Idiopathic Inflammatory Myopathies: A Review of Immunopathological Features and Current Models of Pathogenesis

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Opposing roles of miR-21 and miR-29 in the progression of fibrosis in Duchenne muscular dystrophy

AbstractExcessive extracellular matrix deposition progressively replacing muscle fibres is the endpoint of most severe muscle diseases. Recent data indicate major involvement of microRNAs in regulating pro- and anti-fibrotic genes. To investigate the roles of miR-21 and miR-29 in muscle fibrosis in Duchenne muscle dystrophy, we evaluated their expression in muscle biopsies from 14 patients, and in muscle-derived fibroblasts and myoblasts. In Duchenne muscle biopsies, miR-21 expression was significantly increased, and correlated directly with COL1A1 and COL6A1 transcript levels. MiR-21 expression was also significantly increased in Duchenne fibroblasts, more so after TGF-β1 treatment. In Duchenne fibroblasts the expression of miR-21 target transcripts PTEN (phosphatase and tensin homolog deleted on chromosome 10) and SPRY-1 (Sprouty homolog 1) was significantly reduced; while collagen I and VI transcript levels and soluble collagen production were significantly increased. MiR-29a and miR-29c were significantly reduced in Duchenne muscle and myoblasts, and miR-29 target transcripts, COL3A1, FBN1 and YY1, significantly increased. MiR-21 silencing in mdx mice reduced fibrosis in the diaphragm muscle and in both Duchenne fibroblasts and mdx mice restored PTEN and SPRY-1 expression, and significantly reduced collagen I and VI expression; while miR-29 mimicking in Duchenne myoblasts significantly decreased miR-29 target transcripts. These findings indicate that miR-21 and miR-29 play opposing roles in Duchenne muscle fibrosis and suggest that pharmacological modulation of their expression has therapeutic potential for reducing fibrosis in this condition

Integrated FDG-PET/CT imaging is useful in the apporach to carcinoid tumors of the lung

Background. Carcinoids enter the differential diagnosis of the solitary pulmonary nodule. Bronchial carcinoids have been traditionally considered as FDG-PET negative but recent studies have found an higher sensitivity of integrated FDG-PET/CT for the detection of these neoplasms. The purpose of this study was to investigate the value of integrated FDG-PET/CT for the evaluation of SPN suspected to be carcinoids. Methods. All patients with pathologically proven bronchial carcinoids who had FDG-PET/CT scans between 2006 and 2012 have been retrospectively reviewed. PET/CT was performed with the same scanner and the same technique for all patients. The following data were retrieved: age, sex CT findings (side, location, size, shape, margins), SUVmax, type of operation, pathological findings (size and number of mitoses). Regarding PET findings, only SUVmax was considered, whereas the visual assessment was not undertaken. Carcinoids were defined as typical and atypical and as central and peripheral. The long-term follow-up was also recorded. The SUVmax was compared with the other clinical, radiological and pathological variables to find any significant difference or correlation. Results. Twenty-five patients were retrieved, 24 typical and one atypical carcinoid, 21 peripheral and 4 central lesions. The mean diameter on CT-scan was 25.3mm and the clinical size correlated well with the pathological size. Fifty-six percent of the tumors were ovoid and 68% had smooth margins. The mean SUVmax was 3.6 (range 1.4-12.9). All the lesions were completely resected. The regression analysis showed a direct correlation between the SUVmax and the tumor size (p=0.004). No further correlations were found between the SUVmax and the other variables. None of the patients had recurrent disease or died during the follow-up. Conclusions. Our study showed that FDG-PET/CT might be a useful tool in the evaluation of SPNs suspected to be bronchial carcinoids. When a solitary pulmonary nodule shows an ovoid/round shape and smooth margins on the CT scan and demonstrates an FDG uptake higher than that of the normal lung and with a SUVmax value >1-1.5, a carcinoid should be suspected. If benign lesions can be presumably excluded, surgical resection or at least a biopsy of the lesion is recommended

Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1-3 D4Z4 reduced alleles: Experience of the FSHD Italian National Registry

