PubMed Health⌕ Search

Biomedical subjects

Anthony A Amato

Publications and source records attributed to Anthony A Amato.

At least 19 recordsLinked to original sources
PubMed2007

A local antigen-driven humoral response is present in the inflammatory myopathies.

The inflammatory myopathies are putative autoimmune disorders characterized by muscle weakness and the presence of intramuscular inflammatory infiltrates. Although inclusion body myositis and polymyositis have been characterized as cytotoxic CD8(+) T cell-mediated diseases, we recently demonstrated high frequencies of CD138(+) plasma cells in the inflamed muscle tissue of patients with these diseases. To gain a deeper understanding of the role these B cell family members play in the disease pathology, we examined the molecular characteristics of the H chain portion of the Ag receptor. Biopsies of muscle tissue were sectioned and tissue regions and individual cells were isolated through laser capture microdissection. Ig H chain gene transcripts isolated from the sections, regions, and cells were used to determine the variable region gene sequences. Analysis of these sequences revealed clear evidence of affinity maturation in that significant somatic mutation, isotype switching, receptor revision, codon insertion/deletion, and oligoclonal expansion had occurred within the B and plasma cell populations. Moreover, analysis of tissue regions isolated by laser capture microdissection revealed both clonal expansion and variation, suggesting that local B cell maturation occurs within muscle. In contrast, sequences from control muscle tissues and peripheral blood revealed none of these characteristics found in inflammatory myopathy muscle tissue. Collectively, these data demonstrate that Ag drives a B cell Ag-specific response in muscle in patients with dermatomyositis, inclusion body myositis, and polymyositis. These findings highlight the need for a revision of the current paradigm of exclusively T cell-mediated intramuscular Ag-specific autoimmunity in inclusion body myositis and polymyositis.

Adult↗
PubMed2007

Myeloid dendritic cells in inclusion-body myositis and polymyositis.

Dendritic cells (DCs), immune system cells central to the development of immunity, have not previously been reported in muscle in inclusion-body myositis (IBM). We performed immunohistochemical studies on muscle biopsy specimens from 50 patients using monoclonal antibodies that distinguish two classes of DCs, myeloid DC and plasmacytoid DC. In 17 of 20 IBM and 9 of 10 polymyositis (PM) specimens, myeloid DCs were present in substantial numbers, frequently surrounded and sometimes invading otherwise intact myofibers, and were part of dense collections of cells that included T cells. Dermatomyositis muscle had more plasmacytoid DCs than myeloid DCs, whereas IBM and PM had greater numbers of myeloid DCs. The stellate morphology of myeloid DCs in dense collections of cells that included T cells suggests local intramuscular antigen presentation in IBM and PM.

Antibodies, Monoclonal↗
PubMed2006

Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib.

PURPOSE: To determine the frequency, characteristics, and reversibility of peripheral neuropathy from bortezomib treatment of advanced multiple myeloma. PATIENTS AND METHODS: Peripheral neuropathy was assessed in two phase II studies in 256 patients with relapsed and/or refractory myeloma treated with bortezomib 1.0 or 1.3 mg/m2 intravenous bolus on days 1, 4, 8, and 11, every 21 days, for up to eight cycles. Peripheral neuropathy was evaluated at baseline, during the study, and after the study by patient-reported symptoms using the Functional Assessment of Cancer Therapy Scale/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire and neurologic examination. During the study, peripheral neuropathy was also evaluated by investigator assessment. A subset of patients underwent nerve conduction studies (n = 13). RESULTS: Before treatment, 194 (81%) of 239 patients had peripheral neuropathy by FACT/GOG-Ntx questionnaire, and 203 (83%) of 244 patients had peripheral neuropathy by neurologic examination. Treatment-emergent neuropathy was reported in 35% of patients, including 37% (84 of 228 patients) receiving bortezomib 1.3 mg/m2 and 21% (six of 28 patients) receiving bortezomib 1.0 mg/m2. Grade 1 or 2, 3, and 4 neuropathy occurred in 22%, 13%, and 0.4% of patients, respectively. The incidence of grade > or = 3 neuropathy was higher among patients with baseline neuropathy by FACT/GOG-Ntx questionnaire compared with patients without baseline neuropathy (14% v 4%, respectively). In all 256 patients, neuropathy led to dose reduction in 12% and discontinuation in 5%. Of 35 patients with neuropathy > or = grade 3 and/or requiring discontinuation, resolution to baseline or improvement occurred in 71%. CONCLUSION: Bortezomib-associated peripheral neuropathy seemed reversible in the majority of patients after dose reduction or discontinuation. Although severe neuropathy was more frequent in the presence of baseline neuropathy, the overall occurrence was independent of baseline neuropathy or type of prior therapy.

