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Steven A Greenberg

Publications and source records attributed to Steven A Greenberg.

16 recordsLinked to original sources
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

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

Discovering statistically significant pathways in expression profiling studies.

Accurate and rapid identification of perturbed pathways through the analysis of genome-wide expression profiles facilitates the generation of biological hypotheses. We propose a statistical framework for determining whether a specified group of genes for a pathway has a coordinated association with a phenotype of interest. Several issues on proper hypothesis-testing procedures are clarified. In particular, it is shown that the differences in the correlation structure of each set of genes can lead to a biased comparison among gene sets unless a normalization procedure is applied. We propose statistical tests for two important but different aspects of association for each group of genes. This approach has more statistical power than currently available methods and can result in the discovery of statistically significant pathways that are not detected by other methods. This method is applied to data sets involving diabetes, inflammatory myopathies, and Alzheimer's disease, using gene sets we compiled from various public databases. In the case of inflammatory myopathies, we have correctly identified the known cytotoxic T lymphocyte-mediated autoimmunity in inclusion body myositis. Furthermore, we predicted the presence of dendritic cells in inclusion body myositis and of an IFN-alpha/beta response in dermatomyositis, neither of which was previously described. These predictions have been subsequently corroborated by immunohistochemistry.

Algorithms↗
PubMed2005

CrossChip: a system supporting comparative analysis of different generations of Affymetrix arrays.

SUMMARY: To increase compatibility between different generations of Affymetrix GeneChip arrays, we propose a method of filtering probes based on their sequences. Our method is implemented as a web-based service for downloading necessary materials for converting the raw data files (*.CEL) for comparative analysis. The user can specify the appropriate level of filtering by setting the criteria for the minimum overlap length between probe sequences and the minimum number of usable probe pairs per probe set. Our website supports a within-species comparison for human and mouse GeneChip arrays. AVAILABILITY: http://www.crosschip.org

Algorithms↗
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

Molecular diagnosis of inheritable neuromuscular disorders. Part I: Genetic determinants of inherited disease and their laboratory detection.

Understanding of the genetic basis of inheritable neuromuscular disorders has grown rapidly over the last decade, resulting in improved classification and understanding of their pathogenesis. A consequence of these advances has been the development of genetic tests of blood specimens for the diagnosis of many of these diseases. For many patients, these blood tests have eliminated the need for other more invasive diagnostic tests such as muscle or nerve biopsy, and for some patients, reduced exposure to immunosuppressive medication and its complications. The first part of this review focuses on the nature of genetic disorders, the laboratory methods used in the performance of genetic tests, and general practical aspects of their use and interpretation. The second part discusses the applicability of these tests to the range of neuromuscular disorders.

Humans↗
PubMed2005

Molecular diagnosis of inheritable neuromuscular disorders. Part II: Application of genetic testing in neuromuscular disease.

Molecular genetic advances have led to refinements in the classification of inherited neuromuscular disease, and to methods of molecular testing useful for diagnosis and management of selected patients. Testing should be performed as targeted studies, sometimes sequentially, but not as wasteful panels of multiple genetic tests performed simultaneously. Accurate diagnosis through molecular testing is available for the vast majority of patients with inherited neuropathies, resulting from mutations in three genes (PMP22, MPZ, and GJB1); the most common types of muscular dystrophies (Duchenne and Becker, facioscapulohumeral, and myotonic dystrophies); the inherited motor neuron disorders (spinal muscular atrophy, Kennedy's disease, and SOD1 related amyotrophic lateral sclerosis); and many other neuromuscular disorders. The role of potential multiple genetic influences on the development of acquired neuromuscular diseases is an increasingly active area of research.

Humans↗
PubMed2004

Acquired rippling muscle disease with myasthenia gravis.

Rippling muscle disease (RMD) is a rare disorder that occurs in both familial and sporadic forms. Seven patients have previously been reported with myasthenia gravis and sporadic RMD. There have been conflicting reports of the electrophysiological characteristics of rippling muscles in this acquired form. Another such patient is reported, and the clinical, electrophysiological, and laboratory features of this disorder are described. In addition, this patient had alopecia areata and recurrent metastatic thymoma, years after resection of a benign thymoma. This report emphasizes the clinical manifestations of RMD in association with myasthenia gravis (RMD-MG), and its distinctive features, in this and previously reported patients.

Adult↗
PubMed2004

Molecular classification of nemaline myopathies: "nontyping" specimens exhibit unique patterns of gene expression.

