-
Cureus Jun 2024Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal plasma cell disorder characterized by monoclonal immunoglobulins and/or an abnormal...
Uncommon Presentation of IgM Monoclonal Gammopathy of Undetermined Significance (MGUS) and Anti-Myelin-Associated Glycoprotein (MAG)-Associated Demyelinating Peripheral Neuropathy as Respiratory Failure: A Case Report.
Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal plasma cell disorder characterized by monoclonal immunoglobulins and/or an abnormal free immunoglobulin light chain ratio. MGUS can be associated with immune-mediated neuropathies, including chronic inflammatory demyelinating neuropathy and its variants. Here, we report the case of a 76-year-old male who presented with progressive weakness, initially in the lower extremities and later including the upper extremities. Serum protein electrophoresis and immunofixation identified an IgM kappa monoclonal protein and further testing confirmed high titers of anti-myelin-associated glycoprotein (MAG) antibodies, leading to a diagnosis of anti-MAG-associated demyelinating peripheral neuropathy. The coexistence of MGUS and anti-MAG antibodies requires meticulous diagnosis and management, especially in patients who present with atypical symptoms of the disease.
PubMed: 38912071
DOI: 10.7759/cureus.62865 -
Frontiers in Immunology 2024Although fingolimod, a sphingosine 1-phosphate receptor agonist, has shown to be an effective treatment reducing relapse rate and also slowing down the disability...
BACKGROUND
Although fingolimod, a sphingosine 1-phosphate receptor agonist, has shown to be an effective treatment reducing relapse rate and also slowing down the disability progression in relapsing-remitting multiple sclerosis (RRMS) patients, it is important to quickly identify those suboptimal responders.
OBJECTIVE
The main objective was to assess different clinical, radiological, genetic and environmental factors as possible early predictors of response in MS patients treated with fingolimod for 24 months. The secondary objective was to analyze the possible contribution of the environmental factors analyzed to the progression and activity of the disease along the 2-years of follow-up.
METHODS
A retrospective study with 151 patients diagnosed with MS, under fingolimod treatment for 24 months, with serum samples at initiation and six months later, and with clinical and radiological data at initiation and 24 months later, were included in the study. Clinical and radiological variables were collected to establish NEDA-3 (no evidence of disease activity: patients without relapses, disability progression and new T2 lesions or Gd+ lesions) and EDA (evidence of disease activity: patients with relapses and/or progression and/or new T2 lesions or gadolinium-positive [Gd+] lesions) conditions. Human leukocyte antigen II (HLA-II), EBNA-1 IgG and VCA IgG from Epstein-Barr virus (EBV) and antibody titers against Human herpesvirus 6A/B (HHV-6A/B) were also analyzed.
RESULTS
A total of 151 MS patients fulfilled the inclusion criteria: 27.8% was NEDA-3 (37.5% among those previously treated with high efficacy therapies >24 months). The following early predictors were statistically significantly associated with NEDA-3 condition: sex (male; p=0.002), age at baseline (older; p=0.009), relapses 2-years before fingolimod initiation ≤1 (p=0.010), and absence of Gd+ lesions at baseline (p=0.006). Regarding the possible contribution of the environmental factors included in the study to the activity or the progression of the disease, we only found that EBNA-1 IgG titers decreased in 20.0% of PIRA (progression independent from relapse activity) patients vs. 73.3% of RAW (relapse-associated worsening) patients (p=0.006; O.R. = 11.0).
CONCLUSION
MS patients that are male, older, and with a low clinical and radiological activity at fingolimod initiation have a greater probability to reach NEDA-3 condition after two years with this therapy. An intriguing association of EBV with the progression of the disease has also been described, but it should be further study in a larger cohort to confirm these results.
