in
inflammatory myopathies. In myositis, however, the major Fas-mediated
cytotoxicity which activates caspases bypasses apoptosis. We therefore evaluated
the expression of proteins promoting cell survival, such as bcl-2, bcl-x(l)
and
cyclin-dependent kinase inhibitors, on muscle biopsies from 14 patients with
polymyositis, dermatomyositis, inclusion body myositis and HIV-associated
myositis. Our data demonstrate that inflammatory cells are immunoreactive for
bcl-x(l), p16 and p57, three apoptosis-preventing proteins. Hence, we assume
that these proteins might protect T cells from apoptotic nuclear changes. Our
results could explain the non-self-limiting nature of inflammatory myopathies.
PMID: 11063832 [PubMed - indexed for MEDLINE]
213: J Neurol Sci. 2000 Oct 1;179(S 1-2):92-102.
Peripheral neuropathy associated with hereditary and sporadic inclusion body
myositis: confirmation by electron microscopy and morphometry.
Hermanns B, Molnar M, Schroder JM.
Institut fur Neuropathologie, Universitatsklinikum der Rheinisch-Westfalischen
Technischen Hochschule Aachen, Pauwelsstrasse 30, D-52074, Aachen, Germany.
Inclusion body myositis (IBM) is a disabling myopathy affecting proximal and
distal muscle groups. The involvement of peripheral nerves in IBM is still a
controversial matter. In a previous morphometric study at the light microscopic
level only, we described a peripheral neuropathy in sural nerve biopsies of
eight patients with sporadic IBM (s-IBM). Here we present a larger series of
14
cases in which a combined muscle and nerve biopsy was available for additional
electron microscopic investigation. In two of the new cases, the IBM had a
hereditary background (h-IBM). The presence of neuropathy was confirmed in all
14 cases studied. Morphometry using an optic-electronic, digital evaluation
system showed large variation of severity presumably due to age and coincidal
factors such as diabetes mellitus or lymphoma. Ultrastructural analysis revealed
a variety of changes considered to be non-specific. Signs of axonal damage
predominated. In addition, there were numerous changes in Schwann cells and
myelin sheaths. Neither inflammatory changes nor tubulofilamentous inclusions
were detectable in the sural nerves. Peripheral neuropathy, although
occasionally without apparent clinical manifestation, appears to be a common
and
aggravating feature in IBM; its pathogenesis, however, remains elusive.
PMID: 11054491 [PubMed - indexed for MEDLINE]
214: Neuromuscul Disord. 2000 Dec;10(8):604-11.
Mitochondrial DNA variants in inclusion body myositis.
Kok CC, Boyt A, Gaudieri S, Martins R, Askanas V, Dalakas M, Kiers L, Mastaglia
F, Garlepp M.
Australian Neuromuscular Research Institute, Queen Elizabeth II Medical Centre,
Nedlands, Western Australia, Australia.
Mitochondrial DNA variants have been shown to be associated with many diseases.
Mutations at mitochondrial DNA nucleotide positions 3192, 3196, 3397 and 4336
have been described in association with late-onset Alzheimer's disease. The
pathological similarities between inclusion body myositis and Alzheimer's
disease prompted an analysis of the relationship between the reported mutations
and sporadic inclusion body myositis. The 4336G variant was not significantly
increased in patients with inclusion body myositis or Alzheimer's disease when
compared to controls. None of the patients with inclusion body myositis carried
mutations at nucleotide positions 3192, 3196 and 3397. A transition at
nucleotide position 4580 was detected in some patients with inclusion body
myositis and Alzheimer's disease but was not significantly higher in frequency
when compared to controls. Phylogenetic analysis showed that the 4336G and 4580A
variants clustered together in their respective group. A group of patients with
inclusion body myositis also clustered together on a separate branch of the
phylogenetic tree. Closer investigation of this group revealed a common
polymorphism at nucleotide position 16311. The frequency of the 16311C variant
was higher in inclusion body myositis than in Alzheimer's disease and controls,
although when only caucasian patients were considered the increased frequency
was not statistically significant. Further studies will be required to determine
whether this variant plays a role in the pathogenesis of inclusion body
myositis.
PMID: 11053689 [PubMed - indexed for MEDLINE]
215: Brain. 2000 Oct;123 ( Pt 10):2030-9.
Clonal restriction of T-cell receptor expression by infiltrating lymphocytes
in
inclusion body myositis persists over time. Studies in repeated muscle biopsies.
Amemiya K, Granger RP, Dalakas MC.
Neuromuscular Disease Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Bethesda, Maryland 20892-1382, USA.
Inclusion body myositis (IBM) is an inflammatory myopathy characterized
immunohistologically by prominent invasion of the non-necrotic, MHC-I class
antigen-expressing muscle fibres by CD8+ cytotoxic T cells. If the autoinvasive
CD8+ T cells are recruited specifically to the muscle and play a primary
pathogenetic role in the disease, a clonal restriction persisting over time
should be anticipated. In this study, we analysed the T-cell receptor (TCR)
gene
usage by endomysial T lymphocytes in three sequential muscle biopsies from three
different IBM patients over a 19-22 month period using immunohistochemistry,
reverse transcription-polymerase chain reaction (RT-PCR) and sequence analysis
of the complementarity determining region (CDR3) of the amplified TCRs. We found
that CD8+ T lymphocytes persist in the endomysial infiltrates in all biopsies
during a 19-22 month period. The most frequently detected TCRs were the V beta
3, V beta 5.1, V beta 6.7 and V beta 13 gene families, and several of the
autoinvasive CD8+ T cells expressed the TCRs V beta 6.7 and V beta 5.1. A
restricted usage of the examined V beta 6 gene family was found to persist in
the complementarity CDR3 determining region of the autoinvasive T cells over
the
22 month period. Identical V beta 6 CDR3 gene arrangements were also found in
the multiple muscle biopsies from two of the three IBM patients. The results
indicate that in IBM there is a restricted expression of the TCR gene families
among the autoinvasive T lymphocytes with homologies in the CDR3 region that
persist over the course of the disease. A continuous, antigen-driven T-cell
response is prominent in the muscle of patients with IBM.
PMID: 11004120 [PubMed - indexed for MEDLINE]
216: Immunobiology. 2000 Aug;202(2):199-203.
Common variable immunodeficiency (CVID) and inclusion body myositis (IBM).
Gause A, Inderrieden DC, Laas R, Arlt AC, Gross WL.
Poliklinik fur Rheumatologie, Universitatsklinikum Lubeck und
Krankenhausabteilung der Rheumaklinik Bad Bramstedt, Germany.
a.gause@rheuma-zentrum.de
A case of a 38-year old man with a common variable immunodeficiency syndrome
(CVID) is demonstrated who suffered at the same time from a histologically
proven inclusion body myositis (IBM). The myositis did not resolve after
institution of regular intravenous IgG infusions. This case demonstrates a very
long lasting benign course of IBM. The occurrence with CVID may be a clinical
hint for a viral pathogenesis of IBM. So far only two similar cases are reported
in the literature.
Publication Types:
Case Reports
PMID: 10993295 [PubMed - indexed for MEDLINE]
217: Int J Exp Pathol. 2000 Aug;81(4):231-9.
Accumulation of amyloid-beta protein in exocrine glands of transgenic mice
overexpressing a carboxyl terminal portion of amyloid protein precursor.
Fukuchi K, Li L, Hart M, Lindsey JR.
Departments of Comparative Medicine; Medicine, Schools of Medicine and
Dentistry, University of Alabama at Birmingham, Birmingham, Alabama, USA.
fukuchi@uab.edu
Amyloid-beta protein (Abeta) and its precursor (betaPP) play important roles
in
the pathogenesis of Alzheimer disease and inclusion-body myositis. In humans,
Abeta deposits are found in brain, skeletal muscle, and skin. Therefore, we
have
investigated possible Abeta deposits in multiple tissues of two transgenic mouse
lines overexpressing the signal plus Abeta-bearing 99-amino acid carboxyl
terminal sequences of betaPP under the control of a cytomegalovirus
enhancer/beta-actin promoter. One of the lines developed Abeta-immunoreactive
intracellular deposits consistently in the pancreas and lacrimal gland, and
occasionally in gastric, DeSteno's, and lingual glands. Although the Abeta
deposits increased during ageing and degenerative changes of the tissues were
observed, little or no extracellular Abeta deposits were observed up to the
age
of 25 months. These lines of transgenic mice are useful for studying the
molecular mechanisms of development and clearance of intracellular Abeta
deposits.
PMID: 10971744 [PubMed - indexed for MEDLINE]
218: Br J Dermatol. 2000 Sep;143(3):671.
Comment on:
Br J Dermatol. 1999 Nov;141(5):926-30.
Dermatomyositis with the features of inclusion body myositis associated with
carcinoma of the bladder: a true association?
Grau JM, Perea M.
Publication Types:
Comment
Letter
PMID: 10971365 [PubMed - indexed for MEDLINE]
219: Arch Phys Med Rehabil. 2000 Aug;81(8):1123-6.
Inclusion body myositis masquerading as polymyositis: a case study.
Boon AJ, Stolp-Smith KA.
Department of Physical Medicine and Rehabilitation, Mayo Clinic and Mayo
Foundation, Rochester, MN 55905, USA.
A case of inclusion body myositis masquerading as unresponsive polymyositis
is
presented. A 56-year-old woman diagnosed with "biopsy-proven" polymyositis
in
1991 was referred to our clinic in 1997 with progressive, painless weakness
that
was unresponsive to steroid therapy. Further evaluation, including
electromyography and review of the original muscle biopsy specimen, found a
diagnosis of inclusion body myositis, leading to a change in the patient's
prognosis and management. Inclusion body myositis is frequently mistaken for
polymyositis, despite the fact that it is now the most common inflammatory
myopathy affecting people older than 50 years. The purpose of this report is
to
increase awareness of this disease, to enhance early diagnosis, and to ensure
appropriate management. We discuss the clinical findings, pathogenesis, and
physiatric management, as well as compare this disease with other idiopathic
inflammatory myopathies.
Publication Types:
Case Reports
PMID: 10943766 [PubMed - indexed for MEDLINE]
220: Neurol Sci. 2000 Apr;21(2):99-102.
An Italian family with autosomal recessive quadriceps-sparing inclusion-body
myopathy (ARQS-IBM) linked to chromosome 9p1.
Mirabella M, Christodoulou K, Di Giovanni S, Ricci E, Tonali P, Servidei S.
Institute of Neurology, Catholic University, Policlinico Gemelli, Rome, Italy.
We report an Italian family with autosomal recessive quadriceps-sparing
inclusion-body myopathy (ARQS-IBM). The patients (two second cousins) developed
a slowly progressive distal and proximal myopathy with complete sparing of the
quadriceps. Muscle biopsy showed rimmed vacuoles in numerous muscle fibers,
and
electron microscopy documented accumulation of 15-21 nm filaments. DNA analysis
established linkage to 9p1 and haplotype analysis revealed that the patients
shared a recombined common haplotype. The gene locus of ARQS-IBM was initially
mapped to chromosome 9p1-q1 in families of Iranian-Jewish origin and later
confirmed in a few other ethnic groups. This is the first report of Italian
patients with ARQS-IBM showing positive linkage to chromosome 9p1. Our data
suggest that patients having distal and proximal myopathy with rimmed vacuoles
and possible recessive inheritance, often classified as distal myopathies,
should be thoroughly investigated according to the diagnostic criteria of h-IBM
and, when positive, studied for linkage to chromosome 9p1.
Publication Types:
Case Reports
PMID: 10938188 [PubMed - indexed for MEDLINE]
221: Ultrastruct Pathol. 2000 May-Jun;24(3):151-6.
Muscle involvement in rheumatoid arthritis: an ultrastructural study.
de Palma L, Chillemi C, Albanelli S, Rapali S, Bertoni-Freddari C.
Department of Orthopedics, University of Ancona, Italy.
An electron microscopic investigation has been carried out on muscle bioptic
samples from patients affected by rheumatoid arthritis (RA). This study was
undertaken to seek further ultrastructural alterations affecting striated
muscles in RA pathology. Bioptic samples were collected on a total of 30
surgical interventions of hip (10), knee (8), and foot (12). This yielded three
muscle types: gluteus maximus, vastus lateralis, and extensor digitorum
communis. Muscle samples from 12 patients with no RA stigmata, selected to match
RA patients by age and gender, constituted the control group. Tissue samples
were prepared both for conventional histochemical methods and according to
conventional electron microscopic procedures, including morphometric analysis.
Although to a different extent in each sample, in muscles from RA vs. controls
the authors observed the simultaneous presence of discrete muscular alterations
such as wider separation of myofibrils, myelin figures, dilated sarcotubular
system, pleomorphic mitochondria, myofibril flaking, and lipofuscin deposition
in the subsarcolemmal region. In addition to a progressive atrophy, the above
findings are suggestive of rheumatoid myositis and lend further support to the
still poorly documented presence of an idiopathic inflammatory myopathy and
inclusion body myositis associated with RA.
PMID: 10914426 [PubMed - indexed for MEDLINE]
222: Acta Neuropathol (Berl). 2000 Jul;100(1):23-8.
Multiple mitochondrial DNA deletions in hereditary inclusion body myopathy.
Jansson M, Darin N, Kyllerman M, Martinsson T, Wahlstrom J, Oldfors A.
Department of Pathology, Sahlgrenska University Hospital, Goteborg, Sweden.
We have recently described an autosomal dominant hereditary inclusion body
myopathy (h-IBM). Clinically it is is characterized by congenital joint
contractures and slowly progressive, proximal muscle weakness and
ophthalmoplegia. There is deterioration of muscle function between 30 and 50
years of age. While young patients show minor pathological changes in muscle,
the middle-aged and old patients show rimmed vacuoles and inclusions of
filaments measuring 15-18 nm in diameter. Except for the absence of significant
inflammation the histopathology is similar to that found in sporadic inclusion
body myositis (s-IBM). In s-IBM mitochondrial alterations including cytochrome
c
oxidase (COX) -deficient muscle fibers are common. These are due to multiple
mitochondrial DNA (mtDNA) deletions. In this study we investigated the
occurrence of mitochondrial alterations in autosomal dominant h-IBM. Young
affected individuals showed no mitochondrial changes but three patients aged
38,
51 and 59 years, respectively, showed ragged red fibers and COX-deficient muscle
fibers. Polymerase chain reaction analysis showed multiple mtDNA deletions.
By
in situ hybridization clonal expansions of mtDNA with deletions were
demonstrated in COX-deficient muscle fibers. Most of the analyzed deletion
breakpoints showed nucleotide repeats flanking the deletions. The results show
that COX-deficient muscle fibers and somatic mtDNA deletions are present in
this
family with h-IBM. The same factors may be involved in the development of mtDNA
deletions in s-IBM and this family with h-IBM.
PMID: 10912916 [PubMed - indexed for MEDLINE]
223: Neurology. 2000 Jul 25;55(2):296-8.
Disease progression in sporadic inclusion body myositis: observations in 78
patients.
Peng A, Koffman BM, Malley JD, Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurologic Diseases and
Stroke, National Institutes of Health, Bethesda, MD, USA.
Functional decline for each decade at symptom onset and need for cane, walker,
or wheelchair were assessed in 78 biopsy-proved patients with sporadic inclusion
body myositis. Patients with disease onset between 40 and 59 years used a walker
after 10.2 +/- 5.8 years, whereas those with disease onset between 60 and 79
years used a walker after 5.7 +/- 5.0 years (p = 0.05). Because patients
progress faster to disability when symptoms begin after the age of 60, age at
disease onset may define patient subsets for stratification in clinical trials.
PMID: 10908910 [PubMed - indexed for MEDLINE]
224: J Neuropathol Exp Neurol. 2000 Jul;59(7):592-8.
Novel immunolocalization of alpha-synuclein in human muscle of inclusion-body
myositis, regenerating and necrotic muscle fibers, and at neuromuscular
junctions.
Askanas V, Engel WK, Alvarez RB, McFerrin J, Broccolini A.
USC Neuromuscular Center, Department of Neurology, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, Los Angeles
90017-1912, USA.
Alpha-synuclein (alpha-syn) is an important component of neuronal and glial
inclusions in brains of patients with several neurodegenerative disorders.
Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle
disease of older patients. Its muscle phenotype shows several similarities with
Alzheimer disease brain. A distinct feature of s-IBM pathology is specific
vacuolar degeneration of muscle fibers characterized by intracellular amyloid
inclusions formed by both amyloid-beta (Abeta) and paired-helical filaments
composed of phosphorylated tau. We immunostained alpha-syn in muscle biopsies
of
s-IBM, disease-control, and normal patients. Approximately 60% of Abeta-positive
vacuolated muscle fibers (VMF) contained well-defined inclusions immunoreactive
with antibodies against alpha-syn. In those fibers. alpha-syn co-localized with
Abeta, both by light microscopy, and ultrastructurally. Paired-helical filaments
did not contain alpha-syn immunoreactivity. In all muscle biopsies, alpha-syn
was strongly immunoreactive at the postsynaptic region of the neuromuscular
junctions. alpha-syn immunoreactivity also occurred diffusely in regenerating
and necrotic muscle fibers. In cultured human muscle fibers, alpha-syn and its
mRNA were expressed by immunocytochemistry, immunoblots, and Northern blots.
