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Journal of Clinical Neuromuscular... Dec 2018This update begins with myasthenia gravis and the roles of anti-agrin and cortactin antibodies. Regarding diagnosis, a report on repeated ice pack testing is highlighted... (Review)
Review
This update begins with myasthenia gravis and the roles of anti-agrin and cortactin antibodies. Regarding diagnosis, a report on repeated ice pack testing is highlighted as are several reports on the close correlation of electrodiagnostic testing with clinical features and the response to treatment. The incidence of head drop and associated clinical and ventilatory features are gleaned from a retrospective study. We also discuss a study that assessed the predominantly symmetric and conjugate ocular findings in MuSK-myasthenia gravis. Other topics that are covered include quality of life and preoperative risk. We then summarize the positive treatment trials of subcutaneous immunoglobulin and eculizumab. Turning to Lambert-Eaton Myasthenic Syndrome, we report on an epidemiologic study performed on the veteran affairs population, the results of the DAPPER study of 3, 4 diaminopyridine, and look to the future for other treatment options involving calcium gating modifiers.
Topics: Autoantibodies; Cohort Studies; Cortactin; Electrodiagnosis; Female; Humans; Male; Myasthenia Gravis; Neuromuscular Junction; Quality of Life; Receptor Protein-Tyrosine Kinases; Receptors, Cholinergic; Retrospective Studies
PubMed: 30439753
DOI: 10.1097/CND.0000000000000218 -
Journal of Clinical Neuromuscular... Mar 2021This update covers recommendations for myasthenia gravis (MG) in patients with coronavirus 2019 disease as well as reports of the clinical features of patients with MG... (Review)
Review
This update covers recommendations for myasthenia gravis (MG) in patients with coronavirus 2019 disease as well as reports of the clinical features of patients with MG and coronavirus 2019. Updated advisory committee recommendations for the use of thymectomy in generalized MG are also provided. Other MG topics include lipoprotein receptor-4 and agrin antibody associations, factors influencing conversion of ocular to generalized MG, the use of rituximab for more recent onset disease, immunoglobulins for maintenance therapy, and fatigue and depression.
Topics: COVID-19; Humans; Myasthenia Gravis; Neuromuscular Junction; Thymectomy
PubMed: 33595998
DOI: 10.1097/CND.0000000000000345 -
Neuroscience Letters Jan 2020The receptor tyrosine kinase MuSK (muscle-specific kinase) is the key signaling molecule during the formation of a mature and functional neuromuscular junction (NMJ).... (Review)
Review
The receptor tyrosine kinase MuSK (muscle-specific kinase) is the key signaling molecule during the formation of a mature and functional neuromuscular junction (NMJ). Signal transduction events downstream of MuSK activation induce both pre- and postsynaptic differentiation, which, most prominently, includes the clustering of acetylcholine receptors (AChRs) at synaptic sites. MuSK activation requires a complex interplay between its co-receptor Lrp4 (low-density lipoprotein receptor-related protein-4), the motor neuron-derived heparan-sulfate proteoglycan Agrin and the intracellular adaptor protein Dok-7. A tight regulation of MuSK kinase activity is crucial for proper NMJ development. Defects in MuSK signaling are the cause of muscle weakness as reported in congenital myasthenic syndromes and myasthenia gravis. This review focuses on recent structure-based analyses of MuSK, Agrin, Lrp4 and Dok-7 interactions and their function during MuSK activation. Conclusions about the regulation of the MuSK kinase that were derived from molecular structures will be highlighted. In addition, the role of MuSK during development and disease will be discussed.
Topics: Agrin; Animals; Humans; LDL-Receptor Related Proteins; Muscle Proteins; Neuromuscular Junction; Neuromuscular Junction Diseases; Receptor Protein-Tyrosine Kinases; Receptors, Cholinergic
PubMed: 31811897
DOI: 10.1016/j.neulet.2019.134676 -
Seminars in Neurology Oct 2016The basic abnormality in myasthenia gravis (MG) is a reduction in acetylcholine receptors (AChRs) at neuromuscular junctions due to the effects of autoantibodies that... (Review)
Review
The basic abnormality in myasthenia gravis (MG) is a reduction in acetylcholine receptors (AChRs) at neuromuscular junctions due to the effects of autoantibodies that are directed against the AChRs in most patients, or against neighboring proteins involved in the clustering of AChRs (MuSK, LRP-4, or agrin). Clinically, MG is characterized by muscle weakness and fatigue, often in typical patterns. The diagnosis may be missed early, and depends on the recognition of clinical manifestations, the measurement of autoantibodies, and/or electrophysiological features. The treatment of MG involves the enhancement of neuromuscular transmission by anticholinesterase drugs (pyridostigmine), and by immunotherapy. Therapy should be designed to improve the clinical features quickly, and keep the symptoms in abeyance over the long term. Rapid improvement can be achieved when necessary by the administration of intravenous immunoglobulin or plasma exchange. Intermediate rates of improvement over months involve the use of adrenal corticosteroids, the calcineurin inhibitors cyclosporine or tacrolimus, and in some patients, the B-cell inhibitor rituximab. For long-term treatment, mycophenolate and azathioprine are the most effective agents. A thymectomy may also have long-term beneficial effects. The majority of MG patients can live normal lives, but most patients require lifelong treatment. The physician's skill in managing the immunotherapeutic agents and avoiding adverse side effects is of paramount importance in the treatment of MG.