Topics: Humans; Fingolimod Hydrochloride; Female; Male; Disease Progression; Adult; Epstein-Barr Virus Nuclear Antigens; Retrospective Studies; Immunoglobulin G; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Treatment Outcome; Immunosuppressive Agents; Multiple Sclerosis
PubMed: 38911861
DOI: 10.3389/fimmu.2024.1384411 -
Frontiers in Immunology 2024Bilateral facial palsy with paresthesia (FDP) is a rare variant of GBS, characterized by simultaneous bilateral facial palsy and paresthesia of the distal limbs....
Bilateral facial palsy with paresthesia (FDP) is a rare variant of GBS, characterized by simultaneous bilateral facial palsy and paresthesia of the distal limbs. Mounting evidence indicates that the presence of anti-GT1a IgG has a pathogenic role as an effector molecule in the development of cranial nerve palsies in certain patients with GBS, whereas anti-GT1a antibody is rarely presented positive in FDP. Here, we report the case of a 33-year-old male diagnosed with FDP presented with acute onset of bilateral facial palsy and slight paresthesias at the feet as the only neurological manifestation. An antecedent infection with no identifiable reason for the fever or skin eruptions was noted in the patient. He also exhibited cerebrospinal fluid albuminocytologic dissociation and abnormal nerve conduction studies. Notably, the testing of specific serum anti-gangliosides showed positive anti-GT1a IgG/IgM Ab. The patient responded well to intravenous immunoglobulin therapy. This case brings awareness to a rare variant of GBS, and provides the first indication that anti-GT1a antibodies play a causative role in the development of FDP. The case also suggests that prompt management with IVIG should be implemented if FDP is diagnosed.
Topics: Humans; Male; Adult; Paresthesia; Facial Paralysis; Autoantibodies; Gangliosides; Immunoglobulins, Intravenous; Immunoglobulin G; Guillain-Barre Syndrome
PubMed: 38911860
DOI: 10.3389/fimmu.2024.1410634 -
Frontiers in Immunology 2024Secondary progressive multiple sclerosis (SPMS) is defined by the irreversible accumulation of disability following a relapsing-remitting MS (RRMS) course. Despite...
BACKGROUND
Secondary progressive multiple sclerosis (SPMS) is defined by the irreversible accumulation of disability following a relapsing-remitting MS (RRMS) course. Despite treatments advances, a reliable tool able to capture the transition from RRMS to SPMS is lacking. A T cell chimeric MS model demonstrated that T cells derived from relapsing patients exacerbate excitatory transmission of central neurons, a synaptotoxic event absent during remitting stages. We hypothesized the re-emergence of T cell synaptotoxicity during SPMS and investigated the synaptoprotective effects of siponimod, a sphingosine 1-phosphate receptor (S1PR) modulator, known to reduce grey matter damage in SPMS patients.
METHODS
Data from healthy controls (HC), SPMS patients, and siponimod-treated SPMS patients were collected. Chimeric experiments were performed incubating human T cells on murine cortico-striatal slices, and recording spontaneous glutamatergic activity from striatal neurons. Homologous chimeric experiments were executed incubating EAE mice T cells with siponimod and specific S1PR agonists or antagonists to identify the receptor involved in siponimod-mediated synaptic recovery.
RESULTS
SPMS patient-derived T cells significantly increased the striatal excitatory synaptic transmission (n=40 synapses) compared to HC T cells (n=55 synapses), mimicking the glutamatergic alterations observed in active RRMS-T cells. Siponimod treatment rescued SPMS T cells synaptotoxicity (n=51 synapses). Homologous chimeric experiments highlighted S1P5R involvement in the siponimod's protective effects.
CONCLUSION
Transition from RRMS to SPMS involves the reappearance of T cell-mediated synaptotoxicity. Siponimod counteracts T cell-induced excitotoxicity, emphasizing the significance of inflammatory synaptopathy in progressive MS and its potential as a promising pharmacological target.