Our
study provides the first demonstration that alpha-syn participates in normal
and
pathologic processes of human muscle. Therefore. its function is not exclusive
to the brain and neurodegenerative diseases.
PMID: 10901230 [PubMed - indexed for MEDLINE]
225: Baillieres Best Pract Res Clin Rheumatol. 2000 Mar;14(1):55-71.
Inflammatory muscle disease: therapeutic aspects.
Catoggio LJ, Soriano ER.
Rheumatology Section, Medical Services, Hospital Italiano de Buenos Aires,
Argentina. ljcatoggio@connmed.com.ar
The present treatment of the inflammatory myopathies remains unsatisfactory
in
several areas, perhaps due in part to our incomplete knowledge of their
aetiology. These conditions have been grouped together for practical purposes
and because of a similar approach to treatment. However, recent data regarding
pathological findings, serological patterns and different outcomes, suggest
that
some of these myopathies may be distinct, and perhaps approaches to treatment
should be tailored according to these findings. This chapter will attempt to
update our current management, offer an analysis of recent data regarding newer
treatment modalities and highlight areas lacking solid data that need to be
further addressed. Although corticosteroids are still considered to be the
mainstay of treatment, the earlier use of immunosuppressive therapy will be
discussed, as will the use of autoantibody profiles for tailoring treatment.
Newer modalities for the monitoring of therapeutic response and their current
place in clinical practice will be analysed. The management of refractory cases
will be addressed as will the current management of calcinosis, a problem more
frequently encountered in children.
PMID: 10882214 [PubMed - indexed for MEDLINE]
226: Am J Pathol. 2000 Jun;156(6):1835-40.
Association of active extracellular signal-regulated protein kinase with paired
helical filaments of inclusion-body myositis muscle suggests its role in
inclusion-body myositis tau phosphorylation.
Wilczynski GM, Engel WK, Askanas V.
Department of Neurology, University of Southern California Keck School of
Medicine, Good Samaritan Hospital, Los Angeles, CA 90017-1912, USA.
The possible role of extracellular signal-regulated kinase (ERK) in the
pathogenesis of inclusion-body myositis (IBM) was investigated by immunostaining
the active phosphorylated form of ERK in muscle biopsies of six IBM and 14
control patients. Between 80% and 90% of IBM vacuolated muscle fibers contained
well-defined ERK-immunoreactive inclusions, which were co-localized by light
microscopy, with phosphorylated tau in 70 to 80% of those fibers.
Immunoelectronmicroscopy colocalized ERK to small amorphous tufts adjacent to
the muscle fiber paired-helical filaments. Strong ERK immunoreactivity was also
present at the postsynaptic domain of all human neuromuscular junctions. Our
study suggests 1) that ERK, a signal transducer, might play a role in IBM
pathogenesis, including participation in the pathological phosphorylation of
IBM
tau; and 2) that signal transduction abnormalities may be a component of the
IBM
pathogenic cascade. Our novel immunolocalization of ERK at the postsynaptic
domain of human neuromuscular junctions supports a role in transcription of
junctional-protein genes. The ERK localized in nonjunctional regions of IBM
fibers may underlie the known pathological up-regulation of junctional proteins
there.
PMID: 10854206 [PubMed - indexed for MEDLINE]
227: Ann Neurol. 2000 Jun;47(6):811-6.
Partial laminin alpha2 chain deficiency in a patient with myopathy resembling
inclusion body myositis.
Di Blasi C, Mora M, Pareyson D, Farina L, Sghirlanzoni A, Vignier N, Blasevich
F, Cornelio F, Guicheney P, Morandi L.
Department of Neuromuscular Diseases, Istituto Nazionale Neurologico Carlo
Besta, Milano, Italy.
It is becoming evident that clinical phenotypes associated with partial laminin
alpha2 chain deficiency are variable. We recently observed a 29-year-old man
with leukoencephalopathy and vacuolar myopathy resembling inclusion body
myositis. Laminin alpha2 immunohistochemical analysis showed reduction of the
protein on muscle fiber surfaces. Molecular analysis revealed two novel compound
heterozygous mutations in the LAMA2 gene. This is the first report linking a
mutation in the LaMA2 gene with leukoencephalopathy and inclusion body-like
myositis.
Publication Types:
Case Reports
PMID: 10852549 [PubMed - indexed for MEDLINE]
228: Muscle Nerve. 2000 Jun;23(6):970-2.
Prevalence of sporadic inclusion body myositis in Western Australia.
Phillips BA, Zilko PJ, Mastaglia FL.
Centre for Neuromuscular and Neurological Disorders, Australian Neuromuscular
Research Institute, University of Western Australia, Australia.
A 10-year retrospective review was conducted to ascertain the prevalence of
inclusion body myositis (IBM) in Western Australia. Seventeen patients with
sporadic IBM aged 45-90 years were identified and the prevalence of IBM was
calculated to be 9.3 x 10(-6). The prevalence was higher in men (10.9 x 10(-6))
than in women (7.7 x 10(-6)). The mean age of onset of IBM was 56.6 years, and
the mean delay between onset of symptoms and diagnosis was 4.4 years. The
age-adjusted prevalence over the age of 50 years was 35.3 x 10(-6). The results
suggest a higher prevalence of IBM than has previously been reported. Copyright
2000 John Wiley & Sons, Inc.
PMID: 10842277 [PubMed - indexed for MEDLINE]
229: Neurosci Lett. 2000 Jun 16;287(1):1-4.
Redox factor-1 in muscle biopsies of patients with inclusion-body myositis.
Broccolini A, Engel WK, Alvarez RB, 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.
To determine whether redox factor-1 (Ref-1) participates in the pathogenesis
of
inclusion-body myositis (IBM), we immunolocalized Ref-1 in muscle biopsies of
IBM patients by light- and electron-microscopy. Approximately 70-80% of the
IBM
vacuolated muscle fibers had focal inclusions strongly immunoreactive for Ref-1.
By immunoelectronmicroscopy, Ref-1 was localized to paired-helical filaments,
6-10 nm amyloid-like fibrils and amorphous material. Virtually all regenerating
and necrotic muscle fibers in various muscle biopsies had diffusely strong Ref-1
immunoreactivity. At all neuromuscular junctions, postsynaptically there was
strong Ref-1 immunoreactivity. Our study suggests that Ref-1 plays a role in
IBM
pathogenesis, and in other pathologic and normal processes of human muscle.
PMID: 10841976 [PubMed - indexed for MEDLINE]
230: Aust N Z J Med. 2000 Apr;30(2):275-6.
Inclusion body myositis associated with systemic lupus erythematosus (SLE)
Limaye V, Scott G, Kwiatek R, Pile K.
Publication Types:
Case Reports
Letter
PMID: 10833124 [PubMed - indexed for MEDLINE]
231: J Neuroimmunol. 2000 Jul 1;106(1-2):1-5.
Expression of human IAP-like protein in skeletal muscle: a possible explanation
for the rare incidence of muscle fiber apoptosis in T-cell mediated inflammatory
myopathies.
Li M, Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Diseases
and
Stroke, National Institute of Health, Building 10, Room 4N248, 10 Center Drive,
MSC 1382, Bethesda, MD 20892-1382, USA.
In Polymyositis (PM) and sporadic Inclusion Body Myositis (s-IBM), the CD8(+)
cytotoxic T cells invade the muscle membrane and release perforin and granzyme
B
to induce cell death. Although granzyme B is a direct activator of executioner
caspases, there is no convincing evidence of apoptosis in the muscle fibers
of
these patients. To search for an explanation, we examined the muscle expression
of the human IAP-Like Protein (hILP), an evolutionarily conserved cell death
suppressor, that exerts major anti-apoptotic effects by inhibiting the
executioner caspases. Muscle biopsy specimens from patients with inflammatory
myopathies and controls were studied with: (a) immunocytochemistry using
antibodies against hILP and caspase-3 in single and double-labeled confocal
laser microscopy; (b) immunoblotting of muscle extracts immunoreacted with
anti-hILP antibodies; and (c) subcellular fractionation of muscle lysates
immunoreacted with antibodies against hILP. We found that hILP is expressed
on
the sarcolemmal region and co-localizes with dystrophin. Caspase-3 is
undetectable. Subcellular fractionation of the muscle specimens confirmed that
hILP is a membrane-associated protein. By immunoblotting, the 57 kD hILP was
abundantly expressed in the normal as well as the diseased muscles. We conclude
that in s-IBM and PM the expression of hILP, a major cell death suppressor,
on
the muscle membrane may prevent the induction of apoptosis by the autoinvasive
cytotoxic T cells on the cell surface, by inhibiting the caspase activation.
PMID: 10814776 [PubMed - indexed for MEDLINE]
232: Toxicol Pathol. 2000 Mar-Apr;28(2):363-6.
Recent developments in animal models of human neurodegenerative diseases.
Guyer C.
Department of Veterinary Pathobiology, University of Illinois, Urbana 61802,
USA.
Publication Types:
Congresses
PMID: 10805156 [PubMed - indexed for MEDLINE]
233: J Immunol. 2000 May 15;164(10):5459-65.
The inhibition of apoptosis in myositis and in normal muscle cells.
Nagaraju K, Casciola-Rosen L, Rosen A, Thompson C, Loeffler L, Parker T, Danning
C, Rochon PJ, Gillespie J, Plotz P.
Arthritis and Rheumatism Branch, National Institute of Arthritis and
Musculoskeletal and Skin Diseases, and National Cancer Institute, National
Institutes of Health, Bethesda, MD 20892, USA.
The mechanism of injury and death of muscle cells in the inflammatory myopathies
(dermatomyositis, polymyositis, and inclusion body myositis) remains obscure.
We
and others have not detected apoptosis in the muscle biopsies from patients
with
myositis despite clear evidence of cell damage and loss. We provide evidence
in
this study that Fas ligand (FasL) as well as Fas is present on muscle cells
and
inflammatory cells in myositis biopsies: Fas is present on most muscle cells
and
lymphocytes, and FasL is present on degenerating muscle cells and many
infiltrating mononuclear cells. The expression of both Fas and FasL in the
inflamed tissue makes the absence of apoptosis more striking. To address the
mechanisms of this resistance to classical apoptosis in muscle cells, we have
investigated the expression of the antiapoptotic molecule FLICE (Fas-associated
death domain-like IL-1-converting enzyme)-inhibitory protein (FLIP) in muscle
biopsies of myositis patients and in cultured human skeletal muscle cells. Using
laser capture microscopy, we have shown that FLIP is expressed in the muscle
fibers and on infiltrating lymphocytes of myositis biopsies. Furthermore, we
have shown that FLIP, but not Bcl-2, is expressed in cultured human skeletal
muscle cells stimulated with proinflammatory cytokines, and inhibition of FLIP
with antisense oligonucleotides promotes significant cleavage of
poly(ADP-ribose) polymerase autoantigen, a sensitive indicator of apoptosis.
These studies strongly suggest that the resistance of muscle to Fas-mediated
apoptosis is due to the expression of FLIP in muscle cells in the inflammatory
environment in myositis.
PMID: 10799913 [PubMed - indexed for MEDLINE]
234: Clin Neuropathol. 2000 Jan-Feb;19(1):13-20.
Inclusion body myositis (IBM).
Gayathri N, Anisya-Vasanth, Veerendra Kumar M, Das S, Santosh V, Yasha TC,
Ramamohan Y, Taly AB, Gourie-Devi M, Shankar SK.
Department of Neuropathology, National Institute of Mental Health and
Neurosciences, Bangalore, India.
Clinical, histological, immunohistochemical and ultrastructural features of
5
cases of inclusion body myositis -4 sporadic (s-IBM) and one hereditary (h-IBM)
form are described. These patients (3 men, 2 women) had chronic progressive
weakness of varying severity in all 4 extremities with sparing of cranial
muscles. Elevation of CPK was noted in 2 patients. Electromyography revealed
features of myopathy in 4 and additional neurogenic changes in 2 subjects.
Clinical diagnosis was often other than inclusion body myositis. Presence of
characteristic eosinophilic inclusions within the vacuoles established the
diagnosis. The inclusions were congophilic and showed positivity to ubiquitin,
beta-amyloid and SMI-31 in the sporadic cases while congophila was absent in
the
hereditary form. Immunostaining to hyperphosphorylated-tau was negative in both
s-IBM and h-IBM. Membraneous whorls were observed at ultrastructural level.
None
of the patients improved with steroids and trial with other immunosuppressants
was unsuccessful.
PMID: 10774946 [PubMed - indexed for MEDLINE]
235: Am J Med Sci. 2000 Apr;319(4):227-33.
Autoantibodies in inflammatory myopathies.
Garlepp MJ, Mastaglia FL.
School of Pharmacy, Curtin University of Technology, Western Australia, Perth.
tgarlepp@cc.curtin.edu.au
Publication Types:
Review
Review, Tutorial
PMID: 10768607 [PubMed - indexed for MEDLINE]
236: Neurology. 2000 Apr 25;54(8):1665-70.
The muscle mitogen-activated protein kinase is altered in sporadic inclusion
body myositis.
Li M, Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institute of Health, Bethesda, MD 20892-1382, USA.
OBJECTIVE: To examine the origin of hyperphosphorylated proteins within the
vacuolated myofibers in sporadic inclusion body myositis (s-IBM) and search
for
dysregulated intracellular protein phosphorylation. BACKGROUND: s-IBM is
morphologically characterized by primary endomysial inflammation and vacuolated
myofibers containing tubulofilaments that originate from cytoskeletal proteins.
Mitogen-activated protein kinases (MAPKs) play a role in regulating
phosphorylation and maintaining the stability of the cytoskeletal architecture.
METHODS: Muscle biopsies from seven patients with s-IBM and 15 controls were
examined for the expression of the active components of the various MAPKs,
including p44/42MAPK, p38MAPK, p46JNK1, p54JNK2, and p54JNK3, using
immunocytochemistry and Western blot analysis. The expression of selected
phosphorylated components was also examined in the same specimens. RESULTS:
In
s-IBM, but not the disease controls, the vacuolated muscle fibers express active
p42MAPK but not JNK or p38MAPK. Western blots of cell lysates confirmed the
hyperexpression of p42MAPK and demonstrated a novel 35 kD phosphoprotein.
Antibodies against phosphoepitopes of the 35 kD protein preferentially
immunostained antigens within the vacuolated muscle fibers of s-IBM but not
disease controls. CONCLUSION: In s-IBM, there is increased p42MAPK activation
and abnormal intracellular protein phosphorylation with selective accumulation
of a 35 kD phosphoprotein within the vacuolated fibers. Although the
hyperexpression of 35kD protein may represent cytoskeletal by-products due to
heightened p42MAPK activation, its abundant expression only in s-IBM implies
that hyperphosphorylated myofibrillar proteins may be involved in the primary
disease process.
Publication Types:
Clinical Trial
Controlled Clinical Trial
PMID: 10762511 [PubMed - indexed for MEDLINE]
237: Ann Neurol. 2000 Apr;47(4):544-9.
Inclusion body myositis, muscle blood vessel and cardiac amyloidosis, and
transthyretin Val122Ile allele.
Askanas V, Engel WK, Alvarez RB, Frangione B, Ghiso J, Vidal R.
Department of Neurology, University of Southern California, Keck School of
Medicine, Good Samaritan Hospital, Los Angeles, CA, USA.
Typical of sporadic inclusion body myositis muscle biopsies are vacuolated
muscle fibers containing intracellular amyloid deposits and accumulations of
"Alzheimer-characteristic" proteins. There is no muscle blood vessel
or cardiac
amyloidosis. We report on a 70-year-old African-American man homozygous for
the
transthyretin Val122Ile allele who has both sporadic inclusion body myositis
and
cardiac amyloidosis. His unique pathological features included transthyretin
immunoreactivity in prominent muscle blood vessel amyloid and congophilic
amyloid deposits within vacuolated muscle fibers.
Publication Types:
Case Reports
PMID: 10762172 [PubMed - indexed for MEDLINE]
238: Am J Pathol. 2000 Apr;156(4):1151-5.
Paired helical filaments of inclusion-body myositis muscle contain RNA and
survival motor neuron protein.
Broccolini A, Engel WK, Alvarez RB, Askanas V.
University of Southern California Neuromuscular Center, Los Angeles, California
90017-1712, USA.
Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle
disease of older persons. Pathologically, the muscle biopsy manifests various
degrees of inflammation and specific vacuolar degeneration of muscle fibers
characterized by paired helical filaments (PHFs) composed of phosphorylated
tau.