Adult↗
PubMed2006

Nuclear membrane proteins are present within rimmed vacuoles in inclusion-body myositis.

The rimmed vacuoles within muscle in inclusion-body myositis (IBM) are structures of uncertain origin. Two hypotheses have been proposed for their formation: that they develop as a consequence of abnormal lysosomal function or in association with the breakdown of myonuclei. We tested the latter hypothesis by studying muscle samples from 14 patients with IBM and 18 controls using immunohistochemistry for nuclear membrane proteins, examining semithin sections, and performing electron microscopy. We found that in IBM muscle vacuoles were immunoreactive for the inner nuclear membrane proteins emerin and lamin A/C. Myonuclei with fragmented or focally absent nuclear membranes were present in immunohistochemical and electron microscopy studies. The association of nuclear membrane proteins with rimmed vacuoles confirms the hypotheses that rimmed vacuoles in IBM form in association with myonuclear pathology and that IBM differs from other inflammatory myopathies in that abnormalities of myonuclei are more prominent.

Dystrophin↗
PubMed2005

Interferon-alpha/beta-mediated innate immune mechanisms in dermatomyositis.

Dermatomyositis has been modeled as an autoimmune disease largely mediated by the adaptive immune system, including a local humorally mediated response with B and T helper cell muscle infiltration, antibody and complement-mediated injury of capillaries, and perifascicular atrophy of muscle fibers caused by ischemia. To further understand the pathophysiology of dermatomyositis, we used microarrays, computational methods, immunohistochemistry and electron microscopy to study muscle specimens from 67 patients, 54 with inflammatory myopathies, 14 with dermatomyositis. In dermatomyositis, genes induced by interferon-alpha/beta were highly overexpressed, and immunohistochemistry for the interferon-alpha/beta inducible protein MxA showed dense staining of perifascicular, and, sometimes all myofibers in 8/14 patients and on capillaries in 13/14 patients. Of 36 patients with other inflammatory myopathies, 1 patient had faint MxA staining of myofibers and 3 of capillaries. Plasmacytoid dendritic cells, potent CD4+ cellular sources of interferon-alpha, are present in substantial numbers in dermatomyositis and may account for most of the cells previously identified as T helper cells. In addition to an adaptive immune response, an innate immune response characterized by plasmacytoid dendritic cell infiltration and interferon-alpha/beta inducible gene and protein expression may be an important part of the pathogenesis of dermatomyositis, as it appears to be in systemic lupus erythematosus.

Adult↗
PubMed2005

Inflammatory neuropathies.

We discuss two of the most common of the acquired inflammatory neuropathies: Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy, as well as their variants. We review their clinical presentation, electrophysiologic findings, and management, highlighting knowledge gained from the recent literature. Unfortunately, although treatments exist for both Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy, none are completely curative and all have significant potential side effects and/or expense. Better understanding of the underlying pathophysiology of these diseases is needed in order to develop more targeted therapies.

Guillain-Barre Syndrome↗
PubMed2005

Toxic myopathies.

Muscle tissue is highly sensitive to drugs and toxins because ot its high metabolic activity and potential sites for disruption of energy-producing pathways. Early recognition of toxic myopathies is important, as they potentially are reversible on removal of the offending toxin, with greater likelihood of complete resolution the sooner this is achieved. Clinical features range from mild muscle pain and cramps to severe weakness with rhabdomyolysis, renal failure, and even death. The pathogenic bases can be multifactorial. This article reviews drugs responsible for common types of toxic myopathy and their clinical and histopathologic features and illustrates possible underlying cellular mechanisms.

Animals↗
PubMed2005

Preservation of in vitro muscle fiber function in dermatomyositis and inclusion body myositis: a single fiber study.

Five patients with untreated dermatomyositis, five with inclusion body myositis, and 16 healthy elderly volunteer subjects (controls) underwent open (dermatomyositis and inclusion body myositis) or percutaneous (controls) muscle biopsy. Biopsied muscles included deltoid, biceps and vastus lateralis. Chemically skinned single muscle fibers were activated with Ca(+2); the slack test was performed to determine maximal unloaded shortening velocity (Vo). Parameters measured include single fiber cross sectional area, maximal force, specific force and Vo. 429 Type I and 94 Type IIA fibers were studied. Cross sectional area and maximal force were greater in inclusion body myositis than dermatomyositis or control for Type I and IIA fibers. Specific force of Type I fibers was similar in inclusion body myositis and dermatomyositis but greater than in controls. Vo was greater in Type I, but not IIA, fibers in dermatomyositis compared with inclusion body myositis and controls. The force and velocity generating capacity of single muscle fibers is preserved in patients with dermatomyositis and inclusion body myositis suggesting that dysfunction of the contractile proteins does not contribute to clinical muscle weakness.