Topics: Humans; Animals; Mice; Female; Multiple Sclerosis, Chronic Progressive; T-Lymphocytes; Azetidines; Benzyl Compounds; Male; Adult; Synapses; Middle Aged; Encephalomyelitis, Autoimmune, Experimental; Sphingosine 1 Phosphate Receptor Modulators; Mice, Inbred C57BL; Sphingosine-1-Phosphate Receptors; Synaptic Transmission; Neurons
PubMed: 38911847
DOI: 10.3389/fimmu.2024.1416133 -
ENeurologicalSci Jun 2024Intractable hiccups, persisting beyond 48 h, pose a clinical challenge, particularly in demyelinating diseases like Neuromyelitis Optica (NMO) and Multiple Sclerosis...
BACKGROUND
Intractable hiccups, persisting beyond 48 h, pose a clinical challenge, particularly in demyelinating diseases like Neuromyelitis Optica (NMO) and Multiple Sclerosis (MS). Understanding the complex neural pathways of the hiccup reflex and the impact of high-dose steroid therapy is crucial for managing this rare but distressing symptom. The hiccup reflex involves afferents from the vagus, phrenic, and sympathetic nerves, with the reflex center in the anterior horns at the C3 to 5 level and the medulla oblongata. The potential interplay between demyelination and corticosteroid therapy in triggering persistent hiccups requires exploration.
CASE REPORT
This case report details a 21-year-old male with undiagnosed demyelinating disorder, presenting persistent hiccups following high-dose steroid therapy for an acute disease flare. The patient's history included vertigo and progressive neurological symptoms, leading to an MS diagnosis with significant brain and spinal lesions. Persistent hiccups, initiated by steroid administration, were recurrent but responsive to metoclopramide after other measures failed.
DISCUSSION
The discussion centers on investigating the cause of hiccups in a patient with demyelination following steroid administration. Steroids' impact on neurological systems, including neurotransmitter function, and the potential disruption of neurological pathways due to demyelination may contribute to hiccups. Successful hiccup resolution with metoclopramide suggests a potential pharmacological approach for corticosteroid-induced hiccups in demyelinating diseases. This case emphasizes the need for further research into the intricate relationship between demyelination, steroid therapy, and hiccups to enhance management strategies for this uncommon yet impactful symptom.
PubMed: 38911508
DOI: 10.1016/j.ensci.2024.100509 -
Journal of Rehabilitation Medicine Jun 2024To examine the relationship between perceived and physiological strains of real-time societal participation in people with multiple sclerosis. (Observational Study)
Observational Study
OBJECTIVE
To examine the relationship between perceived and physiological strains of real-time societal participation in people with multiple sclerosis.
DESIGN
Observational study.
SUBJECTS/PATIENTS
70 people with multiple sclerosis.
METHODS
Perceived and physiological strain of societal participation (10 participation-at-location and 9 transport domains) were measured in real time using the Whereabouts smartphone app and Fitbit over 7 consecutive days. Longitudinal relationships between perceived (1 not strenuous to 10 most strenuous) and physiological strains (heart rate reserve) were examined using mixed-model analyses. Type of event (participation-at-location or transport) was added as covariate, with further adjustments for fatigue and walking ability.
RESULTS
Median perceived strain, summarized for all societal participation domains, varied between 3 and 6 (range: 1-10), whereas physiological strain varied between 18.5% and 33.2% heart rate reserve. Perceived strain (outcome) and physiological strain were not associated (β -0.001, 95%CI -0.008; 0.005, with a 7-day longitudinal correlation coefficient of -0.001). Transport domains were perceived as less strenuous (β -0.80, 95%CI -0.92; -0.68). Higher fatigue levels resulted in higher perceived strain (all societal participation domains) (β 0.05, 95%CI 0.02; 0.08).
CONCLUSION
Societal participation resulted in low-to-moderate perceived and physiological strain. Perceived and physiological strain of societal participation were unrelated and should be considered different constructs in multiple sclerosis.
Topics: Humans; Multiple Sclerosis; Male; Female; Middle Aged; Adult; Fatigue; Social Participation; Heart Rate; Perception
PubMed: 38910543
DOI: 10.2340/jrm.v56.40838 -
Lipids in Health and Disease Jun 2024Lipid droplet (LD)-laden microglia is a key pathological hallmark of multiple sclerosis. The recent discovery of this novel microglial subtype,...