IBM vacuolated fibers also contain accumulations of several other
Alzheimer-characteristic proteins. Molecular mechanisms leading to formation
of
the PHFs and accumulations of proteins in IBM muscle are not known. We report
that the abnormal muscle fibers of IBM contained (i) acridine-orange-positive
RNA inclusions that colocalized with the immunoreactivity of phosphorylated
tau
and (ii) survival motor neuron protein immunoreactive inclusions, which by
immuno-electron microscopy were confined to paired helical filaments. This study
demonstrates two novel components of the IBM paired helical filaments, which
may
lead to better understanding of their pathogenesis.
PMID: 10751338 [PubMed - indexed for MEDLINE]
239: J Neuropathol Exp Neurol. 2000 Feb;59(2):164-9.
Increased expression of beta-chemokines in muscle of patients with inflammatory
myopathies.
Confalonieri P, Bernasconi P, Megna P, Galbiati S, Cornelio F, Mantegazza R.
Divisione Malattie Neuromuscolari, Istituto Nazionale Neurologico Carlo Besta,
Milan, Italy.
Idiopathic inflammatory myopathies (IIM) are muscle diseases of autoimmune
pathogenesis characterized by mononuclear cell infiltration within muscle
tissue. Since immune cell homing and accumulation at the site of antigenic
challenge is usually mediated by chemokines, we evaluated the expression of
2
beta-chemokines--monocyte chemoattractant protein-1 (MCP-1) and macrophage
inflammatory protein-1alpha (MIP-1alpha)--by immunohistochemistry and polymerase
chain reaction in muscles of polymyositis, inclusion body myositis, and
dermatomyositis patients, and related their expression to immunopathological
alterations in muscle. MCP-1 and MIP-1alpha transcripts were detected by PCR
in
all IIM muscles, but not in controls. By immunohistochemistry, the chemokines
were found in all IIM muscle sections located in infiltrating inflammatory cells
and also in neighboring extracellular matrix. The extent to which extracellular
matrix was filled by each chemokine differed in each disease. In view of the
known ability of chemokines to bind extracellular matrix and their possible
synthesis by extracellular matrix components, we suggest that chemokine storage
in the extracellular matrix can act as a microenvironmental factor amplifying
lymphocyte activation and migration, thereby maintaining the autoimmune attack
against unknown muscle antigens.
PMID: 10749105 [PubMed - indexed for MEDLINE]
240: J Biol Chem. 2000 Mar 24;275(12):8703-10.
Sporadic inclusion body myositis correlates with increased expression and
cross-linking by transglutaminases 1 and 2.
Choi YC, Park GT, Kim TS, Sunwoo IN, Steinert PM, Kim SY.
Department of Neurology, College of Medicine, Yonsei University, Seoul 135-270,
Republic of Korea. ycchoi@yumc.yonsei.ac.kr
Sporadic inclusion body myositis (SIBM) is characterized by vacuolar
degeneration of muscle fibers and intrafiber clusters of paired helical
filaments with abnormal amyloid deposition. Because of their potential
involvement in other degenerative disorders, we have examined the expression
of
transglutaminases (TGases) in normal and SIBM tissues. We report that at least
two different enzymes, the ubiquitous TGase 2 as well as the TGase 1 enzyme,
are
present in muscle tissues. However, in comparison with normal tissue, the
expression of TGases 1 and 2 was increased 2.5- and 4-fold in SIBM, accompanied
by about a 20-fold higher total TGase activity. By immunohistochemical staining,
in normal muscle, TGase 2 expression was restricted to some endomysial
connective tissue elements, whereas TGase 1 and beta-amyloid proteins were not
detectable. In SIBM muscle, both TGases 1 and 2 as well as amyloid proteins
were
brightly expressed and co-localized in the vacuolated muscle fibers, but none
of
these proteins colocalized with inflammatory cell markers. Next, we isolated
high molecular weight insoluble proteins from SIBM muscle tissue and showed
that
they were cross-linked by about 6 residues/1000 residues of the isopeptide bond.
Furthermore, by amino acid sequencing of solubilized tryptic peptides, they
contain amyloid and skeletal muscle proteins. Together, these findings suggest
that elevated expression of TGases 1 and 2 participate in the formation of
insoluble amyloid deposits in SIBM tissue and in this way may contribute to
progressive and debilitating muscle disease.
PMID: 10722712 [PubMed - indexed for MEDLINE]
241: Neurology. 2000 Mar 14;54(5):1033-41.
Comment in:
Neurology. 2000 Mar 14;54(5):1020-1.
AlphaB-crystallin immunolocalization yields new insights into inclusion body
myositis.
Banwell BL, Engel AG.
Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic,
Rochester, MN 55905, USA.
OBJECTIVE: To study the expression of the small heat shock protein,
alphaB-crystallin (alphaBC), in inclusion body myositis (IBM). BACKGROUND: In
humans, alphaBC is constitutively expressed in the eye lens, muscle, and heart,
but not in lymphoid tissues. Induced expression of alphaBC occurs under
metabolic stress, in virus-infected lymphocytes, and in degenerative brain
lesions, including neurofibrillary tangles and senile plaques in AD. The
previously reported pathologic similarities between AD and IBM prompted us to
study alphaBC expression in IBM. METHODS: Immunolocalization of alphaBC in
muscle of 11 patients with IBM, 50 patients with other muscle diseases, and
4
controls; and quantitative analysis of the frequency of fibers with 1) increased
alphaBC expression in IBM and polymyositis and 2) structural abnormality
(vacuolated, non-necrotic and invaded by mononuclear cells, Congo red-positive,
SMI-31 positive, and ubiquitin positive) in IBM. RESULTS: We detected enhanced
expression of alphaBC not only in all structurally abnormal IBM fibers, but
also, and with severalfold higher frequency, in IBM fibers without significant
structural abnormality (X fibers) (p values in paired t-tests < 0.001). We
also
found enhanced alphaBC in abnormal fibers in other diseases; X fibers, however,
were extremely sparse or absent, except in two atypical cases of polymyositis
refractory to immunotherapy. CONCLUSION: That the X fibers are much more
frequent than the structurally abnormal fibers in IBM points to a pathogenic
stressor acting upstream to the development of structural abnormalities. The
identification of this stressor is now of paramount importance for deciphering
the enigma of IBM.
PMID: 10720271 [PubMed - indexed for MEDLINE]
242: Neurology. 2000 Mar 14;54(5):1020-1.
Comment on:
Neurology. 2000 Mar 14;54(5):1033-41.
Biologically stressed muscle fibers in sporadic IBM: a clue for the enigmatic
etiology?
Karpati G, Hohlfeld R.
Publication Types:
Comment
Editorial
PMID: 10720268 [PubMed - indexed for MEDLINE]
243: Am J Med. 2000 Mar 6;108 Suppl 4a:43S-46S.
Management of upper esophageal sphincter disorders: indications and
complications of myotomy.
Kelly JH.
Department of Otolaryngology, Head and Neck Surgery, Greater Baltimore Medical
Center, Maryland 21204, USA.
Since 1951, when it was first used as a treatment for post-poliomyelitis
dysphagia, cricopharyngeal myotomy (CPM) has been used in the treatment of
various neurogenic, myogenic, structural, and idiopathic disorders. Yet, the
efficacy of CPM in treating patients with upper esophageal sphincter (UES)
disorders remains controversial. Despite favorable reports regarding its
success, too few studies about indications, complications, and outcomes of CPM
have been conducted to quell the controversy. Swallowing is accomplished when
three primary conditions exist: (1) the cricopharyngeus muscle (CP)
relaxes--that is, it is not tonically contracted, (2) the laryngo-hyoid complex
elevates in an anterior-superior direction to open the sphincter, and (3)
pharyngeal pressure is sufficient to propel a bolus through the open sphincter.
CPM is indicated when the second and third conditions are "adequate"
but the
first is inadequate, thus resulting in pharyngeal dysphagia associated with
a
defective opening of the UES. UES dysfunction is determined most often through
patient history, physical examination, and testing. Patients with Zenker's
(pharyngoesophageal) diverticulum, oculopharyngeal dystrophy, or inclusion body
myositis are among those reported to have the most positive responses to CPM.
Modified barium swallow is the most common measurement of UES dysfunction;
manometry also is used, but to a lesser degree because of catheter motion during
swallowing. There are four approaches to CPM, including: (1) the external
technique, which is indicated when a muscle biopsy or neck exploration is
needed; (2) the endoscopic approach, which is reported to work best with
patients with Zenker's diverticulum and offers the choice of electrocautery,
laser, or the surgical stapler--the last option being the best choice for
high-risk patients; (3) balloon dilatation of the UES, a low-risk option that
reportedly works best in patients with fibrosis of the CP; and (4) botulinum
toxin injection of the CP transcervically or endoscopically, which offers low
risk and minimal or no anesthesia. This approach best serves cases of failed
relaxation of the CP. Each approach has potential complications, but reports
of
such are few and rarely severe. In all cases, massive reflux should be
controlled before CPM and the patient should be medically stable. Patient
selection for CPM remains inadequate. To assess the efficacy of CPM, more
multi-institutional outcome studies need to be conducted. In the meanwhile,
clinical judgment and selective testing via modified barium swallow are the
best
methods for identifying patients who may derive the most benefit from CPM.
Publication Types:
Review
Review, Tutorial
PMID: 10718451 [PubMed - indexed for MEDLINE]
244: J Neurol. 2000 Jan;247(1):22-8.
High-dose immunoglobulin therapy in sporadic inclusion body myositis: a
double-blind, placebo-controlled study.
Walter MC, Lochmuller H, Toepfer M, Schlotter B, Reilich P, Schroder M,
Muller-Felber W, Pongratz D.
Department of Neurology, Friedrich-Baur-Institut, Medizinische Klink, University
of Munich, Germany. Maggie.Walter@lrz.uni-muenchen.de
Sporadic inclusion body myositis (s-IBM) is an acquired inflammatory muscle
disease of unknown cause. In general, s-IBM presents with slowly progressive,
asymmetric weakness, and atrophy of skeletal muscle. There is a mild transitory
or nil responsiveness to standard immunosuppressive treatment. A controlled
cross-over study of 22 s-IBM patients over 3 months showed a partial improvement
in those treated with high-dose intravenous immunoglobulin therapy (IVIG) versus
placebo. The present study included 22 patients aged 32-75 years and with a
mean
duration of disease of 5.2+/-3.6 years. They were randomized by a double-blind,
placebo-controlled, cross-over design to monthly infusions of 2 g/kg bodyweight
IVIG or to placebo for 6 months each, followed by the alternative treatment.
After 6 and 12 months the response to treatment was evaluated, using a modified
Medical Research Council scale, Neuromuscular Symptom Score (NSS), the patient's
own assessment of improvement, arm outstretched time, and electromyography.
No
serious side effects were seen, in particular no viral infection and no major
cardiac or neurological complications. Overall there was no progression of the
disease in 90% of patients, unlike that which might have been expected in
untreated patients. A mild and significant improvement (11%) in clinical
symptoms was found using NSS, but not with other test procedures. There was
a
trend to mild improvement in treated patients when using other tests. Individual
responses to treatment was heterogeneous. The validity of this study may be
reduced by mismatch of groups with regard to age at onset and variability in
disease expression. The findings of this study largely confirm those of a
previous IVIG trial. Treatment with IVIG may be mildly effective in s-IBM by
preventing disease progression or inducing mild improvement. Long-term studies
are needed to evaluate further the benefit of IVIG therapy in s-IBM.
Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 10701893 [PubMed - indexed for MEDLINE]
245: J Neurosci Res. 2000 Feb 15;59(4):553-60.
Muscular dystrophy in adult and aged anti-NGF transgenic mice resembles an
inclusion body myopathy.
Capsoni S, Ruberti F, Di Daniel E, Cattaneo A.
Neuroscience Program, International School for Advanced Studies (SISSA),
Trieste, Italy.
The role of nerve growth factor (NGF) and its receptors in the physiology of
skeletal muscles has not been extensively studied in animal models. We describe
the production of transgenic lines of mice expressing a neutralizing antibody
against NGF (alphaD11) and the morphological and histochemical analysis of
skeletal muscles from adult and aged anti-NGF mice. This study reveals that
the
chronic deprivation of NGF results in a decreased size of myofibers of dorsal
and hindlimb muscles in adult but not in postnatal day (P)2 mice. In myofibers
from adult anti-NGF mice, the presence of central nuclei, vacuolization of the
cytoplasm, and inflammatory cell infiltration was observed. The
immunohistochemical analysis of these muscular fibers revealed an upregulation
of p75 expression, a decrease in adenosine triphosphatase (ATP)ase activity,
and
a subsarcolemmal Congo Red-positive staining. Immunostaining with an antibody
against amyloid precursor protein showed an increased labeling of the cytoplasm
of myofibers from adult and aged anti-NGF mice. These features are reminiscent
of human myopathies, such as inclusion body myositis. We conclude that NGF
deficits might be relevant for a class of human myopathies. Copyright 2000
Wiley-Liss, Inc.
PMID: 10679795 [PubMed - indexed for MEDLINE]
246: Brain. 2000 Feb;123 ( Pt 2):374-9.
Synergistic effect of beta-amyloid protein and interferon gamma on nitric oxide
production by C2C12 muscle cells.
Baron P, Galimberti D, Meda L, Prat E, Scarpini E, Conti G, Moggio M, Prelle
A,
Scarlato G.
Institute of Neurology, University of Milan, IRCCS Ospedale Maggiore
Policlinico, Milan, Italy.
Nitric oxide (NO) is an important mediator of diverse physiological and
pathological responses. NO-induced oxidative stress has been proposed in the
pathogenesis of muscle tissue damage in inclusion-body myositis (IBM), which
is
characterized by deposition of beta-amyloid protein (Abeta) in vacuolated muscle
fibres. To determine whether Abeta can induce NO production in skeletal muscle,
we stimulated C2C12 mouse skeletal muscle cells in vitro with Abeta[1-42] or
Abeta[25-35] peptides in the presence or absence of interferon gamma
(IFN-gamma). Neither Abeta peptides nor IFN-gamma were able to stimulate nitrite
(NO(2)(-)) production by C2C12 cells when given alone. However, combination
of
IFN-gamma with either Abeta[1-42] or Abeta[25-35] resulted in significant
NO(2)(-) release into cell-free supernatants. Northern blot analysis of RNA
obtained from Abeta/IFN-gamma-stimulated C2C12 cells revealed increased mRNA
accumulation of inducible nitric oxide synthase (iNOS). Moreover, approximately
4% of muscle cells incubated with Abeta peptides and IFN-gamma showed
ultrastructural features of DNA fragmentation. These findings, taken together,
indicate that the association of Abeta with IFN-gamma stimulates NO(2)(-)
production via induction of iNOS gene expression in skeletal muscle cells, with
occasional evidence for nuclear changes suggesting apoptotic morphology. These
data further support a role for Abeta deposition in the pathogenesis of
postulated oxidative damage in IBM.
PMID: 10648444 [PubMed - indexed for MEDLINE]
247: J Neurol Neurosurg Psychiatry. 2000 Feb;68(2):230-3.
A case of inclusion body myositis with benign monoclonal gammopathy successfully
responding to repeated immunoabsorption.
Nakayama T, Horiuchi E, Watanabe T, Murayama S, Nakase H.
Department of Neurology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo
105-8470, Japan.
A 69 year old woman with inclusion body myositis is described. She presented
with benign monoclonal gammopathy. She was resistant to steroid therapy, but
responded to repeated immunoabsorption. Up to now, there has been no established
therapy for inclusion body myositis, including IVIg. It is suggested that
immunoabsorption could be an alternative therapy for inclusion body myositis,
when it was accompanied by immunological abnormality.
Publication Types:
Case Reports
PMID: 10644796 [PubMed - indexed for MEDLINE]
248: Clin Immunol. 2000 Feb;94(2):99-104.
Downregulation of TGF-beta1 mRNA and protein in the muscles of patients with
inflammatory myopathies after treatment with high-dose intravenous
immunoglobulin.
Amemiya K, Semino-Mora C, Granger RP, Dalakas MC.
Neuromuscular Diseases Section, National Institutes of Health, Bethesda,
Maryland 20892, USA.
We used reverse transcription-polymerase chain reaction to study the level
of
TGF-beta1 mRNA expression and immunocytochemistry to examine the immunoreactive
TGF-beta1 in muscle biopsy specimens from five patients with dermatomyositis
(DM) and five patients with inclusion body myositis (IBM) obtained before and
after 3 months treatment with intravenous immunoglobulin (IVIg). At baseline,
the mRNA expression of TGF-beta1 was increased up to fivefold in the muscles
of
DM patients compared to that of IBM patients. After IVIg, TGF-beta1 was
downregulated and the TGF-beta1 mRNA decreased twofold in the muscles of
patients with DM who had successfully responded to therapy, but remained
unchanged in the muscles of patients with IBM who did not respond. The
downregulation of TGF-beta1 in DM was associated with improvement of the muscle
cytoarchitecture and reduction of the endomysial inflammation and connective
tissue, suggesting that in DM the excess of TGF-beta1 may be involved in the
pathogenesis of chronic inflammation, fibrosis, and accumulation of
extracellular matrix proteins. Copyright 2000 Academic Press.