Adult↗
PubMed2004

Efficacy of mycophenolate mofetil in patients with chronic immune demyelinating polyneuropathy.

The authors retrospectively reviewed the efficacy of mycophenolate mofetil (MMF; mean dose, 2 g/day given for an average of 14 months) in 21 patients with immune demyelinating polyneuropathy. There were no significant differences in the median strength, sensory, or Rankin scores before and after treatment. In patients with immunoglobulin (Ig) M neuropathy, the M-protein decreased by 22%. Three patients with chronic inflammatory demyelinating polyneuropathy (30%) and one patient with IgM neuropathy (13%) improved. The authors found that MMF induced a modest benefit in ~20% of their patients and stabilized patient condition, allowing reduction of steroid or IVIg therapy.

Adrenal Cortex Hormones↗
PubMed2004

Transthyretin amyloidosis presenting with multifocal demyelinating mononeuropathies.

We describe a patient with transthyretin amyloidosis who presented with multifocal mononeuropathies with features of demyelination on nerve conduction studies, a constellation of findings not previously described in amyloid polyneuropathy. Genetic testing revealed a valine122isoleucine mutation in the coding region of the transthyretin gene, a mutation that generally presents with late-onset cardiac amyloidosis. Our patient was also unusual in that she was 34 years old at the time of presentation and had no cardiac involvement.

Adult↗
PubMed2004

Uncertainties in the pathogenesis of adult dermatomyositis.

PURPOSE OF REVIEW: Dermatomyositis is an inflammatory disorder of muscle affecting both children and adults. The pathogenesis of adult dermatomyositis is reviewed here, with particular attention to gaps and uncertainties in our current understanding of this disease, in order to focus attention on the outstanding research questions with regard to disease mechanisms. RECENT FINDINGS: The conceptual model of the pathophysiology of dermatomyositis has been based on work extending back over at least 35 years, with important findings related to the deposition of membrane attack complex, the character of the inflammatory infiltrate, and the primacy of capillary abnormalities established over 10 years ago. The lack of significant additions to the understanding of this disease over the past few years suggests a state of contentment with current knowledge. Accordingly, we emphasize the uncertainties of this knowledge and the need for re-addressing some of its basic tenets. SUMMARY: Although evidence remains strong that dermatomyositis is a disorder with an early involvement of the capillaries, the concept that it results from an antibody-mediated attack upon the endothelium is uncertain. It is not clear whether membrane attack complex is activated by antibody-dependent or independent means, whether or not intramuscular B cells are antigen specific and synthesize significant quantities of antibodies, whether the presence of tubuloreticular inclusions precedes, follows, or is independent of membrane attack complex deposition, what is the mechanism of perifascicular atrophy, and what is the relationship of dermatomyositis to systemic lupus erythematosus.

Adult↗
PubMed2003

Late-onset distal muscular dystrophy affecting the posterior calves.

Miyoshi myopathy, caused by mutations in the membrane protein dysferlin, is the most common muscular dystrophy that presents in the posterior calves. Its onset is before the age of 30 years and it is associated with marked elevations of serum creatine kinase (CK). In contrast, little is known about calf myopathies with onset after the age of 30, and it is not clear whether such patients have a dysferlinopathy. We describe five patients with a myopathy predominantly affecting the calf muscles, with onset after the age of 30. Muscle tissue was analyzed by immunoblot for dystrophin and dysferlin. All five had normal dysferlin but one had a dystrophinopathy. Serum CK levels ranged from 3 to 15 times the upper limit of normal. In contrast, all of 13 patients presenting before age 30 with calf weakness had a dysferlinopathy. Thus, isolated calf atrophy and weakness with onset after age 30, and associated with serum CK levels that are only moderately elevated, represents a distinct myopathy phenotype. Most of these cases are sporadic, although the overall phenotype appears genetically heterogeneous and dysferlinopathy is uncommon.

Adult↗
PubMed2003

Neuromuscular complications of cancer.

Neuromuscular complications of cancer are common and can affect any component of the peripheral nervous system from peripheral nerve cell body to muscle. Perhaps the most common complication is a length-dependent symmetric axonal polyneuropathy that is often multifactorial in etiology, resulting from metabolic and treatment effects of the primary malignancy. However, neuromuscular disorders may also be the presenting complaint in many conditions, including disorders caused by malignant infiltration of nerve and disorders cause by paraneoplastic syndromes. Although many of the paraneoplastic conditions are poorly responsive to treatment, not all are, and one hopes that prompt diagnosis of the underlying malignancy will lead to improved patient outcome. Recognition of iatrogenic neuromuscular complications is also important to modify treatment protocols when possible and thus decrease the risk of long-term neurologic disability.

Biopsy↗