OBJECTIVES: Facioscapulohumeral muscular dystrophy type 1 (FSHD1) has been genetically linked to reduced numbers ( 64 8) of D4Z4 repeats at 4q35. Particularly severe FSHD cases, characterised by an infantile onset and presence of additional extra-muscular features, have been associated with the shortest D4Z4 reduced alleles with 1-3 repeats (1-3 DRA). We searched for signs of perinatal onset and evaluated disease outcome through the systematic collection of clinical and anamnestic records of de novo and familial index cases and their relatives, carrying 1-3 DRA. SETTING: Italy. PARTICIPANTS: 66 index cases and 33 relatives carrying 1-3 DRA. OUTCOMES: The clinical examination was performed using the standardised FSHD evaluation form with validated inter-rater reliability. To investigate the earliest signs of disease, we designed the Infantile Anamnestic Questionnaire (IAQ). Comparison of age at onset was performed using the non-parametric Wilcoxon rank-sum or Kruskal-Wallis test. Comparison of the FSHD score was performed using a general linear model and Wald test. Kaplan-Meier survival analysis was used to estimate the age-specific cumulative motor impairment risk. RESULTS: No patients had perinatal onset. Among index cases, 36 (54.5%) showed the first signs by 10 years of age. The large majority of patients with early disease onset (26 out of 36, 72.2%) were de novo; whereas the majority of patients with disease onset after 10 years of age were familial (16, 53.3%). Comparison of the disease severity outcome between index cases with age at onset before and over 10 years of age, failed to detect statistical significance (Wald test p value=0.064). Of 61 index cases, only 17 (27.9%) presented extra-muscular conditions. Relatives carrying 1-3 DRA showed a large clinical variability ranging from healthy subjects, to patients with severe motor impairment. CONCLUSIONS: The size of the D4Z4 allele is not always predictive of severe clinical outcome. The high degree of clinical variability suggests that additional factors contribute to the phenotype complexity

The effects of primary care monitoring strategies on COVID-19 related hospitalisation and mortality: a retrospective electronic medical records review in a northern Italian province, the MAGMA study

Background: Most symptomatic SARS-CoV-2 infections produce mild to moderate symptoms. Although most patients are managed in the outpatient setting, little is known about the effect of general practitioners' (GP) management strategies on the outcomes of COVID-19 outpatients in Italy. Objectives: Describe the management of Italian GPs of SARS-CoV-2 infected adult patients and explore whether GP active care and monitoring are associated with reducing hospitalisation and death. Methods: Retrospective observational study of SARS-CoV-2 infected adult outpatients managed by GPs in Modena (Italy) from March 2020 to April 2021. Information on management and monitoring strategies, patients' socio-demographic characteristics, comorbidities, and outcomes (hospitalisation and death due to COVID-19) were retrieved through an electronic medical record review and analysed descriptively and through multiple logistic regression. Results: Out of the 5340 patients from 46 GPs included in the study, 3014 (56%) received remote monitoring, and 840 (16%) had at least one home visit. More than 85% of severe or critical patients were actively monitored (73% daily) and 52% were visited at home. Changes over time in patients' therapeutic management were observed in concordance with the guidelines' release. Active daily remote monitoring and home visits were strongly associated with reduced hospitalisation rate (OR 0.52, 95% CI 0.33-0.80 and OR 0.50, 95% CI 0.33-0.78 respectively). Conclusion: GPs effectively managed an increasing number of outpatients during the first waves of the pandemic. Active monitoring and home visits were associated with reduced hospitalisation in COVID-19 outpatients

Shallow Dark Matter Cusps in Galaxy Clusters

We study the evolution of the stellar and dark matter components in a galaxy cluster of $10^{15} \, \rm{M_{\odot}}$ from $z=3$ to the present epoch using the high-resolution collisionless simulations of Ruszkowski & Springel (2009). At $z=3$ the dominant progenitor halos were populated with spherical model galaxies with and without accounting for adiabatic contraction. We apply a weighting scheme which allows us to change the relative amount of dark and stellar material assigned to each simulation particle in order to produce luminous properties which agree better with abundance matching arguments and observed bulge sizes at $z=3$. This permits the study of the effect of initial compactness on the evolution of the mass-size relation. We find that for more compact initial stellar distributions the size of the final Brightest Cluster Galaxy grows with mass according to $r\propto M^{2}$, whereas for more extended initial distributions, $r\propto M$. Our results show that collisionless mergers in a cosmological context can reduce the strength of inner dark matter cusps with changes in logarithmic slope of 0.3 to 0.5 at fixed radius. Shallow cusps such as those found recently in several strong lensing clusters thus do not necessarily conflict with CDM, but may rather reflect on the initial structure of the progenitor galaxies, which was shaped at high redshift by their formation process.Comment: 8 pages, 4 figures, submitted to MNRA

Elevated TGF \u3b22 serum levels in Emery-Dreifuss Muscular Dystrophy: Implications for myocyte and tenocyte differentiation and fibrogenic processes