PMID: 10637094 [PubMed - indexed for MEDLINE]
249: Neurology. 2000 Jan 11;54(1):65-71.
Expression of matrix metalloproteinases in the muscle of patients with
inflammatory myopathies.
Choi YC, Dalakas MC.
Neuromuscular Disease Section, National Institute of Neurological Disorders
and
Stroke, National Institute of Health, Bethesda, MD 20892-1382, USA.
OBJECTIVE: To investigate the role of matrix metalloproteinases (MMPs) in the
pathogenesis of inflammatory myopathies and the amyloid formation in sporadic
inclusion body myositis (s-IBM). BACKGROUND: MMPs comprise a family of
calcium-dependent zinc endoproteinases induced by cytokines and secreted by
inflammatory cells. They enhance T-cell migration or adhesion and degrade
components of the extracellular matrix proteins. Some MMPs also have been
implicated in the formation of beta-amyloid. METHODS: We examined the expression
of MMPs with single and double immunocytochemistry using antibodies against
MMP-2, MMP-3, MMP-7, MMP-9, major histocompatibility complex (MHC) class I,
CD8+
cells, macrophage, and beta-amyloid precursor protein (beta-APP) on serial
muscle biopsy sections from patients with s-IBM, polymyositis (PM),
dermatomyositis (DM), and disease control specimens. The enzyme activity of
MMPs
was measured by gelatin substrate zymography. RESULTS: Only the gelatinases,
MMP-9 and MMP-2, were expressed in the muscle. In s-IBM and PM, but not the
control specimens, MMP-9 and MMP-2 immunostained the non-necrotic and MHC
class-I-expressing muscle fibers, and MMP-9, but not MMP-2, immunostained the
autoinvasive CD8+ cytotoxic T cells. Zymography in muscle homogenates confirmed
the increased MMP-2 and MMP-9 enzymatic activity. MMP-2, but not MMP-9,
immunostained the rimmed vacuoles in s-IBM and colocalized with beta-APP,
suggesting a possible involvement with the amyloid deposits. CONCLUSIONS:
Because collagen IV is prominent on the muscle membrane, the overexpression
of
matrix metalloproteinases (MMPs) 2 and 9 on the non-necrotic muscle fibers in
polymyositis (PM) and sporadic inclusion body myositis (s-IBM) may facilitate
lymphocyte adhesion and enhance T-cell-mediated cytotoxicity by degrading
extracellular matrix proteins. The findings may have practical implications
in
considering therapeutic trials with MMP inhibitors in patients with PM and
s-IBM.
PMID: 10636127 [PubMed - indexed for MEDLINE]
250: Curr Eye Res. 2000 Feb;20(2):137-43.
Prion protein expression in mammalian lenses.
Frederikse PH, Zigler SJ Jr, Farnsworth PN, Carper DA.
Department of Ophthalmology, Department of Pharmacology & Physiology, UMDNJ-New
Jersey Medical School, Newark, New Jersey 07103, USA. frederph@umdnj.edu
PURPOSE: Aging and oxidative stress resulting from over-expression of Alzheimer
precursor protein (betaAPP) have been studied as important factors contributing
to the major age-related (sporadic), and minor (hereditary) forms of Alzheimer's
disease (AD), and muscle inclusion body myositis, (IBM). AD and prion proteins
accumulate in plaques linked with AD and scrapie diseases, and in rimmed
vacuoles of IBM. Soluble beta-amyloid (Abeta) fibrillar forms are now thought
to
play a critical role in and outside of cells by producing oxidative stress.
In
lens, betaAPP and Abeta increase in cultured lenses exposed to oxidative stress,
and in areas of lens fiber cell degeneration in thiamine (vitamin B1) deprived
mice, a classic model of systemic oxidative stress. The purpose of the present
study is to extend our studies of amyloid disease-related protein expression
in
mammalian lenses. METHODS: Western blot, immunohistochemical detection, and
RT-PCR methods were used to identify and quantitate prion protein expression
in
human, monkey, and guinea pig lenses. RESULTS: We demonstrate for the first
time
that prion protein gene expression increases with oxidative stress in cultured
human lens epithelial cells. In addition, we detected greater prion protein
gene
expression in fiber cells than epithelial cells in vivo. This is consistent
with
increases in prion protein expression demonstrated in myoblasts and neuronal
cells induced to differentiate. Our initial investigations of prion protein
in
human lens cataracts identified increased prion protein immunoreactivity in
regions of lens fiber cell degeneration. CONCLUSIONS: The present data indicate
that prion protein expression increases during lens development, and is
substantially increased in cultured human lens epithelial cells exposed to
oxidative stress. We also provide evidence that prion protein immunoreactivity
can be increased in regions of fiber cell disorganization. These data suggest
a
potential role for prion protein as a marker for some types of lens pathology,
and in the mechanism of oxidative stress-related lens degeneration.
PMID: 10617916 [PubMed - indexed for MEDLINE]
251: Brain. 2000 Jan;123 ( Pt 1):93-104.
Apoptosis in mitochondrial encephalomyopathies with mitochondrial DNA mutations:
a potential pathogenic mechanism.
Mirabella M, Di Giovanni S, Silvestri G, Tonali P, Servidei S.
Institute of Neurology, Catholic University, Rome, Italy.
Mitochondrial encephalomyopathies caused by mitochondrial DNA (mtDNA) defects
are a genetically and phenotypically heterogeneous group of disorders. The site,
percentage and distribution of mutations do not explain the overall clinical
heterogeneity that is found. Apoptosis (programmed cell death) is an
evolutionarily conserved mechanism that is essential for tissue development
and
homeostasis. Dysregulation of apoptosis has been implicated in the pathogenesis
of various human diseases, such as cancer and autoimmune and neurodegenerative
disorders. Recent in vitro evidence has indicated the central role of
mitochondria in the apoptotic process. We investigated the occurrence of
apoptosis in muscle biopsies of 36 patients carrying different mtDNA mutations
and four patients with inclusion body myositis and mitochondrial abnormalities.
Apoptotic features, mainly localized in cytochrome c oxidase-negative fibres,
were observed in muscle fibres of patients carrying a high percentage of single
mtDNA deletions (>40%) and of tRNA point mutations (>70%). By contrast,
no
apoptotic changes were observed in inclusion body myositis and in patients
carrying mutations of mtDNA structural genes. Our study suggests that apoptosis
is not simply a means whereby cells with dysfunctional mitochondria are
eliminated, but that it seems to play a role in the pathogenesis of
mitochondrial disorders associated with mtDNA defects affecting mitochondrial
protein synthesis. The imbalance and relative abundances of nuclear-encoded
and
mtDNA-encoded subunits may favour cytochrome c inactivation and release.
Cytochrome c, together with respiratory chain dysfunction, could activate
apoptotic pathways that, in turn, inhibit the rate of mitochondrial translation
and the importation of nuclear-encoded mitochondrial protein precursors. This
vicious circle may amplify the biochemical defects and tissue damage and
contribute to the modulation of clinical features.
PMID: 10611124 [PubMed - indexed for MEDLINE]
252: Neurology. 1999 Dec 10;53(9):2184-7.
Cultured inclusion-body myositis muscle fibers do not accumulate beta-amyloid
precursor protein and can be innervated.
McFerrin J, Engel WK, Askanas V.
USC Neuromuscular Center, Department of Neurology, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, Los Angeles
90017-1912, USA.
Cultured muscle fibers from patients with sporadic inclusion-body myositis
(s-IBM), similar to normal control muscle fibers, 1) did not have beta-amyloid
precursor protein (betaAPP) immunoreactivity; and 2) became normally innervated,
as evidenced by the following features: full cross-striation, continuous
contraction, and acetylcholinesterase and acetylcholine receptors accumulated
only at neuromuscular junctions. Thus, factors responsible for betaAPP
accumulation and denervation-like changes in s-IBM muscle biopsies are not
operative in the relatively short-term, non-aged, cultured s-IBM muscle fibers.
PMID: 10599804 [PubMed - indexed for MEDLINE]
253: Adv Exp Med Biol. 1999;455:187-91.
Dermatomyositis and drugs.
Dourmishev AL, Dourmishev LA.
Department of Dermatology, University of Medicine, Sofia, Bulgaria.
Dermatomyositis (DM) is an idiopathic inflammatory disorder consisting of skin
and skeletal muscle involvement. Patients with skeletal muscle involvement have
polymyositis (PM), and those unresponsive to therapy and with characteristic
findings on muscle biopsy have inclusion body myositis. Patients without muscle
damage and typical skin lesions have amyopathic dermatomyositis. Disease in
children (juvenile dermatomyositis) is not associated with malignancy as it
may
be in adults (paraneoplastic dermatomyositis). Overlap syndrome (OS) is mixed
connective tissue disease combining some features of DM, SS and LES.
Scleromyositis is overlap syndrome associated with anti-PM-Sci antibodies.
Patients with PM, DM or OS with "interstitial lung disease" and anti-synthetase
antibodies have an "anti-synthetase syndrome". Various drugs, including
d-penicillamine, NSAIDs, anti-infectious agents, as well as lipid lowering
drugs, the HMG-CoA reductase inhibitors may cause myopathy and skin lesions
(drug induced dermatomyositis). "Dermatomyositis" occurring as adverse
reactions
of drugs are rare, irregular and impossible to predict in individual patients.
They are very interesting in that they may be keys for explaining the pathogenic
mechanisms of the disease.
Publication Types:
Review
Review, Tutorial
PMID: 10599342 [PubMed - indexed for MEDLINE]
254: Adv Exp Med Biol. 1999;455:181-6.
Dermatomyositis. Diagnosis and evaluation of dermatomyositis, polymyositis,
and
inclusion-body myositis.
Krajnc I.
Department Of Internal Medicine, Rheumatology, Teaching Hospital Maribor,
Ljubljanska, Slovenia.
In diseases of an unknown etiology, such as the idiopathic inflammatory
myopathies, we must tackle first of all the question of classification and the
degree of disease activity before we can institute treatment. The majority of
idiopathic inflammatory myopathies are diagnosed clinically and confirmed by
biopsy. The presently applicable methods of diagnosis and evaluation of
idiopathic inflammatory myopathy have certain limitations, and hence it is
necessary to apply new methods of rating the disease activities. Magnetic
resonance imaging (MRI) and 99m-technetium muscle-scanning are the latest
noninvasive methods for evaluation of disease activities with myositis. Future
laboratory methods to determine the numerous myositis-specific autoantibodies
will probably enable identification of subsets of these diseases.
Publication Types:
Review
Review, Tutorial
PMID: 10599341 [PubMed - indexed for MEDLINE]
255: Curr Opin Neurol. 1999 Oct;12(5):527-33.
Inclusion body myositis.
Oldfors A, Lindberg C.
Department of Pathology, Goteborg Neuromuscular Center, Sahlgrenska University
Hospital, Sweden. anders.oldfors@ss.gu.se
Sporadic inclusion body myositis is a severely disabling muscle disease that
mainly affects elderly individuals. The typical distribution of muscle weakness,
poor response to immunosuppressive treatment, pathological accumulation of
various proteins in vacuolated muscle fibres, inflammatory reaction and
mitochondrial changes have all been subjects of recent research that has led
to
better understanding of the pathogenic events that leads to muscle degeneration
and weakness.
Publication Types:
Review
Review, Tutorial
PMID: 10590889 [PubMed - indexed for MEDLINE]
256: Eur Cytokine Netw. 1999 Dec;10(4):471-8.
Cytokines in the muscle tissue of idiopathic inflammatory myopathies:
implications for immunopathogenesis and therapy.
Megens-de Letter MA, Visser LH, van Doorn PA, Savelkoul HF.
Department of Neurology, St. Elisabeth Hospital Tilburg, PO Box 90151, 5000
LC
Tilburg, The Netherlands. megens-deletter@wxs.nl
The inflammatory myopathies (IM), dermatomyositis (DM), polymyositis (PM) and
idiopathic inclusion body myositis (IBM) are acquired immune-mediated
myopathies. About their pathogenesis and etiology no definitive insights are
available yet. Here we present a review of cytokine studies in IM. Combined
with
cellular immunohistochemical findings a model is presented describing a common
mechanism of immune activation in IM. This model is based on a "hit"
triggering
local cytokine production with dominance of pro-inflammatory cytokines, like
IFN-gamma and Th1-mediated activities. The altered Th1-Th2 balance necessitates
detection of the anti-inflammatory arm of immune activation, which includes
Th2-derived IL-4, IL-1, and Th3/Tr1 derived IL-10 and TGF-beta. Redirection
of
the ratio provides targets for novel immunotherapy by direct inhibition of the
IFN-gamma-mediated Th1 response, stimulation of Th3/Tr1, or IL-4-secreting
Th2-cells, negative feedback inhibition with IFN-beta and IFN-gamma and
inactivation of MHC molecules.
Publication Types:
Review
Review, Tutorial
PMID: 10586113 [PubMed - indexed for MEDLINE]
257: Br J Dermatol. 1999 Nov;141(5):926-30.
Comment in:
Br J Dermatol. 2000 Sep;143(3):671.
Dermatomyositis with the features of inclusion body myositis associated with
carcinoma of the bladder.
Talanin NY, Bushore D, Rasberry R, Rudolph T, Tuli M, Friedman-Musicante R.
Division of Dermatology, Department of Medicine, The University of Tennessee,
Memphis, TN 38163, USA.
Inclusion body myositis (IBM) is a unique category of inflammatory myopathy.
It
is characterized histologically by the presence of muscle fibres with rimmed
vacuoles and abnormal intracellular accumulations of proteins. We report here
a
62-year-old patient with bladder carcinoma, where the signs of IBM overlapped
with clinical features of dermatomyositis (DM). A combination of cutaneous
changes typical for DM with histological and other features of IBM is
exceedingly rare, and has not been previously addressed in dermatological
literature. To the best of our knowledge this is also the first description
of
the association of DM/IBM with internal malignancy.
Publication Types:
Case Reports
PMID: 10583182 [PubMed - indexed for MEDLINE]
258: Lancet. 1999 Nov 13;354(9191):1696.
Weak at the knees.
Webster G, Beynon H.
Royal Free Hospital, London, UK.
Publication Types:
Case Reports
PMID: 10568573 [PubMed - indexed for MEDLINE]
259: Neurology. 1999 Nov 10;53(8):1671-6.
Aberrant expression of cyclin-dependent kinase 5 in inclusion body myositis.
Nakano S, Akiguchi I, Nakamura S, Satoi H, Kawashima S, Kimura J.
Department of Neurology, Faculty of Medicine, Kyoto University, Japan.
snakano@isola.kuhp.kyoto-u.ac.jp
OBJECTIVE: To investigate abnormal protein expression in inclusion body myositis
(IBM). BACKGROUND: In IBM, ectopic deposition of beta-amyloid protein as well
as
several other proteins in some muscle fibers occurs. Some, but not all, of these
proteins are also expressed in myofibrillar myopathy (MFM). The authors recently
reported aberrant expressions of several cyclin-dependent kinases (CDKs)-enzymes
regulating the cell replication cycle-in MFM. They therefore tested the notion
that aberrant expression of CDKs also occurs in IBM. Among CDKs, CDK1, CDK2,
and
CDK5 have been demonstrated to phosphorylate tau, which is a component of
inclusions in IBM. CDK5 appears in a stage of myogenesis when CDK1 and CDK2
are
downregulated. METHODS: Cryostat sections of muscle specimens from 10 patients
with sporadic IBM were immunostained for CDK1, CDK2, and CDK5. Fourteen patients
with polymyositis and eight individuals with dermatomyositis served as disease
control subjects. RESULTS: In IBM, numerous CDK5-positive inclusions were
present in vacuolated fibers. CDK5 expression was not observed in any disease
control subject. Regenerating fibers expressed CDK1 and CDK2 in all diseases.
CONCLUSION: The results suggest that cyclin-dependent kinases (CDK)5, but no
other CDKs, is involved in the formation of inclusions in IBM.
PMID: 10563611 [PubMed - indexed for MEDLINE]
260: Curr Opin Rheumatol. 1999 Nov;11(6):456-61.
Treatment of inclusion body myositis.
Cherin P.
