| 1. |
- Piehl, F., et al.
(författare)
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Efficacy and Safety of Rituximab for New-Onset Generalized Myasthenia Gravis The RINOMAX Randomized Clinical Trial
- 2022
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Ingår i: Jama Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157.
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Rituximab is a third-line option for refractory generalized myasthenia gravis (MG) based on empirical evidence, but its effect in new-onset disease is unknown. OBJECTIVE To investigate the efficacy and safety of rituximab compared with placebo as an add-on to standard of care for MG. DESIGN, SETTING, AND PARTICIPANTS This randomized, double-blind, placebo-controlled study took place throughout 48 weeks at 7 regional clinics in Sweden. Key inclusion criteria were age older than 18 years, onset of generalized symptoms within 12 months or less, and a Quantitative Myasthenia Gravis (QMG) score of 6 or more. Patients were screened from October 20, 2016, to March 2, 2020. Key exclusion criteria included pure ocular MG, suspected thymoma, previous thymectomy, and prior noncorticosteroid immunosuppressants or high doses of corticosteroids. INTERVENTIONS Participants were randomized 1:1 without stratification to a single intravenous infusion of 500 mg of rituximab or matching placebo. MAIN OUTCOMES AND MEASURES Minimal disease manifestations at 16 weeks defined as a QMG score of 4 or less with prednisolone, 10 mg or less daily, and no rescue treatment. RESULTS Of 87 potentially eligible patients, 25 were randomized to rituximab (mean [SD] age, 67.4 [13.4] years; 7 [28%] female) and 22 to placebo (mean [SD] age, 58 [18.6] years; 7 [32%] female). Compared with placebo, a greater proportion with rituximab met the primary end point; 71% (17 of 24) in the rituximab group vs 29% (6 of 21) in the placebo group (Fisher exact test P = .007; probability ratio, 2.48 [95% CI, 1.20-5.11]). Secondary end points, comparing changes in Myasthenia Gravis Activities of Daily Living and Myasthenia Gravis Quality of Life at 16 weeks with QMG at 24 weeks did not differ between groups with censoring for rescue treatment (per-protocol analysis) but were in favor of active treatment when rescue treatment was taken into account by worst rank imputation (post hoc analysis). Rescue treatments were also more frequent in the placebo arm (rituximab: 1 [4%]; placebo, 8 [36%]). One patient in the placebo arm had a myocardial infarction with cardiac arrest and 1 patient in the active arm experienced a fatal cardiac event. CONCLUSIONS AND RELEVANCE A single dose of 500 mg of rituximab was associated with greater probability of minimal MG manifestations and reduced need of rescue medications compared with placebo. Further studies are needed to address long-term benefit-risk balance with this treatment.
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| 2. |
- Feugnet, G., et al.
(författare)
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Improved laser-induced fluorescence method for bio-attack early warning detection system
- 2008
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Ingår i: Proceedings of SPIE - The International Society for Optical Engineering. - : SPIE.
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Konferensbidrag (refereegranskat)abstract
- Laser Induced Fluorescence (LIF) could permit fast early warning systems either for point or standoff detection if a reliable classification of warfare biological agents versus biological or non-biological fluorescing background can be achieved. In order to improve LIF discrimination capability, a new system is described in which the fluorescence pattern is enriched by the use of multiple wavelength delayed excitation while usual spectral fluorescence analysis is extended to time domain to use both aspects as criteria for classification. General considerations and guidelines for the system design are given as well as results showing good discrimination between background and simulants.
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| 3. |
- Vergoossen, Dana L. E., et al.
(författare)
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Enrichment of serum IgG4 in MuSK myasthenia gravis patients
- 2022
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Ingår i: Journal of Neuroimmunology. - : Elsevier. - 0165-5728 .- 1872-8421. ; 373
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Tidskriftsartikel (refereegranskat)abstract
- Muscle-specific kinase (MuSK) myasthenia gravis (MG) is a neuromuscular autoimmune disease belonging to a growing group of IgG4 autoimmune diseases (IgG4-AIDs), in which the majority of pathogenic autoantibodies are of the IgG4 subclass. The more prevalent form of MG with acetylcholine receptor (AChR) antibodies is caused by IgG1-3 autoantibodies. A dominant role for IgG4 in autoimmune disease is intriguing due to its antiinflammatory characteristics. It is unclear why MuSK autoantibodies are predominantly IgG4. We hypothesized that MuSK MG patients have a general predisposition to generate IgG4 responses, therefore resulting in high levels of circulating IgG4. To investigate this, we quantified serum Ig isotypes and IgG subclasses using nephelometric and turbidimetric assays in MuSK MG and AChR MG patients not under influence of immunosuppressive treatment. Absolute serum IgG1 was increased in both MuSK and AChR MG patients compared to healthy donors. In addition, only MuSK MG patients on average had significantly increased and enriched serum IgG4. Although more MuSK MG patients had elevated serum IgG4, for most the IgG4 serum levels fell within the normal range. Correlation analyses suggest MuSK-specific antibodies do not solely explain the variation in IgG4 levels. In conclusion, although serum IgG4 levels are slightly increased, the levels do not support ubiquitous IgG4 responses in MuSK MG patients as the underlying cause of dominant IgG4 MuSK antibodies.