Among rare diseases caused by mutations in LMNA gene, Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B are characterized by muscle weakness and wasting, joint contractures, cardiomyopathy with conduction system disorders. Circulating biomarkers for these pathologies have not been identified. Here, we analyzed the secretome of a cohort of patients affected by these muscular laminopathies in the attempt to identify a common signature. Multiplex cytokine assay showed that transforming growth factor beta 2 (TGF \u3b22) and interleukin 17 serum levels are consistently elevated in the vast majority of examined patients, while interleukin 6 and basic fibroblast growth factor are altered in subgroups of patients. Levels of TGF \u3b22 are also increased in fibroblast and myoblast cultures established from patient biopsies as well as in serum from mice bearing the H222P Lmna mutation causing Emery-Dreifuss Muscular Dystrophy in humans. Both patient serum and fibroblast conditioned media activated a TGF \u3b22-dependent fibrogenic program in normal human myoblasts and tenocytes and inhibited myoblast differentiation. Consistent with these results, a TGF \u3b22 neutralizing antibody avoided fibrogenic marker activation and myogenesis impairment. Cell intrinsic TGF \u3b22-dependent mechanisms were also determined in laminopathic cells, where TGF \u3b22 activated AKT/mTOR phosphorylation. These data show that TGF \u3b22 contributes to the pathogenesis of Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B and can be considered a potential biomarker of those diseases. Further, the evidence of TGF \u3b22 pathogenetic effects in tenocytes provides the first mechanistic insight into occurrence of joint contractures in muscular laminopathies

Cosmology in 2D: the concentration-mass relation for galaxy clusters

The aim of this work is to perform a systematic study of the measures of the mass and concentration estimated by fitting the convergence profile of a large sample of mock galaxy cluster size lenses, created with the publicly available code MOKA. We found that the main contribution to the bias in mass and in concentration is due to the halo triaxiality and second to the presence of substructures within the host halo virial radius. We show that knowing the cluster elongation along the line of sight helps in correcting the mass bias, but still keeps a small negative bias for the concentration. If these mass and concentration biases will characterize the galaxy cluster sample of a wide field survey it will be difficult to well recover within one sigma the cosmological parameters that mainly influence the c - M relation, using as reference a 3D c - M relation measured in cosmological N-body simulation. In this work we propose how to correct the c - M relation for projection effects and for adiabatic contraction and suggest to use these as reference for real observed data. Correcting mass and concentration estimates, as we propose, gives a measurement of the cosmological parameter within 1 - {\sigma} confidence contours.Comment: 18 pages, 14 figures - replaced to match the accepted version for publication by MNRA

Sunyaev-Zel'dovich clusters in millennium gas simulations

Large surveys using the Sunyaev–Zel’dovich (SZ) effect to find clusters of galaxies are now starting to yield large numbers of systems out to high redshift, many of which are new dis- coveries. In order to provide theoretical interpretation for the release of the full SZ cluster samples over the next few years, we have exploited the large-volume Millennium gas cosmo- logical N-body hydrodynamics simulations to study the SZ cluster population at low and high redshift, for three models with varying gas physics. We confirm previous results using smaller samplesthattheintrinsic(spherical)Y500–M500relationhasverylittlescatter(σlog10Y ≃0.04), is insensitive to cluster gas physics and evolves to redshift 1 in accordance with self-similar expectations. Our preheating and feedback models predict scaling relations that are in excel- lent agreement with the recent analysis from combined Planck and XMM–Newton data by the Planck Collaboration. This agreement is largely preserved when r500 and M500 are derived using thehydrostaticmassproxy,YX,500,albeitwithsignificantlyreducedscatter(σlog10Y ≃0.02),a result that is due to the tight correlation between Y500 and YX,500. Interestingly, this assumption also hides any bias in the relation due to dynamical activity. We also assess the importance of projection effects from large-scale structure along the line of sight, by extracting cluster Y500 values from 50 simulated 5 × 5-deg2 sky maps. Once the (model-dependent) mean signal is subtracted from the maps we find that the integrated SZ signal is unbiased with respect to the underlying clusters, although the scatter in the (cylindrical) Y500–M500 relation increases in the preheating case, where a significant amount of energy was injected into the intergalactic medium at high redshift. Finally, we study the hot gas pressure profiles to investigate the origin of the SZ signal and find that the largest contribution comes from radii close to r500 in all cases. The profiles themselves are well described by generalized Navarro, Frenk & White profiles but there is significant cluster-to-cluster scatter. In conclusion, our results support the notion that Y500 is a robust mass proxy for use in cosmological analyses with clusters