Topics: Autoantibodies; Humans; Immunoglobulins, Intravenous; Myasthenia Gravis; Neuromuscular Junction; Thymectomy
PubMed: 27704496
DOI: 10.1055/s-0036-1586265 -
Current Opinion in Clinical Nutrition... May 2016Denervation is a hallmark of age-related and other types of muscle wasting. This review focuses on recent insights and current viewpoints regarding the mechanisms and... (Review)
Review
PURPOSE OF REVIEW
Denervation is a hallmark of age-related and other types of muscle wasting. This review focuses on recent insights and current viewpoints regarding the mechanisms and clinical relevance of maintaining the neuromuscular junction to counteract muscle wasting resulting from aging or neural disease/damage.
RECENT FINDINGS
Activity-dependent regulation of autophagy, the agrin-muscle specific kinase-Lrp4 signaling axis, and sympathetic modulation are principal mechanisms involved in stabilizing the neuromuscular junction. These findings are derived from several animal models and were largely confirmed by human gene expression analysis as well as insights from rare neuromuscular diseases such as amyotrophic lateral sclerosis and congenital myasthenic syndromes. Based on these insights, agrin-derived fragments are currently being evaluated as biomarkers for age-related muscle wasting. Tuning of autophagy, of the agrin pathway, and of sympathetic input are being studied as clinical treatment of muscle wasting disorders.
SUMMARY
Basic research has revealed that maintenance of neuromuscular junctions and a few signaling pathways are important in the context of age-dependent and other forms of muscle wasting. These findings have recently started to enter clinical practice, but further research needs to substantiate and refine our knowledge.
Topics: Animals; Autophagy; Gene Expression Regulation; Humans; Models, Biological; Muscle Proteins; Muscular Atrophy; Nerve Degeneration; Nerve Tissue Proteins; Neuromuscular Junction; Neuromuscular Junction Diseases; Wasting Syndrome; Wnt Signaling Pathway
PubMed: 26870889
DOI: 10.1097/MCO.0000000000000267 -
Handbook of Clinical Neurology 2016Diseases of the neuromuscular junction comprise a wide range of disorders. Antibodies, genetic mutations, specific drugs or toxins interfere with the number or function... (Review)
Review
Diseases of the neuromuscular junction comprise a wide range of disorders. Antibodies, genetic mutations, specific drugs or toxins interfere with the number or function of one of the essential proteins that control signaling between the presynaptic nerve ending and the postsynaptic muscle membrane. Acquired autoimmune disorders of the neuromuscular junction are the most common and are described here. In myasthenia gravis, antibodies to acetylcholine receptors or to proteins involved in receptor clustering, particularly muscle-specific kinase, cause direct loss of acetylcholine receptors or interfere with the agrin-induced acetylcholine receptor clustering necessary for efficient neurotransmission. In the Lambert-Eaton myasthenic syndrome (LEMS), loss of the presynaptic voltage-gated calcium channels results in reduced release of the acetylcholine transmitter. The conditions are generally recognizable clinically and the diagnosis confirmed by serologic testing and electromyography. Screening for thymomas in myasthenia or small cell cancer in LEMS is important. Fortunately, a wide range of symptomatic treatments, immunosuppressive drugs, or other immunomodulating therapies is available. Future research is directed to understanding the pathogenesis, discovering new antigens, and trying to develop disease-specific treatments.
Topics: Autoantibodies; Electromyography; Humans; Neuromuscular Junction; Neuromuscular Junction Diseases; Receptors, Cholinergic
PubMed: 27112691
DOI: 10.1016/B978-0-444-63432-0.00024-4 -
Cell Reports. Medicine Sep 2023The tumor microenvironment (TME) is influenced by a "disorganized" extracellular matrix (ECM) that sensitizes cancer cells toward mechanical stress, signaling, and... (Review)
Review
The tumor microenvironment (TME) is influenced by a "disorganized" extracellular matrix (ECM) that sensitizes cancer cells toward mechanical stress, signaling, and structural alterations. In hepatocellular carcinoma (HCC), lack of knowledge about key ECM proteins driving the TME refractory to targeted therapies poses a barrier to the identification of new therapeutic targets. Herein, we discuss the contributions of various ECM components that impact hepatocytes and their surrounding support network during tumorigenesis. In addition, the underpinnings by which ECM proteins transduce mechanical signals to the liver TME are detailed. Finally, in view of the bidirectional feedback between the ECM, transformed hepatocytes, and immune cells, we highlight the potential role of the ECM disorganization process in shaping responses to immune checkpoint inhibitors and targeted therapies. Our comprehensive characterization of these ECM components may provide a roadmap for innovative therapeutic approaches to restrain HCC.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Extracellular Matrix; Hepatocytes; Tumor Microenvironment
PubMed: 37652015
DOI: 10.1016/j.xcrm.2023.101170 -
Journal of Neuroimmunology May 2024The article highlights upcoming potential treatments, which target different phases of inflammation and offer remyelinating strategies as well as direct and indirect... (Review)
Review
BACKGROUND
The article highlights upcoming potential treatments, which target different phases of inflammation and offer remyelinating strategies as well as direct and indirect neuroprotective and oligodendrocyte protective effects, providing a hopeful outlook for patients with primary and secondary progressive multiple sclerosis (PPMS and SPMS).