Service de Medecine Interne du Pr Herson, Paris, France.
patrick.cherin@psl.ap-hop-paris.fr
Sporadic inclusion body myositis (s-IBM) is considered the most common muscle
disease in patients older than 50 years, with a male predominance. Features
of
s-IBM include insidious onset, slowly and relentlessly progressive muscle
weakness, a characteristic distribution and atrophy of both the proximal and
distal muscle groups, and resistance to immunosuppressive drugs. The most
characteristic pathologic feature is vacuolar degeneration of muscle fibers
accompanied by intrafiber congophilia and clusters ("tangles") of
paired-helical
filaments, containing phosphorylated tau. The response of s-IBM to immunotherapy
remains controversial. Some reports emphasized partial improvement in early
stages of the disease. However, the lack of clear response to corticosteroids
and immunosuppressive therapies, the deterioration of clinical strength despite
suppression of inflammation but increasing number of fibers with vacuoles and
amyloid deposits under therapy, and the accumulation of
"Alzheimer-characteristic" proteins in vacuolated muscle fibers suggest
that
s-IBM may be a degenerative rather than an auto-immune inflammatory myopathy,
and a secondary inflammation response.
Publication Types:
Review
Review, Tutorial
PMID: 10551668 [PubMed - indexed for MEDLINE]
261: Muscle Nerve. 1999 Nov;22(11):1479-97.
Intravenous immunoglobulin in the treatment of autoimmune neuromuscular
diseases: present status and practical therapeutic guidelines.
Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Building 10, Room 4N248, 10 Center Drive
MSC 1382, Bethesda, Maryland 20892-1382, USA. dalakas@helix.nih.gov
This review summarizes the current status of intravenous immunoglobulin (IVIg)
in the treatment of autoimmune neuromuscular disorders and the possible
mechanisms of action of the drug based on work in vivo, in vitro, and in animal
models. Supply of idiotypic antibodies, suppression of antibody production,
or
acceleration of catabolism of immunoglobulin G (IgG) are relevant in explaining
the efficacy of IVIg in myasthenia gravis (MG), Lambert-Eaton myasthenic
syndrome (LEMS), and antibody-mediated neuropathies. Suppression of pathogenic
cytokines has putative relevance in inflammatory myopathies and demyelinating
neuropathies. Inhibition of complement binding and prevention of membranolytic
attack complex (MAC) formation are relevant in dermatomyositis (DM),
Guillain-Barre syndrome (GBS), and MG. Modulation of Fc receptors or T-cell
function is relevant in chronic inflammatory demyelinating polyneuropathy
(CIDP), GBS, and inflammatory myopathies. The clinical efficacy of IVIg, based
on controlled clinical trials conducted in patients with GBS, CIDP, multifocal
motor neuropathy (MMN), DM, MG, LEMS, paraproteinemic IgM anti-myelin-associated
glycoprotein (anti-MAG) demyelinating polyneuropathies, and inclusion body
myositis is summarized and practical issues related to each disorder are
addressed. The present role of IVIg therapy in other disorders based on small
controlled or uncontrolled trials is also summarized. Finally, safety issues,
risk factors, adverse reactions, spurious results or serological tests, and
practical guidelines associated with the administration of IVIg in the treatment
of neuromuscular disorders are presented. Copyright 1999 John Wiley & Sons,
Inc.
Publication Types:
Review
Review, Tutorial
PMID: 10514226 [PubMed - indexed for MEDLINE]
262: Dysphagia. 1999 Summer;14(3):187.
Dysphagia in patients with inclusion body myositis.
Buchholz DW, Neumann S.
PMID: 10507903 [PubMed - indexed for MEDLINE]
263: Neurology. 1999 Aug 11;53(3):659.
Comment on:
Neurology. 1998 Aug;51(2):598-600.
Inclusion body myositis in twins.
Naumann M, Toyka KV.
Publication Types:
Comment
Letter
PMID: 10449152 [PubMed - indexed for MEDLINE]
264: J Neurol Sci. 1999 Jun;165 Suppl 1:S14-20.
Problems and pitfalls in the diagnosis of ALS.
Ludolph AC, Knirsch U.
Department of Neurology, University of Ulm, Germany.
albert.ludolph@medizin.uni-ulm.de
Although misdiagnosis of amyotrophic lateral sclerosis (ALS) is rare, it may
be
more difficult to make a diagnosis in some groups of patients than in others.
If
a patient presents in the later stages of the disease, only a small number of
alternative diagnoses need to be considered. These include spinal muscular
atrophies of adult onset, inclusion body myositis and motor neuropathies with
conduction block. The latter group in particular may present a serious
diagnostic problem, as several groups have recently reported patients suffering
from lower motor neuron syndrome without detectable conduction block, who
responded unexpectedly to treatment with immunoglobulins. As recent laboratory
results suggest that a lengthy pre-clinical period may precede clinical ALS,
there is increased pressure for clinicians to make an early diagnosis so that
the maximum effect can be achieved from neuroprotective drugs. Thus, diseases
such as distal motor amyotrophies, pressure palsies of motor branches of hand
nerves, and cervical myelopathies, which can be differentiated mainly by their
time-course, may be relevant in the differential diagnosis of ALS in some
patients. During recent years, a few patients have been seen in our clinic who
presented with pure motor deficits but later developed a more complex pattern
of
vulnerability suggestive of multisystem degeneration. The existence of patients
with a disease that borders the spectrum of motor neuron diseases cannot be
disputed. These patients include those carrying the Huntington mutation and
those suffering from Guam and New Guinea disease ('ALS/PD'). From our
experience, however, these 'difficult' diagnoses represent less than 10% of
the
patients seen in our clinic.
Publication Types:
Case Reports
PMID: 10448976 [PubMed - indexed for MEDLINE]
265: Am J Pathol. 1999 Aug;155(2):453-60.
Expression of the costimulatory molecule BB-1, the ligands CTLA-4 and CD28,
and
their mRNA in inflammatory myopathies.
Murata K, Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Bethesda, Maryland, USA.
To examine if the muscle fibers in patients with inflammatory myopathies have
the potential to behave as antigen presenting cells (APCs), we investigated
the
expression of costimulatory molecules BB-1, B7-1 (CD80), and B7-2 (CD86), and
their counterreceptors, CD28 or CTLA-4 (CD152), in the muscle biopsies of
patients with polymyositis (PM), PM associated with human immunodeficiency virus
infection (HIV-PM), sporadic inclusion body myositis (s-IBM), dermatomyositis
(DM), and normal or disease controls. The expression of the B7 family of
molecules on the muscle fibers was limited to BB-1. In PM, HIV-PM, and s-IBM,
but not the disease controls, the nonnecrotic, MHC-class I-expressing muscle
fibers, invaded or not by CD8+ T cells, had prominent membrane expression of
BB-1. Several of the BB-1-positive fibers bound strongly in a cell-to-cell
contact with their CD28 or CTLA-4 ligands on the autoinvasive CD8+ T cells,
as
confirmed by confocal microscopy. By reverse transcription-polymerase chain
reaction, the expression of CD28 and CTLA-4 was up-regulated in PM, HIV-PM,
and
s-IBM, but not the controls. Because the BB-1-positive fibers expressed
MHC-class I antigen and bound to up-regulated counterreceptors CD28 and CTLA-4
on the autoinvasive CD8+ T cells only in PM, HIV-PM, and s-IBM, the BB-1
molecule in these diseases should have a functional role in antigen presentation
and T cell differentiation. These findings complement recent studies and suggest
that in PM, HIV-PM, and s-IBM the muscle fibers are not only targets of CD8+
cytotoxic T cells but may also behave as "professional" APC.
PMID: 10433938 [PubMed - indexed for MEDLINE]
266: Neuromuscul Disord. 1999 Jun;9(4):239-46.
Immunolocalization of tumor necrosis factor-alpha and its receptors in
inflammatory myopathies.
De Bleecker JL, Meire VI, Declercq W, Van Aken EH.
Neurology Department, University Hospital, Gent, Belgium.
jan.debleecker@rug.ac.be
Adhesion molecule upregulation occurs in inflammatory myopathies, and is one
of
the myriad functions of tumor necrosis factor-alpha (TNF-alpha). TNF-alpha acts
via two different receptors of 55 (TNF-R55) and 75 kD (TNF-R75). We
immunolocalized TNF-alpha and its receptors in polymyositis, inclusion body
myositis and dermatomyositis. In each myopathy, TNF-alpha was detected in
macrophages, in myonuclei in regenerating muscle fibers, and freely dispersed
in
endomysial or perimysial connective tissue. Many endothelial cells in
dermatomyositis expressed TNF-alpha. TNF-R55 was strongly expressed on myonuclei
of regenerating muscle fibers. TNF-R75 was increased on endothelial cells in
the
midst of inflammatory infiltrates in each myopathy, and on perifascicular and
perimysial endothelia, remote from inflammatory foci in dermatomyositis.
Possible TNF-alpha-mediated effects include: increased transendothelial cell
trafficking, activation of T/B cells and macrophages, induction of MHC-I gene
products, and focal muscle fiber atrophy. In dermatomyositis, the upregulated
TNF-R75, via its consensus elements for transcription factors, may be involved
in endothelial cell degeneration. Strong TNF-R55 expression on regenerating
myonuclei is consistent with a role of TNF-alpha and TNF-R55 in muscle
regeneration.
PMID: 10399751 [PubMed - indexed for MEDLINE]
267: J Neurol Sci. 1999 Mar 15;164(1):76-81.
Bcl-2 and Bax protein expression in human myopathies.
Olive M, Ferrer I.
Servicio de Neurologia, Hospital Principes de Espana, Barcelona, Spain.
Expression of the apoptosis-related proteins Bcl-2 and Bax was analysed by
means
of immunohistochemistry in muscle biopsies from 13 patients suffering from
different muscular diseases (inclusion body myositis n=4, polymyositis n=3,
Becker muscular dystrophy n=4, necrotizing myopathy n=2, and controls n=4),
in
an attempt to learn about the role of these proteins in human muscle diseases
associated with muscle fiber necrosis and regeneration. Increased Bcl-2 and
Bax
immunoreactivity was observed as fine granular precipitates in the cytoplasm
or
as subsarcolemmal aggregates in pathological cases. Increased Bcl-2 and Bax
immunoreactivity was detected in some necrotic fibers, regenerating fibers,
ring
fibers and some apparently normal muscle fibers. In addition, increased Bcl-2
and Bax immunoreactivity was observed in the periphery of rimmed vacuoles and
in
muscle fibers with abnormal mitochondria in patients suffering from inclusion
body myositis. Double-labelling immunohistochemistry disclosed co-localization
of both proteins in about 50% of Bcl-2-immunoreactive fibers. Finally,
double-labelling immunohistochemistry using N-CAM antibodies revealed that some
Bax-positive fibers were regenerating fibers. Since increased Bax
immunoreactivity was not restricted to necrotic muscle fibers, the present
results suggest that over-expression of this protein in human myopathies is
probably independent of the process of cell death.
PMID: 10385052 [PubMed - indexed for MEDLINE]
268: Immunogenetics. 1999 Jun;49(6):508-16.
Mapping of a candidate region for susceptibility to inclusion body myositis
in
the human major histocompatibility complex.
Kok CC, Croager EJ, Witt CS, Kiers L, Mastaglia FL, Abraham LJ, Garlepp MJ.
Australian Neuromuscular Research Institute, Queen Elizabeth II Medical Centre,
Nedlands, Western Australia.
Inclusion body myositis (IBM) is a form of idiopathic inflammatory myopathy
of
unknown aetiology. A strong association with HLA class II (HLA-DR3) suggested
a
role for genes in the human major histocompatibility complex (MHC) in the
predisposition to this disease. In this study, we have taken advantage of the
ancestral haplotype (AH) concept and historical recombinations to map for a
possible susceptibility gene(s) in the MHC. We performed detailed typing of
three MHC-related HSP70 genes and defined allelic combinations in the context
of
MHC AH. We also modified existing methods to give a simple and accurate method
for typing two TNF microsatellites. Using the HSP70 and TNF markers and HLA-DR,
-B, and C4 typing of our patients with IBM, we defined a potential site for
the
MHC-associated susceptibility gene(s) in the region between HLA-DR and C4.
PMID: 10380695 [PubMed - indexed for MEDLINE]
269: Acta Neuropathol (Berl). 1999 Jun;97(6):642-8.
Local expression of monocyte chemoattractant protein-1 (MCP-1) in idiopathic
inflammatory myopathies.
Liprandi A, Bartoli C, Figarella-Branger D, Pellissier JF, Lepidi H.
Laboratoire de Biopathologie Nerveuse et Musculaire, Faculte de Medecine, JE
2053, IBDM Marseille, France.
The idiopathic inflammatory myopathies (IIM), including dermatomyositis (DM),
polymyositis (PM), and inclusion body myositis (IBM), are a group of autoimmune
diseases characterized by the recruitment of lymphocytes and monocytes to the
site of affection. The mechanism for recruitment of these cells likely involves
chemokines. The monocyte chemoattractant protein-1 (MCP-1), a chemoattractant
to
T lymphocytes and monocytes, may play an important role in the pathogenesis
of
IIM. Frozen muscular tissues were obtained from eight cases of DM, five PM,
and
four IBM. We investigated the MCP-1 expression by the reverse transcription-PCR
technique, immunohistochemistry and in situ hybridization. MCP-1 mRNA was
markedly expressed in all the IIM cases. Greater amounts of MCP-1 mRNA were
observed in DM, and in situ hybridization showed MCP-1 mRNA accumulation in
perivascular mononuclear cells. Immunohistochemistry showed MCP-1 expression
in
vessels (endothelial cells and walls of veins and arteries) in all IIM cases.
Very few mononuclear cells in DM perivascular infiltrates expressed MCP-1,
whereas in PM and IBM, it was strongly expressed by mononuclear cells partially
invading non-necrotic muscle fibers. These findings suggest that MCP-1 can
contribute to the inflammatory response by attracting monocytes and T
lymphocytes to sites of cell-mediated immune injury. The morphological
characteristics and distribution of positive cells indicate that macrophages,
lymphocytes, and endothelial cells previously reported to produce MCP-1,
contribute to its production in IIM lesions.
PMID: 10378384 [PubMed - indexed for MEDLINE]
270: Can J Neurol Sci. 1999 May;26(2):139-52.
IGIV in neurology--evidence and recommendations.
Bril V, Allenby K, Midroni G, O'Connor PW, Vajsar J.
Division of Neurology, Toronto Hospital, Ontario, Canada.
OBJECTIVE: To summarize the evidence for neurologic uses of immunoglobulin,
intravenous (IGIV) in light of present-day clinical usage. This summary guided
the development of practice recommendations for the effective and efficient
use
of IGIV in Neurology. METHODS: MEDLINE was searched to identify pertinent
English-language review articles and original reports (n = 231) on the use of
IGIV in neurology (excluding editorials, letters, and comments) published before
March 1998. Evidence on alternative therapies was only included as compared
to
IGIV. The relevant original reports and review articles and older classic
studies (n = 92) were synthesized into an information foundation. Extracted
data
included laboratory and clinical findings, objective measures, and clinical
impressions. Clinical recommendations were based on evidence quality, graded
by
study design, clinical experiences of IGIV in Neurology Advisory Board members,
and the conditions of IGIV use in therapy. RESULTS AND CONCLUSIONS: In
neurology, many disorders are poorly understood, and the mechanisms behind
beneficial regimens even less so. As a result, it is fairly common for
best-practice decisions to rest on weaker evidence. The usefulness of IGIV in
neurology can be described by a "combined score" based on evidence
quality and
strength of impact. Combined scores ranged from A+ (strongly recommended) to
C
(recommended as a last resort). The following clinical recommendations are made:
IGIV is: strongly recommended for the treatment of Guillain-Barre syndrome (A+);
favorably recommended for the treatment of chronic inflammatory demyelinating
polyradiculoneuropathy, dermatomyositis, and multifocal motor neuropathy (A);
recommended as a second resort for the treatment of multiple sclerosis and
myasthenia gravis (B); and recommended as a last resort for the treatment of
polymyositis, inclusion-body myositis, intractable epilepsies, and stiff-man
syndrome (C).
Publication Types:
Review
PMID: 10352875 [PubMed - indexed for MEDLINE]
271: Clin Exp Rheumatol. 1999 Mar-Apr;17(2):235-9.
Inclusion body myositis long after dermatomyositis: a report of two cases.
McCoy AL, Bubb MR, Plotz PH, Davis JC.
Arthritis and Rheumatism Branch, National Institute of Arthritis and
Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda,
Maryland, USA.
Dermatomyositis, polymyositis, and inclusion body myositis are rare illnesses
which appear to be distinct in clinical and pathologic features, pathogenesis,
natural history, and response to therapy. We report two patients who first
developed dermatomyositis, and then, after a disease-free interval of many
years, developed inclusion body myositis. This may have useful therapeutic
implications for patients with dermatomyositis whose illness bocomes refractory
to treatment.
Publication Types:
Case Reports
PMID: 10342053 [PubMed - indexed for MEDLINE]
272: Acta Neuropathol (Berl). 1999 May;97(5):509-14.
Familial inclusion body myopathy with desmin storage.
Fidzianska A, Drac H, Kaminska AM.
Department of Neurology, Warsaw Medical Academy, Poland.