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| 4. |
- Fiorillo, Alyson A., et al.
(författare)
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Estrogen Receptor, Inflammatory, and FOXO Transcription Factors Regulate Expression of Myasthenia Gravis-Associated Circulating microRNAs
- 2020
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Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate important intracellular biological processes. In myasthenia gravis (MG), a disease-specific pattern of elevated circulating miRNAs has been found, and proposed as potential biomarkers. These elevated miRNAs include miR-150-5p, miR-21-5p, and miR-30e-5p in acetylcholine receptor antibody seropositive (AChR+) MG and miR-151a-3p, miR-423-5p, let-7a-5p, and let-7f-5p in muscle-specific tyrosine kinase antibody seropositive (MuSK+) MG. In this study, we examined the regulation of each of these miRNAs using chromatin immunoprecipitation sequencing (ChIP-seq) data from the Encyclopedia of DNA Elements (ENCODE) to gain insight into the transcription factor pathways that drive their expression in MG. Our aim was to look at the transcription factors that regulate miRNAs and then validate some of those in vivo with cell lines that have sufficient expression of these transcription factors This analysis revealed several transcription factor families that regulate MG-specific miRNAs including the Forkhead box or the FOXO proteins (FoxA1, FoxA2, FoxM1, FoxP2), AP-1, interferon regulatory factors (IRF1, IRF3, IRF4), and signal transducer and activator of transcription proteins (Stat1, Stat3, Stat5a). We also found binding sites for nuclear factor of activated T-cells (NFATC1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B), early growth response factor (EGR1), and the estrogen receptor 1 (ESR1). AChR+ MG miRNAs showed a stronger overall regulation by the FOXO transcription factors, and of this group, miR-21-5p, let-7a, and let 7f were found to possess ESR1 binding sites. Using a murine macrophage cell line, we found activation of NF-kappa B -mediated inflammation by LPS induced expression of miR-21-5p, miR-30e-5p, miR-423-5p, let-7a, and let-7f. Pre-treatment of cells with the anti-inflammatory drugs prednisone or deflazacort attenuated induction of inflammation-induced miRNAs. Interestingly, the activation of inflammation induced packaging of the AChR+-specific miRNAs miR-21-5p and miR-30e-5p into exosomes, suggesting a possible mechanism for the elevation of these miRNAs in MG patient serum. In conclusion, our study summarizes the regulatory transcription factors that drive expression of AChR+ and MuSK+ MG-associated miRNAs. Our findings of elevated miR-21-5p and miR-30e-5p expression in immune cells upon inflammatory stimulation and the suppressive effect of corticosteroids strengthens the putative role of these miRNAs in the MG autoimmune response.
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| 5. |
- Laaksonen, Katri, et al.
(författare)
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Nanoparticles of TiO2 and VO2 in dielectric media : Conditions for low optical scattering, and comparison between effective medium and four-flux theories
- 2014
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Ingår i: Solar Energy Materials and Solar Cells. - : Saunders Elsevier. - 0927-0248 .- 1879-3398. ; 130:SI, s. 132-137
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Tidskriftsartikel (refereegranskat)abstract
- Spectral transmittance and reflectance in the 300 to 2500 nm solar-optical wavelength range were calculated for nanoparticles of titanium dioxide and vanadium dioxide with radii between 5 and 100 nm embedded in transparent dielectric media. Both of the materials are of large importance in green nanotechnologies: thus TiO2 is a photocatalyst that can be applied as a porous film or a nanoparticle composite on indoor or outdoor surfaces for environmental remediation, and VO2 is a thermochromic material with applications to energy-efficient fenestration. The optical properties, including scattering, of the nanoparticle composites were computed from the Maxwell–Garnett effective-medium theory as well as from a four-flux radiative transfer model. Predictions from these theories approach one another in the limit of small particles and in the absence of optical interference. Effects of light scattering can be modeled only by the four-flux theory, though. We found that nanoparticle radii should be less than ~20 nm in order to avoid pronounced light scattering.