Nemaline myopathy (NM) is a slowly progressive or nonprogressive neuromuscular disorder caused by mutations in genes encoding skeletal muscle sarcomeric thin filament proteins. It is characterized by great heterogeneity at the clinical, histopathological, and genetic level. Although multiple molecular pathways are commonly affected in all NM patients, little is known about the molecular characteristics of muscles from patients in different NM subgroups. We have analyzed a group of global gene expression data sets for transcriptional patterns characteristic of particular nemaline myopathy classes. Differential expression between disease subgroups was primarily seen in mitochondrial-, structural-, and transcription-related genes. Multiple lines of evidence support the hypothesis that muscles from cases with "nontyping" NM, although clinically classified as typical NM, share a unique pathophysiological state and are characterized by distinct patterns of gene expression. Determination of the specific molecular differences in NM subgroups may eventually lead to improved prognostic determinations and treatment of these patients.

Base Sequence↗
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

Expression profiling reveals altered satellite cell numbers and glycolytic enzyme transcription in nemaline myopathy muscle.

The nemaline myopathies (NMs) are a clinically and genetically heterogeneous group of disorders characterized by nemaline rods and skeletal muscle weakness. Mutations in five sarcomeric thin filament genes have been identified. However, the molecular consequences of these mutations are unknown. Using Affymetrix oligonucleotide microarrays, we have analyzed the expression patterns of >21,000 genes and expressed sequence tags in skeletal muscles of 12 NM patients and 21 controls. Multiple complementary approaches were used for data analysis, including geometric fold analysis, two-tailed unequal variance t test, hierarchical clustering, relevance network, and nearest-neighbor analysis. We report the identification of high satellite cell populations in NM and the significant down-regulation of transcripts for key enzymes of glucose and glycogen metabolism as well as a possible regulator of fatty acid metabolism, UCP3. Interestingly, transcript level changes of multiple genes suggest possible changes in Ca(2+) homeostasis. The increased expression of multiple structural proteins was consistent with increased fibrosis. This comprehensive study of downstream molecular consequences of NM gene mutations provides insights in the cellular events leading to the NM phenotype.

Adult↗
PubMed2003

The history of dermatome mapping.

Dermatome maps are commonly used in clinical neurology. These maps are valuable for the localization of varied sensory phenomena in patients with neurological disorders. The methods used in the construction of the classic maps by Sir Henry Head, Sir Charles Sherrington, Otfrid Foerster, and Jay Keegan and Frederic Garrett are of historical interest and are relevant to the current understanding of dermatome anatomy and physiology. In particular, the work of Derek Denny-Brown and his colleagues demonstrates that patterns of dermatomal sensory loss depend on the anatomical and physiological characteristics of large regions of nervous tissue, multiple adjacent dorsal ganglia, and the nearby caudal and rostral spinal cord.

Animals↗
PubMed2002

Gene expression comparison of biopsies from Duchenne muscular dystrophy (DMD) and normal skeletal muscle.

The primary cause of Duchenne muscular dystrophy (DMD) is a mutation in the dystrophin gene leading to the absence of the corresponding RNA transcript and protein. Absence of dystrophin leads to disruption of the dystrophin-associated protein complex and substantial changes in skeletal muscle pathology. Although the histological pathology of dystrophic tissue has been well documented, the underlying molecular pathways remain poorly understood. To examine the pathogenic pathways and identify new or modifying factors involved in muscular dystrophy, expression microarrays were used to compare individual gene expression profiles of skeletal muscle biopsies from 12 DMD patients and 12 unaffected control patients. Two separate statistical analysis methods were used to interpret the resulting data: t test analysis to determine the statistical significance of differential expression and geometric fold change analysis to determine the extent of differential expression. These analyses identified 105 genes that differ significantly in expression level between unaffected and DMD muscle. Many of the differentially expressed genes reflect changes in histological pathology. For instance, immune response signals and extracellular matrix genes are overexpressed in DMD muscle, an indication of the infiltration of inflammatory cells and connective tissue. Significantly more genes are overexpressed than are underexpressed in dystrophic muscle, with dystrophin underexpressed, whereas other genes encoding muscle structure and regeneration processes are overexpressed, reflecting the regenerative nature of the disease.

Adult↗
PubMed2002

P-ANCA vasculitic neuropathy with 12-year latency between onset of neuropathy and systemic symptoms.

BACKGROUND: The differential diagnosis of chronic progressive multifocal asymmetric neuropathies is challenging. Vasculitic neuropathies, multifocal forms of chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathies, and asymmetric lower motor neuron disorders are important considerations. CASE PRESENTATION: We report a patient with an unusually long 12-year course of nonsystemic vasculitic neuropathy prior to the development of systemic manifestations. CONCLUSION: We discuss some of the difficulties involved in the diagnosis of chronic progressive multifocal asymmetric neuropathies.

Antibodies, Antineutrophil Cytoplasmic↗