We report two adult familial cases of inclusion body myopathy (IBM) with desmin
storage in skeletal muscle. Clinically, both patients presented late-onset,
progressive, symmetrical, both proximal and distal muscle weakness. Muscle
biopsy findings were identical in both cases and consisted of marked variability
in fiber size, increased number of central nuclei and vacuolation involving
10%
of fibers. Single or multiple vacuoles were located subsarcolemmally or in the
center, and were rimmed by basophilic material. At the ultrastructural level,
tubulofilamentous nuclear and cytoplasmic inclusions of 16-21 nm in diameter
were frequently observed. In addition, large subsarcolemmal and central deposits
composed of electron-dense granular material were present in many fibers.
Immunocytochemistry revealed staining for desmin, vimentin and ubiquitin within
both inclusions and vacuolated fibers. Possible structural and functional
associations between these two types of muscle changes remain unclear. They
may
either represent two coexistent disease processes or merely reflect an abnormal
form of muscle fiber degradation, with unidentifiable specificity.
Publication Types:
Case Reports
PMID: 10334489 [PubMed - indexed for MEDLINE]
273: Muscle Nerve. 1999 Apr;22(4):480-7.
Quantitative electrophysiologic studies in sporadic inclusion body myositis.
Barkhaus PE, Periquet MI, Nandedkar SD.
Department of Neurology, Medical College of Wisconsin, Milwaukee, USA.
Sporadic inclusion body myositis (S-IBM) is a progressive, acquired disease
of
unknown etiology. Prior studies have suggested neurogenic involvement based
on
electrophysiologic data, although the biopsy is compatible with a myopathic
process. Quantitative electrophysiologic studies were performed in the biceps
brachii of 17 subjects with biopsy-proven S-IBM. Quantitative motor unit action
potential (MUAP) analysis was compatible with myopathy in 16 subjects, with
the
remaining subject being within normal limits. Quantitative interference pattern
was myopathic in all 13 subjects studied. Macro-EMG MUAP amplitude was reduced
in 3 of 17 studies; the remainder were within normal range, and none was
increased as would be expected in neurogenic disease. Fiber density was normal
to borderline increased in all subjects. Possible reasons for encountering
neurogenic-appearing MUAPs may include choice of muscle studies, because some
patients have co-existing polyneuropathy and large-amplitude MUAPs from
hypertrophied muscle fibers. The data from this study indicate that S-IBM is
a
myopathic process.
Publication Types:
Clinical Trial
PMID: 10204783 [PubMed - indexed for MEDLINE]
274: Acta Neuropathol (Berl). 1999 Mar;97(3):267-74.
Study of some components of the cytoskeleton in muscular disorders with
nonspecific cytoplasmic bodies.
Caron A, Gohel C, Mollaret K, Morello R, Chapon F.
Laboratory of Neuropathology, CHU Cote de Nacre, Caen, France.
To gain a better understanding of the mechanisms involved in the formation
of
cytoplasmic bodies (CBs), the immunohistochemical and biochemical features of
muscle samples with nonspecific CBs were compared to those previously described
by our group in cytoplasmic body myopathy (CBM), a congenital disease in which
specific CBs are found. Accordingly, we studied nonspecific CBs found in the
muscle biopsies of 15 patients with the following diseases: peripheral
neuropathy (n = 5), polymyositis (n = 3), myotonic dystrophy (n = 2),
sarcoidosis (n = 1), inclusion body myositis (n = 1), hereditary inclusion body
myopathy (n = 1), hypothyroidism (n = 1), and muscle atrophy in a patient with
multiple brain infarctions (n = 1). Nonspecific inclusions were stained at their
periphery by anti-desmin but not by anti-dystrophin antibodies, except in the
case of hypothyroidism in which immunostaining was observed with both
antibodies. Biochemical studies showed normal amounts of desmin and
phosphorylation pattern (the latter data are available for only four patients)
as compared to control specimens. Our results differ from those previously
reported in CBM, in which CBs were stained by both antidesmin and
anti-dystrophin antibodies and in which a hyperphosphorylation of desmin was
found. Hypothyroidism is, thus, the only disease in which nonspecific CBs show
the same immunostaining pattern as specific CBs from CBM patients. These
findings indicate that CBs may result from different mechanisms, and that one
of
these mechanisms may be shared by CBM and hypothyroidism.
PMID: 10090674 [PubMed - indexed for MEDLINE]
275: Neurology. 1999 Feb;52(3):669-70.
Minimal expansion of the GCG repeat in the PABP2 gene does not predispose to
sporadic inclusion body myositis.
Mezei MM, Mankodi A, Brais B, Marineau C, Thornton CA, Rouleau GA, Karpati G.
Montreal Neurological Institute and Hospital, McGill University, Quebec, Canada.
PMID: 10025815 [PubMed - indexed for MEDLINE]
276: Lancet. 1999 Feb 6;353(9151):465-6.
Methionine homozygosity at prion gene codon 129 may predispose to sporadic
inclusion-body myositis.
Lampe J, Kitzler H, Walter MC, Lochmuller H, Reichmann H.
Publication Types:
Letter
PMID: 9989722 [PubMed - indexed for MEDLINE]
277: Genomics. 1999 Jan 1;55(1):43-8.
Fine-structure mapping of the hereditary inclusion body myopathy locus.
Eisenberg I, Thiel C, Levi T, Tiram E, Argov Z, Sadeh M, Jackson CL, Thierfelder
L, Mitrani-Rosenbaum S.
Unit for Development of Molecular Biology and Genetic Engineering, The Hebrew
University-Hadassah Medical School, Jerusalem, 91240, Israel.
The gene responsible for a recessive form of hereditary inclusion body myopathy
(HIBM) has previously been mapped to a 10-cM interval on chromosome 9p1-q1.
We
report the results of further mapping studies using two-point linkage analyses
and linkage disequilibrium analyses with 20 HIBM families. We demonstrate that
the HIBM gene (HGMW-approved symbol IBM2) lies between loci D9S1791 and D9S50,
which are about 1 Mb apart. Genetic analyses in 56 affected individuals of
Persian, Afghani, and Iraqi Jewish descent demonstrated a common haplotype at
these loci, indicating that a founding mutation accounts for disease in these
related ethnic groups. beta-Tropomyosin, an abundant skeletal muscle protein
that maps within 1 cM of D9S1791, was excluded as the disease gene because an
intragenic polymorphism did not exhibit linkage disequilibrium in HIBM probands.
We conclude that the disease gene resides in a 1-Mb interval on chromosome 9
and
speculate that a novel muscle protein encoded there is mutated in HIBM.
Copyright 1999 Academic Press.
PMID: 9888997 [PubMed - indexed for MEDLINE]
278: Adv Anat Pathol. 1998 May;5(3):164-9.
Inclusion body myositis--a review.
Vogel H.
Department of Pathology, Baylor College of Medicine, Houston, Texas, USA.
Inclusion body myositis (IBM), a sporadic inflammatory myopathy, is the most
frequently occurring progressive myopathy in adults older than 55 years. It
more
commonly affects men and usually is clinically and pathologically
distinguishable from dermatomyositis or polymyositis. Muscle biopsy specimens
will display inflammation in virtually all cases of sporadic IBM, along with
rimmed vacuoles accompanied by the accumulation of beta-amyloid and other
substances similar to those found in the degenerating neurons of Alzheimer's
disease. The similarities between IBM and other inflammatory myopathies may
contribute to its low level of diagnosis by pathologists. The proper recognition
of IBM is important because, unlike other inflammatory myopathies, IBM is
unresponsive to anti-inflammatory drugs.
Publication Types:
Review
Review, Tutorial
PMID: 9868522 [PubMed - indexed for MEDLINE]
279: Arch Neurol. 1998 Dec;55(12):1509-12.
Molecular immunology and genetics of inflammatory muscle diseases.
Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Bethesda, MD 20892-1382, USA.
Polymyositis, dermatomyositis, and inclusion body myositis, although
immunopathologically distinct, share 3 dominant histological features:
inflammation, fibrosis, and loss of muscle fibers. Progress in molecular
immunology and immunogenetics has enhanced our understanding of these cellular
processes. Based on the T-cell receptor gene rearrangement, the autoinvasive
CD8+ T cells in polymyositis and inclusion body myositis, but not
dermatomyositis, are specifically selected and clonally expanded in situ by
heretofore unknown muscle-specific autoantigens. The messenger RNA of cytokines
is variably expressed, except for a persistent up-regulation of interleukin
1beta in inclusion body myositis and transforming growth factor beta in
dermatomyositis. In inclusion body myositis, the interleukin 1, secreted by
the
chronically activated endomysial inflammatory cells, may participate in the
formation of amyloid because it up-regulates beta-amyloid precursor protein
(beta-APP) gene expression and beta-APP promoter and colocalizes with beta-APP
within the vacuolated muscle fibers. In dermatomyositis, transforming growth
factor beta is overexpressed in the perimysial connective tissue but is
down-regulated after successful immunotherapy and reduction of inflammation
and
fibrosis. The degenerating muscle fibers express several antiapoptotic
molecules, such as Bcl-2, and resist apoptosis-mediated cell death. In myositis,
several of the identified molecules and adhesion receptors play a role in the
process of inflammation, fibrosis, and muscle fiber loss, and could be targets
for the design of semispecific therapeutic interventions.
Publication Types:
Review
Review, Tutorial
PMID: 9865793 [PubMed - indexed for MEDLINE]
280: Neurology. 1998 Dec;51(6):1742-5.
Inclusion body myositis: abnormal protein accumulation does not trigger
apoptosis.
Hutchinson DO.
Department of Neurology, Auckland Hospital, New Zealand.
To examine whether apoptosis may contribute to muscle fiber loss in inclusion
body myositis, we used the terminal deoxynucleotidyl transferase-mediated X-dUTP
nick-end labeling (TUNEL) assay to compare the occurrence of DNA fragmentation
in muscle samples from patients with inclusion body myositis and polymyositis.
TUNEL-positive nuclei in nonnecrotic muscle fibers were rare even in the
vicinity of amyloid-like material; significantly more frequent in polymyositis
than inclusion body myositis; and several times less frequent than necrotic
muscle fibers or mononuclear cell myocytotoxicity in both patient groups.
Apoptosis is unlikely to play a significant role in the pathogenesis of
inclusion body myositis.
PMID: 9855538 [PubMed - indexed for MEDLINE]
281: Scand J Rheumatol. 1998;27(6):389-405.
Sporadic inclusion-body myositis and its similarities to Alzheimer disease
brain. Recent approaches to diagnosis and pathogenesis, and relation to aging.
Askanas V, Engel WK.
Sporadic inclusion-body myositis (s-IBM) is the most common, debilitating and
progressive muscle disease beginning at the age 50 or later. The most
characteristic pathologic feature is vacuolar degeneration of muscle fibers
accompanied by intrafiber congophilia and clusters ("tangles") of
paired-helical
filaments, containing phosphorylated tau. An unusual feature of sporadic
inclusion-body myositis is accumulation within its abnormal muscle fibers of
several proteins that are characteristic of Alzheimer disease brain, including
epitopes of beta-amyloid precursor protein (betaAPP), phosphorylated tau,
alpha-1-antichymotrypsin, apolipoprotein E, and presenilin-1. Indicators of
oxidative stress are also present within abnormal s-IBM muscle fibers. In this
review, we describe new advances seeking the pathogenic mechanism of sporadic
inclusion-body myositis. We hypothesize on the possible pathogenic role of
abnormally accumulated proteins, and we propose that important contributory
factors leading to inclusion-body myositis are the milieu of muscle-fiber aging
and oxidative stress. In addition, we present evidence that overexpression of
adenovirus-transferred betaAPP gene in cultured human muscle fibers induces
aspects of the inclusion-body myositis phenotype, and suggest that
betaAPP-overexpression is an early event in the pathogenic cascade causing
inclusion-body myositis.
Publication Types:
Editorial
Review
PMID: 9855208 [PubMed - indexed for MEDLINE]
282: Neurology. 1998 Dec;51(6 Suppl 5):S37-45.
Controlled studies with high-dose intravenous immunoglobulin in the treatment
of
dermatomyositis, inclusion body myositis, and polymyositis.
Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health Bethesda, MD 20892-1382, USA.
There are three major subsets of the inflammatory myopathies: polymyositis
(PM),
dermatomyositis (DM), and inclusion-body myositis (IBM). High-dose intravenous
immunoglobulin (IVIg) has been tried in controlled clinical trials in patients
with DM and IBM but not with PM. In patients with DM that is resistant or
partially responsive to conventional therapies, IVIg was very effective. The
treated patients experienced dramatic improvement not only in muscle strength
but also of their skin rash. Repeated muscle biopsies with quantitative
histologic studies showed the IVIg-treated patients had a statistically
significant improvement of the muscle cytoarchitecture, with resolution of the
aberrant immunopathologic parameters. In two controlled clinical trials
conducted in IBM patients, IVIg showed marginal improvements in muscle strength
which were nonsignificant. However, a few IBM patients had a definite clinical
improvement with increased activities of daily living, but when analyzed within
the entire IVIg-treated group, their total gains in muscle strength did not
reach statistical significance compared to the placebo-treated group. Of
interest is that certain muscle groups in the IVIg-treated patients, such as
the
muscles of swallowing, showed significant improvement compared to those of the
placebo-treated patients, implying mild regional effects. In PM, uncontrolled
trials have shown improvements in muscle strength, but the controlled clinical
trial is still ongoing.
Publication Types:
Clinical Trial
Controlled Clinical Trial
Review
Review, Tutorial
PMID: 9851729 [PubMed - indexed for MEDLINE]
283: J Neurol Sci. 1998 Oct;160 Suppl 1:S6-24.
Diagnosis of amyotrophic lateral sclerosis.
Rowland LP.
Eleanor and Lou Gehrig MDA/ALS Center, Neurological Institute,
Columbia-Presbyterian Medical Center, New York, NY 10032, USA. lprl@columbia.edu
This review of the differential diagnosis of amyotrophic lateral sclerosis
focuses on two themes. The first is practical, how to establish the diagnosis
based primarily on clinical findings buttressed by electrodiagnosis. The main
considerations are multifocal motor neuropathy and cervical spondylotic
myelopathy. The second theme is the relationship of motor neuron disease to
other conditions, including benign fasciculation (Denny-Brown, Foley syndrome),
paraneoplastic syndromes, lymphoproliferative disease, radiation damage,
monomelic amyotrophy (Hirayama syndrome), as well as an association with
parkinsonism, dementia and multisystem disorders of the central nervous system.
Publication Types:
Review
PMID: 9851643 [PubMed - indexed for MEDLINE]
284: Curr Opin Neurol. 1998 Oct;11(5):453-9.
Hereditary inclusion body myopathies.
Tome FM, Fardeau M.
INSERM Unit. 153, Hopital de la Salpetriere, Paris, France.
Hereditary inclusion body myopathies comprise autosomal recessive and autosomal
dominant muscle disorders that have a variable clinical phenotype but share
similar morphological features. These include rimmed vacuoles within muscle
fibres and collections of intrasarcoplasmic and intranuclear tubulofilamentous
inclusions, 16-18 nm in external diameter. The resemblances and the differences
between the sporadic and the hereditary inclusion body myopathies are discussed.
Recent advances in the identification of various proteins involved in these
diseases are mentioned because they have provided better insight into their
underlying pathophysiological mechanisms. Linkage studies have allowed the
localization of the genetic defect of some hereditary inclusion body myopathies
and related disorders, contributing to their individualization.
Publication Types:
Review
Review, Tutorial
PMID: 9847994 [PubMed - indexed for MEDLINE]
285: J Neuroimmunol. 1998 Nov 2;91(1-2):129-34.
T cell receptor beta-chain repertoire in inclusion body myositis.
Fyhr IM, Moslemi AR, Lindberg C, Oldfors A.
Department of Pathology, Gothenburg University, Sweden.
Inclusion body myositis (IBM) is the most common muscle disease affecting
individuals over 50 years of age. The inflammatory reaction is characterized
by
cell infiltrates predominated by CD8+ cytotoxic T cells. To analyze clonality
of
muscle infiltrating lymphocytes, we studied the complementarity determining
region 3 (CDR3) length distribution of the T cell receptor (TCR). Muscle
infiltrating lymphocytes were studied in three IBM patients and compared with
peripheral blood lymphocytes (PBL) in two of these patients. The study was
performed by reverse transcription polymerase chain reaction (RT-PCR) of RNA
extracted from muscle tissue and PBL followed by analysis of fragment length
distribution of the CDR3 region in each of 24 different Vbeta families. There
was a restricted usage of TCR Vbeta gene families in muscle infiltrating T cells
in all three patients. Some of the TCR Vbeta gene families showed oligoclonal
expansions but polyclonal patterns were dominating. The CDR3 distribution of
most Vbeta families differed between muscle infiltrating lymphocytes and PBL
indicating that T cells have expanded locally or selectively accumulated in
muscle.
PMID: 9846829 [PubMed - indexed for MEDLINE]
286: Am J Pathol. 1998 Dec;153(6):1687-93.