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| 6. |
- Meinen, Sarina, et al.
(författare)
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Fatigue and Muscle Atrophy in a Mouse Model of Myasthenia Gravis Is Paralleled by Loss of Sarcolemmal nNOS
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:8, s. e44148-
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Tidskriftsartikel (refereegranskat)abstract
- Myasthenia Gravis (MG) patients suffer from chronic fatigue of skeletal muscles, even after initiation of proper immunosuppressive medication. Since the localization of neuronal nitric oxide synthase (nNOS) at the muscle membrane is important for sustained muscle contraction, we here study the localization of nNOS in muscles from mice with acetylcholine receptor antibody seropositive (AChR+) experimental autoimmune MG (EAMG). EAMG was induced in 8 week-old male mice by immunization with AChRs purified from torpedo californica. Sham-injected wild type mice and mdx mice, a model for Duchenne muscular dystrophy, were used for comparison. At EAMG disease grade 3 (severe myasthenic weakness), the triceps, sternomastoid and masseter muscles were collected for analysis. Unlike in mdx muscles, total nNOS expression as well as the presence of its binding partner syntrophin alpha-1, were not altered in EAMG. Immunohistological and biochemical analysis showed that nNOS was lost from the muscle membrane and accumulated in the cytosol, which is likely the consequence of blocked neuromuscular transmission. Atrophy of all examined EAMG muscles were supported by upregulated transcript levels of the atrogenes atrogin-1 and MuRF1, as well as MuRF1 protein, in combination with reduced muscle fiber diameters. We propose that loss of sarcolemmal nNOS provides an additional mechanism for the chronic muscle fatigue and secondary muscle atrophy in EAMG and MG.
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| 7. |
- Pazarlis, Konstantinos A., et al.
(författare)
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Study protocol for a randomised controlled trial with clinical, neurophysiological, laboratory and radiological outcome for surgical versus non-surgical treatment for lumbar spinal stenosis : the Uppsala Spinal Stenosis Trial (UppSten)
- 2019
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Ingår i: BMJ Open. - : BMJ PUBLISHING GROUP. - 2044-6055. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Symptomatic lumbar spinal stenosis is the most common indication for spinal surgery. However, more than one-third of the patients undergoing surgery for lumbar stenosis report dissatisfaction with the results. On the other hand, conservative treatment has shown positive results in some cases. This trial will compare the outcomes of surgical versus non-surgical treatment for lumbar stenosis. The study includes a multidimensional follow-up, aiming to study the association between outcome and other studied parameters, mainly electromyography and nerve conduction. Moreover, it may contribute to a better understanding of the pathophysiology of lumbar stenosis and to the development of future pharmacological treatments.Methods and analysis: UppSten is a single-centre randomised controlled trial in which 150 patients with symptomatic lumbar spinal stenosis will be randomised into one of two treatment arms. The patients in the surgical arm will undergo laminectomy; the patients in the non-surgical arm will be given a structured physical training programme. The primary outcome of the study will be the Oswestry Disability Index. Secondary outcomes will include motor amplitude and degree of denervation activity obtained by means of nerve conduction studies and electromyography. Patient-reported outcome measures will be also used as secondary outcomes. Blood sample analysis and the investigation of potential inflammation markers are the additional secondary outcome parameters. Laboratory evaluation will include blood sample collection before the treatment initiation and after 6 months. Flavum ligament biopsies will be performed in the surgical group. Finally, tertiary outcomes will include neurophysiological measures, the objective walking ability and radiological evaluation.Ethics and dissemination: The study is approved by the Local Ethics Committee (Dnr 2017-506), the Hospital's Clinical Trials Committee (2018-0001) and the National Biobank Council and Uppsala Biobank (BbA-827-2018-025).
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| 8. |
- Phillips, W D, et al.