OBJECTIVES
The review aims to identify potential treatments and ongoing clinical trials for PPMS and SPMS, and compare their mechanisms of action, efficacy, and side effects with current treatments.
METHODS
We reviewed ongoing clinical trials for PPMS and SPMS on the NIH website, as well as articles from PubMed, Embase, and clinicaltrails.gov since 2010.
RESULTS
BTKIs like, tolebrutinib, and fenebrutinib are being explored as potential PMS treatments. Vidofludimus calcium, an orally available treatment, has shown a reduction of active and new MRI lesions. Other treatments like simvastatin, N-acetylcysteine (NAC), and alpha-lipoic acid are being explored for their antioxidant properties. AHSCT and mesenchymal stem cell therapy are experimental options for younger patients with high inflammatory activity.
CONCLUSIONS
SPMS and PPMS are being studied for new treatments and future trials should consider combination therapies targeting inflammation, demyelination, and neuronal death, as the pathogenesis of PMS involves complex factors.
Topics: Animals; Humans; Multiple Sclerosis, Chronic Progressive; Agammaglobulinaemia Tyrosine Kinase
PubMed: 38554666
DOI: 10.1016/j.jneuroim.2024.578315 -
Matrix Biology : Journal of the... Jan 2017Basement membranes are delicate, nanoscale and pliable sheets of extracellular matrices that often act as linings or partitions in organisms. Previously considered as... (Review)
Review
Basement membranes are delicate, nanoscale and pliable sheets of extracellular matrices that often act as linings or partitions in organisms. Previously considered as passive scaffolds segregating polarized cells, such as epithelial or endothelial cells, from the underlying mesenchyme, basement membranes have now reached the center stage of biology. They play a multitude of roles from blood filtration to muscle homeostasis, from storing growth factors and cytokines to controlling angiogenesis and tumor growth, from maintaining skin integrity and neuromuscular structure to affecting adipogenesis and fibrosis. Here, we will address developmental, structural and biochemical aspects of basement membranes and discuss some of the pathogenetic mechanisms causing diseases linked to abnormal basement membranes.
Topics: Agrin; Animals; Basement Membrane; Bone Diseases, Developmental; Collagen Type IV; Diabetic Nephropathies; Extracellular Matrix; Gene Expression Regulation; Heparan Sulfate Proteoglycans; Humans; Laminin; Lupus Nephritis; Mechanotransduction, Cellular; Membrane Glycoproteins; Mutation; Protein Isoforms
PubMed: 28040522
DOI: 10.1016/j.matbio.2016.12.009 -
Cellular and Molecular Life Sciences :... Jan 2016As the primary protective barrier for neurons in the brain, the blood-brain barrier (BBB) exists between the blood microcirculation system and the brain parenchyma. The... (Review)
Review
As the primary protective barrier for neurons in the brain, the blood-brain barrier (BBB) exists between the blood microcirculation system and the brain parenchyma. The normal BBB integrity is essential in protecting the brain from systemic toxins and maintaining the necessary level of nutrients and ions for neuronal function. This integrity is mediated by structural BBB components, such as tight junction proteins, integrins, annexins, and agrin, of a multicellular system including endothelial cells, astrocytes, pericytes, etc. BBB dysfunction is a significant contributor to the pathogeneses of a variety of brain disorders. Many signaling factors have been identified to be able to control BBB permeability through regulating the structural components. Among those signaling factors are inflammatory mediators, free radicals, vascular endothelial growth factor, matrix metalloproteinases, microRNAs, etc. In this review, we provide a summary of recent progress regarding these structural components and signaling factors, relating to their roles in various brain disorders. Attention is also devoted to recent research regarding impact of pharmacological agents such as isoflurane on BBB permeability and how iron ion passes across BBB. Hopefully, a better understanding of the factors controlling BBB permeability helps develop novel pharmacological interventions of BBB hyperpermeability under pathological conditions.
Topics: Agrin; Anesthetics; Animals; Annexins; Blood-Brain Barrier; Brain Diseases; Capillary Permeability; Cytokines; Eicosanoids; Humans; Integrins; Iron; MicroRNAs; Platelet Endothelial Cell Adhesion Molecule-1; Receptor-Like Protein Tyrosine Phosphatases, Class 3; Signal Transduction; Tight Junction Proteins
PubMed: 26403789
DOI: 10.1007/s00018-015-2050-8