Comment in:
Am J Pathol. 1998 Dec;153(6):1673-7.
Amyloid-beta deposition in skeletal muscle of transgenic mice: possible model
of
inclusion body myopathy.
Fukuchi K, Pham D, Hart M, Li L, Lindsey JR.
Department of Comparative Medicine, Schools of Medicine and Dentistry,
University of Alabama at Birmingham, 35294-0019, USA. cmed037@uabdpo.dpo.uab.edu
Inclusion body myopathy is a progressive muscle disorder characterized by
nuclear and cytoplasmic inclusions and vacuolation of muscle fibers. Affected
muscle fibers contain deposits of congophilic amyloid, amyloid-beta
immunoreactive filaments, and paired helical filaments, all of which are
pathological hallmarks of Alzheimer's disease in brain. Accumulations of
amyloid-beta and its precursor are thought to play important roles in the
pathogenesis of both inclusion body myopathy and Alzheimer's disease.
Overexpression of mutant forms of beta protein precursor in transgenic mice
by
neuron-specific promoters has been reported to cause amyloid deposits in the
brain. Here we report that overexpression in transgenic mice of the signal plus
99-amino acid carboxyl-terminal sequences of beta protein precursor, under the
control of a cytomegalovirus enhancer/beta-actin promoter, resulted in
vacuolation and increasing accumulation of the 4-kd amyloid-beta and the
carboxyl-terminus in skeletal muscle fibers during aging. These deposits in
transgenic muscle only rarely showed Congo red birefringence. Thus,
overexpression of part of beta protein precursor in transgenic mice led to
development of some of the characteristic features of inclusion body myopathy.
These mice may be a useful model of inclusion body myopathy, which shares a
number of pathological markers with Alzheimer's disease.
PMID: 9846958 [PubMed - indexed for MEDLINE]
287: Am J Pathol. 1998 Dec;153(6):1679-86.
Comment in:
Am J Pathol. 1998 Dec;153(6):1673-7.
Transgenic mice over-expressing the C-99 fragment of betaPP with an
alpha-secretase site mutation develop a myopathy similar to human inclusion
body
myositis.
Jin LW, Hearn MG, Ogburn CE, Dang N, Nochlin D, Ladiges WC, Martin GM.
Department of Pathology, University of Washington, Seattle 98195-6480, USA.
lwjin@u.washington.edu
Inclusion body myositis (IBM) is the most common muscle disease in the elderly.
Amyloid-beta protein (A beta) has been shown to accumulate abnormally in the
vacuolated fibers and to localize to amyloid-like fibrils in muscles from IBM
patients. We studied the skeletal muscles from a line of transgenic mice
over-expressing the carboxyl-terminal 99 amino acids (C99) of the beta-amyloid
precursor protein (betaPP) with a substitution of lysine-612 to valine (K612V),
intended to abolish alpha-secretase recognition and to preserve the A beta
domain of C99. The majority (87%) of the 24-month-old transgenic mice showed
myopathic changes, and approximately one-third of them had degenerating fibers
with sarcoplasmic vacuoles and thioflavin-S-positive deposits.
Ultrastructurally, the inclusions were aggregates of short thin amyloid-like
fibrils, 6 to 8 nm in diameter. These features are similar to those of human
IBM. Immunocytochemistry using an antibody against A beta showed membranous
staining in most muscle fibers of transgenic mice, as well as granular or
vacuolar cytoplasmic staining in the atrophic fibers. Western blots showed a
high level of accumulation of carboxyl-terminal fragments of betaPP in the
muscles of the transgenic mice with the most severe IBM-like lesions. The
expression of IBM-like lesions was age dependent. These transgenic mice provide
a model for the study of IBM and for the peripheral expression of a key element
in the pathogenesis of Alzheimer disease.
PMID: 9846957 [PubMed - indexed for MEDLINE]
288: Am J Pathol. 1998 Dec;153(6):1673-7.
Comment on:
Am J Pathol. 1998 Dec;153(6):1679-86.
Am J Pathol. 1998 Dec;153(6):1687-93.
Does overexpression of betaAPP in aging muscle have a pathogenic role and a
relevance to Alzheimer's disease? Clues from inclusion body myositis, cultured
human muscle, and transgenic mice.
Askanas V, Engel WK.
Neuromuscular Center, Department of Neurology, University of Southern California
School of Medicine, Good Samaritan Hospital, Los Angeles 90017-1912, USA.
askanas@hsc.usc.edu
Publication Types:
Comment
PMID: 9846956 [PubMed - indexed for MEDLINE]
289: Muscle Nerve. 1998 Dec;21(12):1724-8.
Inflammatory myopathy with cytochrome oxidase negative muscle fibers:
methotrexate treatment.
Levine TD, Pestronk A.
Department of Neurology, Washington University School of Medicine, St. Louis,
Missouri 63110, USA.
Inflammatory myopathy with cytochrome oxidase negative muscle fibers (IM/COX-)
is characterized by slowly progressive weakness, most prominent in the
quadriceps, muscle fibers with reduced COX staining and mitochondrial DNA
mutations, and a poor response to corticosteroid treatment. We reviewed records
of quantitative measurements of muscle strength in 7 IM/COX- patients to
evaluate the outcomes after treatment with oral, once weekly, methotrexate for
an average of 15 months. We compared the results to 6 patients with IM/COX-
who
received no long-term immunosuppression, and to 4 with inclusion body myositis
(IBM) who received methotrexate during the same period. Methotrexate treatment
of IM/ COX- was followed by improved muscle strength in 5 of 7 patients,
averaging 17+/-5%. In contrast, there was no improvement in the strength of
6
untreated IM/COX- patients (-6+/-4%; P=0.003), or 4 methotrexate-treated IBM
patients (1+/-2%; P=0.03). We conclude that, despite clinical similarities to
inclusion body myositis, which is usually refractory to immunosuppressive
therapy, strength in IM/COX- appears to improve with methotrexate treatment.
Biopsy studies of inflammatory myopathies with evaluation of muscle for
mitochondrial changes and vacuoles can help to direct the choice of appropriate
immunomodulating treatments.
PMID: 9843075 [PubMed - indexed for MEDLINE]
290: J Neurol. 1998 Dec;245(12):816-8.
Inclusion body myositis: immune globulins improve muscle strength, but not
abnormal postures.
Johannes S, Schubert M, Heidenreich F, Walter GF, Dengler R.
Publication Types:
Case Reports
Letter
PMID: 9840358 [PubMed - indexed for MEDLINE]
291: J Immunol. 1998 Dec 1;161(11):5943-51.
Erratum in:
J Immunol 2000 May 15;164(10):5330.
Human muscle cells express a functional costimulatory molecule distinct from
B7.1
(CD80) and B7.2 (CD86) in vitro and in inflammatory lesions.
Behrens L, Kerschensteiner M, Misgeld T, Goebels N, Wekerle H, Hohlfeld R.
Department of Neuroimmunology, Max-Planck Institute of Neurobiology,
Martinsried, Germany.
The B7 family of costimulatory molecules likely includes members distinct from
B7.1 (CD80) and B7.2 (CD86). After stimulation with IFN-gamma or TNF-alpha,
human myoblasts selectively express BB-1, but not B7.1 or B7.2. BB-1 is detected
by anti-BB-1, a mAb cross-reacting with B7.1 (but not B7.2) and an as yet
undefined costimulatory molecule. The absence of B7.1 and B7.2 in BB-1-positive
myoblasts was confirmed by RT-PCR. The molecule detected by anti-BB-1 is
functional, because anti-BB-1 mAb and CTLA4Ig (but not anti-B7.1- or
anti-B7.2-specific mAbs) completely inhibit Ag presentation by cytokine-induced
myoblasts to HLA-DR-matched Ag-specific CD4+ T cell lines. Stimulation of
myoblasts with IL-4 induces B7.1 and B7.2, as well as BB-1, but with different
time kinetics. Stimulation of CD40-positive myoblasts with anti-CD40 mAb
selectively induces BB-1, whereas stimulation with CD40L-transfected mouse L
cells induces BB-1 and B7.1, with different kinetics. To assess whether BB-1
is
expressed in muscle tissue, we investigated 23 muscle biopsy specimens from
patients with polymyositis, dermatomyositis, inclusion body myositis, Duchenne
muscular dystrophy, and nonmyopathic controls by immunohistochemistry and
confocal laser microscopy. We found that, in all inflammatory myopathy cases,
but not in normal muscle, many muscle fibers strongly react with anti-BB-1.
In
contrast, muscle fibers did not react with B7.1- or B7.2-monospecific mAbs in
any of the pathologic specimens or in normal muscle. Our results demonstrate
that human muscle cells can be induced to selectively express BB-1, a functional
costimulatory molecule distinct from B7.1 and B7.2. This molecule may play an
important role in the immunobiology of muscle.
PMID: 9834075 [PubMed - indexed for MEDLINE]
292: Neuroreport. 1998 Oct 5;9(14):3201-5.
Impaired innervation of cultured human muscle overexpressing betaAPP
experimentally and genetically: relevance to inclusion-body myopathies.
McFerrin J, Engel WK, Askanas V.
USC Neuromuscular Center, Department of Neurology, University of Southern
California School of Medicine, Good Samaritan Hospital, Los Angeles 90017-1912,
USA.
To investigate whether abnormally accumulated betaAPP may be responsible for
denervation of muscle fibers that are present in hereditary inclusion-body
myopathy (h-IBM) and sporadic inclusion-body myositis (s-IBM), we cultured five
h-IBM and eight normal muscle biopsies. In eight other experiments, a 3 kb human
751-betaAPP-cDNA was transferred, using adenovirus vector, into cultured normal
myotubes immediately after myoblast fusion. In all experiments, cultured muscle
fibers were co-cultured with fetal rat spinal cord. Controls had no detectable
betaAPP epitopes, whereas betaAPP epitopes were greatly increased in cultured
h-IBM muscle and in cultured normal muscle after betaAPP-gene transfer.
Innervated normal cultured muscle fibers were continuously contracting and fully
cross-striated, and they had acetylcholine receptors (AChRs) and
acetylcholinesterase (AChE) accumulated only at the neuromuscular junctions
(NMJs). By contrast, both groups of betaAPP-overexpressing cultured muscle
fibers were not contracting and not cross-striated; and did not have NJMs
containing AChRs and AChE. Our results suggest that over-expression of betaAPP
in cultured muscle fibers inhibits their innervation, and that the accumulation
of betaAPP in muscle fibers of both h- and s-IBM patients may be responsible
for
their not becoming or remaining properly innervated or reinnervated, i.e. a
'myogenous-dysinnervation' mechanism.
PMID: 9831451 [PubMed - indexed for MEDLINE]
293: Brain. 1998 Nov;121 ( Pt 11):2119-26.
Normal in vivo skeletal muscle oxidative metabolism in sporadic inclusion body
myositis assessed by 31P-magnetic resonance spectroscopy.
Lodi R, Taylor DJ, Tabrizi SJ, Hilton-Jones D, Squier MV, Seller A, Styles
P,
Schapira AH.
MRC Biochemical and Clinical Magnetic Resonance Unit, Oxford Radcliffe Hospital,
UK.
Sporadic inclusion body myositis (s-IBM) is a chronic inflammatory myopathy
of
unknown pathogenesis. The common findings of ragged red fibres, cytochrome c
oxidase-negative fibres and multiple mitochondrial DNA deletions in the muscle
of patients with s-IBM have suggested that a deficit of energy metabolism may
be
of pathogenic relevance. To test this hypothesis we used 31P magnetic resonance
spectroscopy to assess in vivo skeletal muscle mitochondrial function in the
calf muscles of 12 patients with definite s-IBM. Eleven patients showed multiple
mitochondrial DNA deletions in skeletal muscle and 67% showed ragged red fibres
and/or cytochrome c oxidase-negative fibres. T1-weighted MR images showed
increased signal intensity in the calf muscle of all patients except one. The
involvement of calf muscle was confirmed by 31P magnetic resonance spectroscopy
of resting muscle, which disclosed abnormalities in metabolite ratios in all
patients. However, muscle oxidative metabolism assessed during recovery from
exercise was normal in patients with s-IBM, as maximum rates of mitochondrial
ATP production and post-exercise ADP recovery rates were within the normal range
in all cases. We conclude that muscle mitochondrial abnormalities are a
secondary process and unlikely to play a significant role in the pathogenesis
of
s-IBM.
PMID: 9827771 [PubMed - indexed for MEDLINE]
294: Curr Opin Rheumatol. 1998 Nov;10(6):543-7.
Genetics of inclusion body myopathies.
Argov Z, Eisenberg I, Mitrani-Rosenbaum S.
Department of Neurology, Hadassah University Hospital, Jerusalem.
We review the current knowledge about the genetic susceptibility to develop
inflammatory inclusion body myositis, especially in relation to the increased
presence of the HLA DR3 allele in patients with familial and sporadic forms,
indicating an autoimmune predisposition. The main focus of the review is the
clinical and genetic presentations of the various hereditary inclusion body
myopathies. Criteria for diagnosis and classification of these myopathies are
presented. The spectrum of the recessive forms of hereditary inclusion body
myopathies currently linked to chromosome 9p1-q1 is described, with emphasis
on
the up-to-date status of the gene search for these forms.
Publication Types:
Review
Review, Tutorial
PMID: 9812214 [PubMed - indexed for MEDLINE]
295: Curr Opin Rheumatol. 1998 Nov;10(6):530-42.
Sporadic inclusion-body myositis and hereditary inclusion-body myopathies:
current concepts of diagnosis and pathogenesis.
Askanas V, Engel WK.
Department of Neurology, University of Southern California School of Medicine,
Good Samaritan Hospital, Los Angeles 90017-1912, USA.
We discuss the pathologic diagnostic criteria and review the major new advances
related to seeking the pathogenic mechanism of sporadic inclusion-body myositis
(s-IBM) and hereditary inclusion-body myopathy (h-IBM). A classification of
the
various h-IBM syndromes is also presented. The several forms of the h-IBMs have
different genetic transmissions and probably different genetic defects. In
neither s-IBM nor the h-IBMs are the sequential steps of the pathogenic cascade
understood. Because s-IBM and the h-IBMs have a number of characteristic
pathologic features in common, we postulate that their different causes trigger
the same upstream aberration leading to a similar downstream cascade of
pathologic events, which are ultimately responsible for the characteristic
muscle-fiber degeneration. Muscle-biopsy and experimental evidence is given
supporting our hypothesis that overexpression of beta-amyloid precursor protein
within abnormal muscle fibers is an early upstream event causing the pathogenic
cascade. We also present evidence supporting our concept that muscle aging and
oxidative stress are important factors contributing to the s-IBM-specific muscle
fiber destruction. Additionally, the intriguing parallels between the pathologic
phenotype of IBM muscle fibers and Alzheimer's disease brain are summarized.
Publication Types:
Review
PMID: 9812213 [PubMed - indexed for MEDLINE]
296: Curr Opin Rheumatol. 1998 Nov;10(6):521-9.
New developments in the role of cytokines and chemokines in inflammatory
myopathies.
Lundberg IE, Nyberg P.
Rheumatology Unit, Karolinska Hospital, Stockholm, Sweden.
Cytokines and chemokines are important molecules in the inflammatory response
and in immune regulation. Investigations of the production of these molecules
in
the target organ of inflammation is of particular interest to obtain increased
knowledge of the pathogenesis of chronic inflammatory disorders. By
investigations of muscle tissue from patients with polymyositis, inclusion-body
myositis (IBM), and dermatomyositis a predominance of the cytokines
interleukin-1 alpha and -1 beta and transforming growth factor beta was
observed. Among the chemokines investigated, macrophage inflammatory protein
1
alpha was the most commonly found molecule. A similar pattern of cytokines and
chemokines was present in polymyositis, IBM, and dermatomyositis. This was also
true for the pronounced interleukin-1 alpha expression in the endothelial cells
of capillaries and venules. The results of these studies suggest a major role
of
the proinflammatory cytokines interleukin-1 alpha and -1 beta and the importance
of the endothelial cells in the pathogenesis not only in dermatomyositis, as
previously suggested, but also in polymyositis and IBM. Furthermore, the
pronounced interleukin-1 expression in the inflammatory myopathies makes this
molecule an interesting potential target for development of future therapies
for
these disorders.
Publication Types:
Review
Review, Tutorial
PMID: 9812212 [PubMed - indexed for MEDLINE]
297: Compr Ther. 1998 Oct;24(10):494-502.
Inflammatory myopathies [polymyositis, dermatomyositis, inclusion body myositis]
Bertorini TE.
Department of Neurology, University of Tennessee, Memphis 38163, USA.
Inflammatory myopathies are common treatable diseases of muscle that should
be
differentiated from similar but incurable conditions. This article discusses
the
diagnosis, laboratory studies, pathology, pathogenesis, differential diagnosis,
and treatment of the different autoimmune myopathies.