(författare)
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Guidelines for pre-clinical animal and cellular models of MuSK-myasthenia gravis
- 2015
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 270:SI, s. 29-40
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Tidskriftsartikel (refereegranskat)abstract
- Muscle-specific tyrosine kinase (MuSK) autoantibodies are the hallmark of a form of myasthenia gravis (MG) that can challenge the neurologist and the experimentalist. The clinical disease can be difficult to treat effectively. MuSK autoantibodies affect the neuromuscular junction in several ways. When added to muscle cells in culture, MuSK antibodies disperse acetylcholine receptor clusters. Experimental animals actively immunized with MuSK develop MuSK autoantibodies and muscle weakness. Weakness is associated with reduced postsynaptic acetylcholine receptor numbers, reduced amplitudes of miniature endplate potentials and endplate potentials, and failure of neuromuscular transmission. Similar impairments have been found in mice injected with IgG from MG patients positive for MuSK autoantibody (MuSK-MG). The active and passive models have begun to reveal the mechanisms by which MuSK antibodies disrupt synaptic function at the neuromuscular junction, and should be valuable in developing therapies for MuSK-MG. However, translation into new and improved treatments for patients requires procedures that are not too cumbersome but suitable for examining different aspects of MuSK function and the effects of potential therapies. Study design, conduct and analysis should be carefully considered and transparently reported. Here we review what has been learnt from animal and culture models of MuSK-MG, and offer guidelines for experimental design and conduct of studies, including sample size determination, randomization, outcome parameters and precautions for objective data analysis. These principles may also be relevant to the increasing number of other antibody-mediated diseases that are now recognized.
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| 9. |
- Rostedt Punga, Anna, et al.
(författare)
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Muscle-selective synaptic disassembly and reorganization in MuSK antibody positive MG mice
- 2011
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 230:2, s. 207-217
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Tidskriftsartikel (refereegranskat)abstract
- MuSK antibody seropositive (MuSK+) Myasthenia Gravis (MG) patients present a distinct selective fatigue, and sometimes atrophy, of bulbar, facial and neck muscles. Here, we study the mechanism underlying the focal muscle involvement in mice with MuSK+ experimental autoimmune MG (EAMG). 8 week-old female wildtype C57BL6 mice and transgenic mice, which express yellow fluorescence protein (YFP) in their motor neurons, were immunized with the extracellular domain of rat MuSK and compared with control mice. The soleus, EDL, sternomastoid, omohyoid, thoracic paraspinal and masseter muscles were examined for pre- and postsynaptic changes with whole mount immunostaining and confocal microscopy. Neuromuscular junction derangement was quantified and compared between muscles and correlated with transcript levels of MuSK and other postsynaptic genes. Correlating with the EAMG disease grade, the postsynaptic acetylcholine receptor (AChR) clusters were severely fragmented with a subsequent reduction also of the presynaptic nerve terminal area. Among the muscles analyzed, the thoracic paraspinal, sternomastoid and masseter muscles were more affected than the leg muscles. The masseter muscle was the most affected, leading to denervation and atrophy and this severity correlated with the lowest levels of MuSK mRNA. On the contrary, the soleus with high MuSK mRNA levels had less postsynaptic perturbation and more terminal nerve sprouting. We propose that low muscle-intrinsic MuSK levels render some muscles, such as the masseter, more vulnerable to the postsynaptic perturbation of MuSK antibodies with subsequent denervation and atrophy. These findings augment our understanding of the sometimes severe, facio-bulbar phenotype of MuSK+ MG.
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| 10. |
- Rostedt Punga, Anna, et al.
(författare)
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Signaling and aging at the neuromuscular synapse : lessons learnt from neuromuscular diseases
- 2012
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Ingår i: Current opinion in pharmacology (Print). - : Elsevier BV. - 1471-4892 .- 1471-4973. ; 12:3, s. 340-346
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Tidskriftsartikel (refereegranskat)abstract
- The neuromuscular junction (NMJ) is a specialized synapse between motor neurons and skeletal muscle with a complex signaling network that assures highly reliable neuromuscular transmission. Diseases of the NMJ cause skeletal muscle fatigue and include inherited and acquired disorders that affect presynaptic, intrasynaptic or postsynaptic components. Moreover, fragmentation of the NMJ contributes to sarcopenia, the loss of muscle mass during aging. Studies from recent years indicate that the formation and stabilization of NMJs differs between various muscles and that this difference affects their response under pathological conditions. This review summarizes the most important mechanisms involved in the development, maintenance and dysfunction of the NMJ and it discusses their significance in myasthenic disorders and aging and as targets for possible future treatment of NMJ dysfunction.
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