To study disease severity and response to therapy in a large cohort of patients with anti-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)-associated myositis.
Muscle strength, creatine kinase ...levels and treatments were assessed in anti-HMGCR-positive patients at each clinical visit. Univariate and multivariate analyses were used to analyse the influence of clinical characteristics on strength and the change in strength over time. Whole exome sequencing was performed in a subset of patients.
. Among 50 patients followed for ⩾2 years, only 22 (44%) reached full strength with immunosuppressive therapy; even among those with full strength, 55% continued to have CK levels in excess of 500 IU/l and only three could be tapered off immunosuppressive therapy. Both univariate and multivariate analysis showed that patients who were older at disease onset were stronger at all time points (P < 0.001) and improved faster (P < 0.008) than younger patients; a history of statin exposure was not independently associated with the improvement rate. Younger patients were more likely to have refractory disease (P = 0.02) than older patients. Among eight refractory patients with DNA available for testing, whole exome sequencing did not reveal pathogenic mutations in known dystrophy genes. The risk of cancer was not increased in anti-HMGCR myositis patients compared with the general population.
Anti-HMGCR myositis is usually a chronic disease requiring long-term immunosuppression. Although younger patients had more severe disease and a worse prognosis than older patients, they did not have evidence of a known co-existing muscular dystrophy to explain their persistent, and sometimes progressive, muscle weakness.
Currently, the ability for imaging to capture brain adaptations to injury that occurs in multiple sclerosis (MS) is limited. In particular, how the brain initially contends with the earliest clinical ...manifestations of white matter injury has yet to be defined. The purpose of this study was to determine the impact of acute optic neuritis (ON) on resting state functional connectivity magnetic resonance imaging (rs-fcMRI).
Fifteen patients with a clinically isolated syndrome of acute ON were evaluated at an academic center in a prospective study. Subjects were assessed with structural and functional vision measures, including optical coherence tomography (OCT), high- and low-contrast letter acuity testing, and visual fields and quality-of-life measures (VFQ-25). The rs-fcMRI was compared with age- and sex-matched healthy controls.
We observed reduced functional connectivity within the visual system and a loss of anticorrelations between the visual system and nonvisual networks. Stronger functional connectivity between visual regions correlated with better quality of life, as measured by the VFQ-25, and better acuity scores for both high- and low-contrast testing in the affected eye.
The rs-fcMRI functional connectivity changes within (intranetwork) and between (internetwork) resting state networks occur after acute ON, indicating immediate cortical responses to focal inflammatory demyelination. Thus, focal white matter injury in the central nervous system acutely results in widespread network alterations that may lead to functional neurologic changes seen in MS.
The expression of Trim33 (Tif1γ) increases in skeletal muscles during regeneration and decreases upon maturation. Although Trim33 is required for the normal development of other tissues, its role in ...skeletal muscle is unknown. The current study aimed to define the role of Trim33 in muscle development and regeneration. We generated mice with muscle-specific conditional knockout of Trim33 by combining floxed Trim33 and Cre recombinase under the Pax7 promoter. Muscle regeneration was induced by injuring mouse muscles with cardiotoxin. We studied the consequences of Trim33 knockdown on viability, body weight, skeletal muscle histology, muscle regeneration, and gene expression. We also studied the effect of Trim33 silencing in satellite cells and the C2C12 mouse muscle cell line. Although Trim33 knockdown mice weighed less than control mice, their skeletal muscles were histologically unremarkable and regenerated normally following injury. Unexpectedly, RNAseq analysis revealed dramatically increased expression of cholecystokinin (CCK) in regenerating muscle from Trim33 knockout mice, satellite cells from Trim33 knockout mice, and C2C12 cells treated with Trim33 siRNA. Trim33 knockdown had no demonstrable effect on muscle differentiation or regeneration. However, Trim33 knockdown induced CCK expression in muscle, suggesting that suppression of CCK expression requires Trim33.
Objective
Although more than a dozen myositis‐specific autoantibodies (MSAs) have been identified, most patients with myositis are positive for a single MSA. The specific overexpression of a given ...myositis autoantigen in myositis muscle has been proposed as initiating and/or propagating autoimmunity against that particular autoantigen. The present study was undertaken to test this hypothesis.