Publication Types:
Review
Review, Tutorial
PMID: 9801848 [PubMed - indexed for MEDLINE]
298: Hum Pathol. 1998 Oct;29(10):1128-33.
Rimmed vacuoles with beta-amyloid and ubiquitinated filamentous deposits in
the
muscles of patients with long-standing denervation (postpoliomyelitis muscular
atrophy): similarities with inclusion body myositis.
Semino-Mora C, Dalakas MC.
Neuromuscular Diseases Section, Medical Neurology Branch, National Institute
of
Neurological Disorders and Stroke, National Institutes of Health, Bethesda,
MD
20892, USA.
In the chronically denervated muscles of patients with prior paralytic
poliomyelitis, there are secondary myopathic features, including endomysial
inflammation and rare vacuolated fibers. To assess the frequency and
characteristics of the vacuoles and their similarities with those seen in
inclusion body myositis (IBM), we examined 58 muscle biopsy specimens from
patients with prior paralytic poliomyelitis for (1) the presence of rimmed
vacuoles; (2) acid-phosphatase reactivity; (3) Congo-red-positive amyloid
deposits; (4) electron microscopy, searching for tubulofilaments; and (5)
immunoelectron microscopy, using antibodies against beta-amyloid and ubiquitin.
We found vacuolated muscle fibers in 18 of 58 (31%) biopsies, with a mean
frequency of 2.06 +/- 0.42 fibers per specimen. The vacuoles contained acid
phosphatase-positive material in 6 of the 18 (33.30%) specimens and stained
positive for Congo red in five (27.80%). By immunoelectron microscopy, the
vacuoles contained 5.17 +/- 0.13 nm fibrils and 14.9 +/- 0.31 nm filaments that
immunoreacted with antibodies to beta-amyloid and ubiquitin in a pattern
identical to the one seen in IBM. We conclude that vacuolated muscle fibers
containing filamentous inclusions positive for amyloid and ubiquitin are not
unique to IBM and the other vacuolar myopathies but can also occur in a chronic
neurogenic condition, such as postpoliomyelitis. The chronicity of the
underlying disease, rather than the cause, may lead to vacuolar formation,
amyloid deposition, and accumulation of ubiquitinated filaments.
PMID: 9781653 [PubMed - indexed for MEDLINE]
299: Neurosci Lett. 1998 Sep 25;254(2):77-80.
Immunolocalization of transcription factor NF-kappaB in inclusion-body myositis
muscle and at normal human neuromuscular junctions.
Yang CC, Askanas V, Engel WK, Alvarez RB.
USC Neuromuscular Center, Department of Neurology, University of Southern
California School of Medicine, Good Samaritan Hospital, Los Angeles 90017-1912,
USA.
To investigate whether nuclear factor kappaB (NF-kappaB) is involved in the
pathogenesis of inclusion-body myositis (IBM), we immunostained muscle biopsies
of eight patients with IBM with specific antibodies against its p50 and p65
subunits. Approximately 70% of IBM vacuolated muscle fibers had strong focal
accumulations of both NF-kappaB p50 and p65, which by immunoelectronmicroscopy,
localized mainly to clusters of paired-helical filaments (PHFs). Virtually all
necrotic fibers, in various muscle biopsies, had diffusely strong p50
immunoreactivity, whereas p65 immunoreactivity was present only in a small
subset of necrotic fibers. At all neuromuscular junctions, postsynaptically
there was strong p65 but no p50 immunoreactivity. Our data suggest that
NF-kappaB plays a role in IBM pathogenesis. Different distributions of NF-kappaB
subunits in necrotic fibers and at normal neuromuscular junctions (NMJs)
suggests different roles of each subunit in human muscle pathology and
physiology.
PMID: 9779924 [PubMed - indexed for MEDLINE]
300: Rev Neurol (Paris). 1998 Jan;154(1):13-6.
Dermatomyositis, polymyositis and inclusion body myositis: current concepts.
Illa I, Dalakas MC.
Publication Types:
Editorial
Review
Review, Tutorial
PMID: 9773019 [PubMed - indexed for MEDLINE]
301: Muscle Nerve. 1998 Nov;21(11):1523-5.
Intracellular phosphates in inclusion body myositis--a 31P magnetic resonance
spectroscopy study.
Argov Z, Taivassalo T, De Stefano N, Genge A, Karpati G, Arnold DL.
Department of Neurology, Hebrew University-Hadassah Medical School, Jerusalem,
Israel.
Muscle phosphorus magnetic resonance spectroscopy was used to study oxidative
metabolism at rest and during recovery from exercise in 7 patients with sporadic
inclusion body myositis (s-IBM), compared with normal controls (n=8) and
mitochondrial myopathies (n=20). At rest, 6/7 patients had elevated inorganic
phosphates. Recovery parameters were not different from controls, in contrast
with mitochondrial myopathies, who showed abnormal rest and recovery. The normal
recovery suggests that mitochondrial oxidative capacity is not impaired in
s-IBM.
PMID: 9771678 [PubMed - indexed for MEDLINE]
302: Ann Neurol. 1998 Sep;44(3):423.
Presence of the anti-Jo-1 autoantibody excludes inclusion body myositis.
Hengstman GJ, van Engelen BG, Badrising UA, van den Hoogen FH, van Venrooij WJ.
Publication Types:
Letter
PMID: 9749616 [PubMed - indexed for MEDLINE]
303: Neurology. 1998 Aug;51(2):598-600.
Comment in:
Neurology. 1999 Aug 11;53(3):659.
Inclusion body myositis in twins.
Amato AA, Shebert RT.
Department of Medicine/Neurology, University of Texas Health Science Center
at
San Antonio, 78284-7883, USA.
Sporadic inclusion body myositis (s-IBM) is characterized by late onset of
slowly progressive weakness that involves the quadriceps and volar forearm
muscles early in the course of the disease. There are hereditary forms of
inclusion body myopathy (h-IBM) that histologically resemble s-IBM. The lack
of
inflammation on biopsy and the different ages at onset and patterns of muscle
weakness distinguish s-IBM from h-IBM. We report twin brothers with the typical
clinical and histologic features of s-IBM. The occurrence of s-IBM in these
twins suggests the possibility of a genetic susceptibility to developing s-IBM.
Publication Types:
Case Reports
PMID: 9710045 [PubMed - indexed for MEDLINE]
304: Ann Neurol. 1998 Aug;44(2):242-8.
Autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia,
and rimmed vacuoles.
Darin N, Kyllerman M, Wahlstrom J, Martinsson T, Oldfors A.
Department of Pediatrics, Sahlgrenska University Hospital, Goteborg, Sweden.
We describe a new myopathy in a large family with 19 affected cases. Inheritance
was autosomal dominant. Characteristic clinical features were congenital joint
contractures, which normalized during early childhood, external ophthalmoplegia,
and proximal muscle weakness. Muscle atrophy was most prominent in the
pectoralis and quadriceps muscles. The clinical course was nonprogressive in
childhood, but most adult cases experienced deterioration of muscle function,
starting from 30 to 50 years of age. The major histopathological change of
skeletal muscle in childhood was focal disorganization of myofilaments. In
adults with progressive muscle weakness, the muscle biopsies showed dystrophic
changes and rimmed vacuoles with cytoplasmic and intranuclear inclusions of
15-
to 21-nm filaments. These findings suggests that this new disease should be
classified as a variant of hereditary inclusion body myopathy.
PMID: 9708547 [PubMed - indexed for MEDLINE]
305: Neurosci Res. 1998 May;31(1):1-8.
Chloroquine myopathy suggests that tau is degraded in lysosomes: implication
for
the formation of paired helical filaments in Alzheimer's disease.
Oyama F, Murakami N, Ihara Y.
Department of Neuropathology, Faculty of Medicine, University of Tokyo, Japan.
We have found that amorphous tau deposits in chloroquine myopathy (CM), a
vacuolar myopathy induced by the administration of chloroquine, a well-known
lysosomotropic agent. The dynamics of tau in CM and immunocytochemistry strongly
suggest that the accumulation of tau is due to defective tau degradation in
the
lysosomal compartment in the muscle. This observation may offer a new view on
the formation of paired helical filaments in Alzheimer's disease: this selective
protein degradation pathway may be defective and result in intracellular
accumulation of tau, thereby forming the unusual filaments.
Publication Types:
Review
Review, Tutorial
PMID: 9704973 [PubMed - indexed for MEDLINE]
306: Acta Neuropathol (Berl). 1998 Jul;96(1):41-51.
Pleomorphic mitochondrial and different filamentous inclusions in inflammatory
myopathies associated with mtDNA deletions.
Molnar M, Schroder JM.
Institut fur Neuropathologie, Universitatsklinikum der Rheinisch-Westfalischen
Technischen Hochschule Aachen, Germany. neupath@amsd.imib.rwth-aachen.de
Mitochondrial changes are frequently observed in muscle fibers of patients
with
inclusion body myositis (IBM) and polymyositis (PM), suggesting that
mitochondrial function may be especially impaired in these forms of inflammatory
myopathies. Intranuclear and cytoplasmic tubulofilamentous inclusions are
characteristic, although not totally specific for IBM. In the present cases,
the
inclusions were strikingly pleomorphic when chloroquine had been given for long
periods. The nuclear inclusions were always tubular, whereas the cytoplasmic
filaments had either a tubular, a helical, or a cross-striated structure with
different diameters and arrangements in association with myelin-like figures,
and vacuoles. Abnormal mitochondria containing paracrystalline, globoid, and
other inclusions, noted in IBM, were occasionally also seen in PM or vasculitis.
By contrast, in the latter, no intranuclear or cytoplasmic tubulofilamentous
inclusions were apparent in muscle fibers. This study reports for the first
time
the presence of membrane-bound crystalloid inclusions in a muscle fiber with
numerous abnormal mitochondria; similar structures have thus far only been
observed in macrophages. The identity and function of these inclusions remains
unknown. Using PCR analysis we detected different mtDNA deletions not only in
IBM, but also in PM and vasculitis, indicating at least some degree of
association between the structural mitochondrial abnormalities and the mtDNA
mutations. There was no topographical correlation between the presence of
tubular or helical filaments and the mitochondrial abnormalities. As already
noted by others, the mitochondrial changes in IBM were more frequent than
expected in this age group. It is suggested that the presence of the mtDNA
deletions in IBM and PM are not primary, but rather the result of the
underlying, presumably immunological disorder causing nuclear and secondary
or
simultaneous mitochondrial changes.
PMID: 9678512 [PubMed - indexed for MEDLINE]
307: Arch Neurol. 1998 Jul;55(7):915-20.
Sporadic inclusion-body myositis and hereditary inclusion-body myopathies:
diseases of oxidative stress and aging?
Askanas V, Engel WK.
Neuromuscular Center, Department of Neurology, University of Southern California
School of Medicine, Good Samaritan Hospital, Los Angeles 90017-1912, USA.
Publication Types:
Review
Review, Tutorial
PMID: 9678308 [PubMed - indexed for MEDLINE]
308: Ann N Y Acad Sci. 1998 May 13;841:28-56.
Fourteen newly recognized proteins at the human neuromuscular junctions--and
their nonjunctional accumulation in inclusion-body myositis.
Askanas V, Engel WK, Alvarez RB.
Department of Neurology, University of Southern California School of Medicine,
Good Samaritan Hospital, Los Angeles 90017-1912, USA.
Publication Types:
Review
Review, Tutorial
PMID: 9668220 [PubMed - indexed for MEDLINE]
309: J Neurol Neurosurg Psychiatry. 1998 Jul;65(1):107-10.
Immunoglobulin therapy in inflammatory myopathies.
Mastaglia FL, Phillips BA, Zilko PJ.
Australian Neuromuscular Research Institute, University Department of Medicine,
Queen Elizabeth II Medical Centre, Perth WA.
A prospective open label trial of add on therapy with intravenous immunoglobulin
(i.v.Ig) was carried out in 16 patients with inflammatory myopathy who had
continued to deteriorate or had relapsed on conventional therapy. The response
was assessed using isometric myometry, functional scales, MRC grading, and serum
creatine kinase concentrations with a three month run in period before
commencement of i.v.Ig. Five of seven patients with isolated dermatomyositis
or
polymyositis and all four patients with an overlap syndrome responded to i.v.Ig
with partial or complete remission of disease and normalisation of serum
creatine kinase concentrations. None of five patients with inclusion body
myositis showed any functional improvement although myometry scores improved
in
some muscles in one case. It is concluded that i.v.Ig is an effective
therapeutic option in patients with drug resistant polymyositis or
dermatomyositis. However, further controlled trials are required to confirm
the
efficacy of this form of treatment and to establish optimal doses and
administration regimes.
PMID: 9667570 [PubMed - indexed for MEDLINE]
310: Laryngoscope. 1998 Jul;108(7):1001-5.
Dysphagia in patients with inclusion body myositis.
Houser SM, Calabrese LH, Strome M.
Department of Otolaryngology and Communicative Disorders, Cleveland Clinic
Foundation, Ohio 44195, USA.
OBJECTIVES: Inclusion body myositis (IBM) is an inflammatory myopathy with
a 40%
reported incidence of dysphagia. A protracted course, refractory to medical
therapy, frequently leads to consultation with an otolaryngologist for dysphagia
management. We studied the incidence, symptoms, and mechanisms of dysphagia
in
patients with IBM. STUDY DESIGN: Retrospective study of medical records and
self-reported follow-up survey; dysphagia is defined as difficulty in
swallowing. MATERIALS: Twenty-two patients with biopsy-proven IBM. RESULTS:
The
rate of dysphagia was more than 80% (16 of 19), twice as high as previously
reported. Progressive dysphagia was associated with a significantly worse
functional class. Relevant management guidelines are established, including
the
timing for appropriate surgical intervention. CONCLUSION: Progressive dysphagia
may signify more aggressive IBM or an episodic worsening in status. Recognition
of the disease manifestations will afford proper patient management. Informed
otolaryngologists can have a favorable impact on the dysphagia associated with
IBM.
Publication Types:
Case Reports
PMID: 9665246 [PubMed - indexed for MEDLINE]
311: Brain. 1998 Jun;121 ( Pt 6):1089-97.
Nitric oxide-induced oxidative stress in autosomal recessive and dominant
inclusion-body myopathies.
Yang CC, Alvarez RB, Engel WK, Heller SL, Askanas V.
USC Neuromuscular Center, Good Samaritan Hospital, University of Southern
California School of Medicine, Los Angeles, USA.
Autosomal-recessive and autosomal-dominant hereditary inclusion-body myopathies
are severe, progressive muscle diseases, characterized pathologically by
vacuolated muscle fibres containing paired helical filaments. We immunostained
muscle biopsy specimens from quadriceps-sparing autosomal-recessive and
autosomal-dominant inclusion-body myopathy subjects, disease-control subjects
and normal patients, utilizing isoform-specific antibodies against the neuronal
and inducible forms of nitric oxide synthase, and antibodies against
nitrotyrosine. Approximately 75% of the vacuolated muscle fibres in all
recessive and dominant inclusion-body myopathy patients contained inclusions
strongly immunoreactive with antibodies against neuronal and inducible nitric
oxide synthase which, by immunoelectron microscopy, were colocalized to clusters
of tubulofilaments (previously shown, by us, to be paired helical filaments).
Strong nitrotyrosine immunoreactivity was in the form of multiple dots and large
granular patches, which ultrastructurally did not immunolocalize to
tubulofilaments. Excess intracellular nitric oxide can combine with superoxide
to produce highly toxic peroxynitrite, which can nitrate tyrosines of proteins.
The presence of nitrotyrosine is indicative of nitric oxide-induced oxidative
stress. Our data suggest that oxidative stress plays a role in the pathogenic
cascade of hereditary inclusion-body myopathies.
PMID: 9648544 [PubMed - indexed for MEDLINE]
312: Clin Immunol Immunopathol. 1998 Jun;87(3):240-7.
Cell death and oxidative damage in inflammatory myopathies.
Tews DS, Goebel HH.
Division of Neuropathology, Johannes Gutenberg-University, Mainz, Germany.
There is evidence that muscle fibers in denervating disorders and muscular
dystrophies undergo apoptosis. In 21 patients with autoimmune inflammatory
myopathies, we found no features of muscle fiber apoptosis such as DNA
fragmentation or expression of apoptosis-related proteins. However, muscle
fibers in myositis displayed distinct up-regulation of inducible and neuronal
nitric oxide synthase (NOS). While inducible NOS was distinctly up-regulated
on
the sarcolemma of all kinds of muscle fibers neuronal NOS displayed increased
expression in the sarcoplasm of damaged as well as atrophic muscle fibers. There
were no disease-specific patterns in the different myositis subtypes. Enhanced
expression of NOS with production of nitric oxide may contribute to oxidative
stress mediating muscle fiber damage and muscle fiber necrosis representing
the
predominant cell death mechanism in myositis. Nevertheless, inflammatory cells
displayed numerous DNA-fragmentation-positive nuclei and expression of
apoptosis-related proteins indicating that apoptosis plays a