BACKGROUND
Lipid droplet (LD)-laden microglia is a key pathological hallmark of multiple sclerosis. The recent discovery of this novel microglial subtype, lipid-droplet-accumulating microglia (LDAM), is notable for increased inflammatory factor secretion and diminished phagocytic capability. Lipophagy, the autophagy-mediated selective degradation of LDs, plays a critical role in this context. This study investigated the involvement of microRNAs (miRNAs) in lipophagy during demyelinating diseases, assessed their capacity to modulate LDAM subtypes, and elucidated the potential underlying mechanisms involved.
METHODS
C57BL/6 mice were used for in vivo experiments. Two weeks post demyelination induction at cervical level 4 (C4), histological assessments and confocal imaging were performed to examine LD accumulation in microglia within the lesion site. Autophagic changes were observed using transmission electron microscopy. miRNA and mRNA multi-omics analyses identified differentially expressed miRNAs and mRNAs under demyelinating conditions and the related autophagy target genes. The role of miR-223 in lipophagy under these conditions was specifically explored. In vitro studies, including miR-223 upregulation in BV2 cells via lentiviral infection, validated the bioinformatics findings. Immunofluorescence staining was used to measure LD accumulation, autophagy levels, target gene expression, and inflammatory mediator levels to elucidate the mechanisms of action of miR-223 in LDAM.
RESULTS
Oil Red O staining and confocal imaging revealed substantial LD accumulation in the demyelinated spinal cord. Transmission electron microscopy revealed increased numbers of autophagic vacuoles at the injury site. Multi-omics analysis revealed miR-223 as a crucial regulatory gene in lipophagy during demyelination. It was identified that cathepsin B (CTSB) targets miR-223 in autophagy to integrate miRNA, mRNA, and autophagy gene databases. In vitro, miR-223 upregulation suppressed CTSB expression in BV2 cells, augmented autophagy, alleviated LD accumulation, and decreased the expression of the inflammatory mediator IL-1β.
CONCLUSION
These findings indicate that miR-223 plays a pivotal role in lipophagy under demyelinating conditions. By inhibiting CTSB, miR-223 promotes selective LD degradation, thereby reducing the lipid burden and inflammatory phenotype in LDAM. This study broadens the understanding of the molecular mechanisms of lipophagy and proposes lipophagy induction as a potential therapeutic approach to mitigate inflammatory responses in demyelinating diseases.
Topics: Animals; MicroRNAs; Microglia; Mice; Autophagy; Lipid Droplets; Mice, Inbred C57BL; Demyelinating Diseases; Cathepsin B; Lysophosphatidylcholines; Disease Models, Animal; Male; Gene Expression Regulation; Cell Line
PubMed: 38909243
DOI: 10.1186/s12944-024-02185-y -
Scientific Data Jun 2024The development of platforms for distributed analytics has been driven by a growing need to comply with various governance-related or legal constraints. Among these...
The development of platforms for distributed analytics has been driven by a growing need to comply with various governance-related or legal constraints. Among these platforms, the so-called Personal Health Train (PHT) is one representative that has emerged over the recent years. However, in projects that require data from sites featuring different PHT infrastructures, institutions are facing challenges emerging from the combination of multiple PHT ecosystems, including data governance, regulatory compliance, or the modification of existing workflows. In these scenarios, the interoperability of the platforms is preferable. In this work, we introduce a conceptual framework for the technical interoperability of the PHT covering five essential requirements: Data integration, unified station identifiers, mutual metadata, aligned security protocols, and business logic. We evaluated our concept in a feasibility study that involves two distinct PHT infrastructures: PHT-meDIC and PADME. We analyzed data on leukodystrophy from patients in the University Hospitals of Tübingen and Leipzig, and patients with differential diagnoses at the University Hospital Aachen. The results of our study demonstrate the technical interoperability between these two PHT infrastructures, allowing researchers to perform analyses across the participating institutions. Our method is more space-efficient compared to the multi-homing strategy, and it shows only a minimal time overhead.