Methods
In order to quantify autoantigen RNA expression, RNA sequencing was performed on muscle biopsy samples from control subjects, MSA‐positive patients with myositis, regenerating mouse muscles, and cultured human muscle cells.
Results
Muscle biopsy samples were available from 20 control subjects and 106 patients with autoantibodies recognizing hydroxymethylglutaryl‐coenzyme A reductase (n = 40), signal recognition particles (n = 9), Jo‐1 (n = 18), nuclear matrix protein 2 (n = 12), Mi‐2 (n = 11), transcription intermediary factor 1γ (n = 11), or melanoma differentiation–associated protein 5 (n = 5). The increased expression of a given autoantigen in myositis muscle was not associated with autoantibodies recognizing that autoantigen (all q > 0.05). In biopsy specimens from both myositis muscle and regenerating mouse muscles, autoantigen expression correlated directly with the expression of muscle regeneration markers and correlated inversely with the expression of genes encoding mature muscle proteins. Myositis autoantigens were also expressed at high levels in cultured human muscle cells.
Conclusion
Most myositis autoantigens are highly expressed during muscle regeneration, which may relate to the propagation of autoimmunity. However, factors other than overexpression of specific autoantigens are likely to govern the development of unique autoantibodies in individual patients with myositis.
Objective
Dermatomyositis (DM) patients typically present with proximal weakness and autoantibodies that are associated with distinct clinical phenotypes. We observed that DM patients with ...autoantibodies recognizing the nuclear matrix protein NXP‐2 often presented with especially severe weakness. The aim of this study was to characterize the clinical features associated with anti–NXP‐2 autoantibodies.
Methods
There were 235 DM patients who underwent testing for anti–NXP‐2 autoantibodies. Patient characteristics, including muscle strength, were compared between those with and without these autoantibodies. The number of cancer cases observed in anti–NXP‐2‐positive subjects was compared with the number expected in the general population.
Results
Of the DM patients, 56 (23.8%) were anti–NXP‐2‐positive. There was no significant difference in the prevalence of proximal extremity weakness in patients with and without anti–NXP‐2. In contrast, anti–NXP‐2‐positive patients had more prevalent weakness in the distal arms (35% versus 20%; P = 0.02), distal legs (25% versus 8%; P < 0.001), and neck (48% versus 23%; P < 0.001). Anti–NXP‐2‐positive subjects were also more likely to have dysphagia (62% versus 35%; P < 0.001), myalgia (46% versus 25%; P = 0.002), calcinosis (30% versus 17%; P = 0.02), and subcutaneous edema (36% versus 19%; P = 0.01) than anti–NXP‐2‐negative patients. Five anti–NXP‐2‐positive subjects (9%) had cancer‐associated myositis, representing a 3.68‐fold increased risk (95% confidence interval 1.2–8.6) compared to the expected prevalence in the general population.
Conclusion
In DM, anti–NXP‐2 autoantibodies are associated with subcutaneous edema, calcinosis, and a muscle phenotype characterized by myalgia, proximal and distal weakness, and dysphagia. As anti–NXP‐2‐positive patients have an increased risk of cancer, we suggest that they undergo comprehensive cancer screening.
Historically, research about classroom management has been instrumental in nature. Although some studies have engaged a critical perspective, few have studied management from the perspectives of ...children. Through interviews with third‐grade children, this study asked: How do third graders make sense of a “clip chart” classroom management system in relation to themselves and their classmates? Findings provide insights into how management practices impact both children's behavior and their understandings of themselves and others.
Objective
Patients with immune‐mediated necrotizing myopathy (IMNM) often have autoantibodies recognizing the signal recognition particle (SRP) or HMG‐CoA reductase (HMGCR). Here, we studied a cohort ...of anti‐SRP patients to identify factors associated with disease severity and clinical improvement; we also compared the severity of weakness in those with anti‐SRP versus anti‐HMGCR autoantibodies.
Methods
All anti‐SRP patients in the Johns Hopkins Myositis Cohort from 2002 to 2015 were included. Longitudinal information regarding proximal muscle strength, creatine kinase (CK) levels, and immunosuppressive therapy was recorded at each visit. Univariate and multivariate multilevel regression models were used to assess prognostic factors influencing recovery. Strength in the anti‐SRP patients was compared to strength in 49 previously described anti‐HMGCR subjects.
Results
Data from 37 anti‐SRP patients and 380 total clinic visits were analyzed. Younger age at onset was associated with more severe weakness at the first visit (P = 0.02) and all subsequent visits (P = 0.002). Only 50% of patients reached near‐full or full strength after 4 years of treatment, and most of these continued to have elevated CK levels. Rituximab appeared to be effective in 13 of 17 anti‐SRP patients. Anti‐SRP patients were significantly weaker than those with anti‐HMGCR autoantibodies (−1.3 strength points; P = 0.001).
Conclusion
Younger age at onset is associated with more severe weakness in anti‐SRP myositis. Furthermore, even among anti‐SRP patients whose strength improved with immunosuppression, most had ongoing disease activity as demonstrated by elevated CK levels. Finally, anti‐SRP patients were significantly weaker than anti‐HMGCR patients, providing evidence that these autoantibodies are associated with distinct forms of IMNM.
Titanium alloys are great candidates for applications such as biomedical implants that require biocompatibility, a low Young's modulus and a high strength. However, the properties of Ti alloys are ...highly dependent on phase stability. In the present work, a database for the Ti-Mo-Nb-Ta-Zr system has been evaluated using the CALPHAD (CALculation of PHAse Diagram) approach. The database was completed by evaluating the accuracy of previously modeled systems from literature and modeling systems that, to the best of the authors’ knowledge, had no modeling available in literature. All of the binary systems that make up the Ti-Mo-Nb-Ta-Zr system had previously modeled thermodynamic descriptions available in the literature and in most cases had multiple different descriptions available, which meant determining which previous thermodynamic description most accurately modeled the binary system with a direct focus on the bcc phase. In order to determine the accuracy of the multiple available thermodynamic descriptions from literature a combination of experimental data (also obtained from the literature) and computed thermochemical properties of the bcc phase from DFT (Density Functional Theory)-based first-principles calculations (present work) were used. Once the thermodynamic descriptions for the binary systems were chosen, focus shifted to the Ti-containing ternary systems. The Ti-Mo-Zr, Ti-Nb-Zr and Ti-Ta-Zr systems had previous thermodynamic description available in literature, which were incorporated without changes into the working database. The Ti-Mo-Ta, Ti-Nb-Ta and Ti-Mo-Nb systems had, to the authors’ knowledge, no descriptions available in the literature. Interaction parameters were determined for the Ti-Mo-Ta and Ti-Nb-Ta systems, and no interaction parameters were introduced for the Ti-Mo-Nb system. The database introduced by this work satisfactorily predicts the thermodynamics of the Ti-Mo-Nb-Ta-Zr system.
The thermodynamic properties and phase stability of the Ba-Bi system are investigated computationally and experimentally in the present work. The enthalpies of formation and the finite temperature ...thermodynamic properties of seven compounds are predicted by first-principles calculations based on density functional theory (DFT), indicating five compounds (BaBi3, Ba11Bi10, Ba4Bi3, Ba5Bi3, and Ba2Bi) to be stable. Phase relations at 773 K and 858 K with composition xBa = 0.90 are established by isothermal annealing and powder X-ray diffraction (XRD) to clarify the previously observed phase transition at 796 K. The extremely low chemical activity of Ba in liquid for a wide range of temperatures and compositions indicates very strong short-range ordering in the liquid phase which is modeled in the present work by introducing the Ba4Bi3 and BaBi3 associates in the liquid phase. Both thermodynamic and phase equilibrium data are then used to evaluate the model parameters in Gibbs energy functions of the five stable compounds and three solution phases of liquid, bcc, and rhombohedral phases by the CALPHAD (CALculation of PHAse Diagram) technique. Here the present work shows that the Ba-Bi system consists of three eutectic reactions, two peritectic reactions, one peritectoid reaction, and two congruent reactions, as well as that the concentrations of associates are very high in the liquid phase with very low concentration of atomic Ba, which provides the fundamental understanding as to why Bi can be used to remove Ba ions from molten salt solutions.
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