Topics: Humans; Data Analysis; Hereditary Central Nervous System Demyelinating Diseases; Health Information Interoperability
PubMed: 38909050
DOI: 10.1038/s41597-024-03450-6 -
Peptides Jun 2024Signs and symptoms of hypernatremia largely indicate central nervous system dysfunction. Acute hypernatremia can cause demyelinating lesions similar to that observed in...
Signs and symptoms of hypernatremia largely indicate central nervous system dysfunction. Acute hypernatremia can cause demyelinating lesions similar to that observed in osmotic demyelination syndrome (ODS). We have previously demonstrated that microglia accumulate in ODS lesions and minocycline protects against ODS by inhibiting microglial activation. However, the direct effect of rapid rise in the sodium concentrations on microglia is largely unknown. In addition, the effect of chronic hypernatremia on microglia also remains elusive. Here, we investigated the effects of acute (6 or 24 h) and chronic (the extracellular sodium concentration was increased gradually for at least 7 days) high sodium concentrations on microglia using the microglial cell line, BV-2. We found that both acute and chronic high sodium concentrations increase NOS2 expression and nitric oxide (NO) production. We also demonstrated that the expression of nuclear factor of activated T-cells-5 (NFAT5) is increased by high sodium concentrations. Furthermore, NFAT5 knockdown suppressed NOS2 expression and NO production. We also demonstrated that high sodium concentrations decreased intracellular Ca concentration and an inhibitor of Na/Ca exchanger, NCX, suppressed a decrease in intracellular Ca concentrations and NOS2 expression and NO production induced by high sodium concentrations. Furthermore, minocycline inhibited NOS2 expression and NO production induced by high sodium concentrations. These in vitro data suggest that microglial activity in response to high sodium concentrations is regulated by NFAT5 and Ca efflux through NCX and is suppressed by minocycline.
PubMed: 38908517
DOI: 10.1016/j.peptides.2024.171267 -
Biomedicine & Pharmacotherapy =... Jun 2024Cyclic adenosine monophosphate (cAMP) is a key second messenger that regulates signal transduction pathways pivotal for numerous biological functions. Intracellular cAMP... (Review)
Review
Cyclic adenosine monophosphate (cAMP) is a key second messenger that regulates signal transduction pathways pivotal for numerous biological functions. Intracellular cAMP levels are spatiotemporally regulated by their hydrolyzing enzymes called phosphodiesterases (PDEs). It has been shown that increased cAMP levels in the central nervous system (CNS) promote neuroplasticity, neurotransmission, neuronal survival, and myelination while suppressing neuroinflammation. Thus, elevating cAMP levels through PDE inhibition provides a therapeutic approach for multiple CNS disorders, including multiple sclerosis, stroke, spinal cord injury, amyotrophic lateral sclerosis, traumatic brain injury, and Alzheimer's disease. In particular, inhibition of the cAMP-specific PDE4 subfamily is widely studied because of its high expression in the CNS. So far, the clinical translation of full PDE4 inhibitors has been hampered because of dose-limiting side effects. Hence, focusing on signaling cascades downstream activated upon PDE4 inhibition presents a promising strategy, offering novel and pharmacologically safe targets for treating CNS disorders. Yet, the underlying downstream signaling pathways activated upon PDE(4) inhibition remain partially elusive. This review provides a comprehensive overview of the existing knowledge regarding downstream mediators of cAMP signaling induced by PDE4 inhibition or cAMP stimulators. Furthermore, we highlight existing gaps and future perspectives that may incentivize additional downstream research concerning PDE(4) inhibition, thereby providing novel therapeutic approaches for CNS disorders.
PubMed: 38908196
DOI: 10.1016/j.biopha.2024.117009