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ObjectivesInflammatory myopathy or myositis is a heterogeneous family of immune-mediated diseases including dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM) and inclusion body myositis (IBM). Immune checkpoint inhibitors (ICIs) can also cause myositis (ICI-myositis). This study was designed to define gene expression patterns in muscle biopsies from patients with ICI-myositis.MethodsBulk RNA sequencing was performed on 200 muscle biopsies (35 ICI-myositis, 44 DM, 18 AS, 54 IMNM, 16 IBM and 33 normal muscle biopsies) and single nuclei RNA sequencing was performed on 22 muscle biopsies (seven ICI-myositis, four DM, three AS, six IMNM and two IBM).ResultsUnsupervised clustering defined three distinct transcriptomic subsets of ICI-myositis: ICI-DM, ICI-MYO1 and ICI-MYO2. ICI-DM included patients with DM and anti-TIF1γ autoantibodies who, like DM patients, overexpressed type 1 interferon-inducible genes. ICI-MYO1 patients had highly inflammatory muscle biopsies and included all patients that developed coexisting myocarditis. ICI-MYO2 was composed of patients with predominant necrotising pathology and low levels of muscle inflammation. The type 2 interferon pathway was activated both in ICI-DM and ICI-MYO1. Unlike the other types of myositis, all three subsets of ICI-myositis patients overexpressed genes involved in the IL6 pathway.ConclusionsWe identified three distinct types of ICI-myositis based on transcriptomic analyses. The IL6 pathway was overexpressed in all groups, the type I interferon pathway activation was specific for ICI-DM, the type 2 IFN pathway was overexpressed in both ICI-DM and ICI-MYO1 and only ICI-MYO1 patients developed myocarditis.

ObjectivesIn dermatomyositis (DM), autoantibodies are associated with unique clinical phenotypes. For example, anti-TIF1γ autoantibodies are associated with an increased risk of cancer. The purpose of this study was to discover novel DM autoantibodies.MethodsPhage ImmunoPrecipitation Sequencing using sera from 43 patients with DM suggested that transcription factor Sp4 is a novel autoantigen; this was confirmed by showing that patient sera immunoprecipitated full-length Sp4 protein. Sera from 371 Johns Hopkins patients with myositis (255 with DM, 28 with antisynthetase syndrome, 40 with immune-mediated necrotising myopathy, 29 with inclusion body myositis and 19 with polymyositis), 80 rheumatological disease controls (25 with Sjogren’s syndrome, 25 with systemic lupus erythematosus and 30 with rheumatoid arthritis (RA)) and 200 healthy comparators were screened for anti-SP4 autoantibodies by ELISA. A validation cohort of 46 anti-TIF1γ-positive patient sera from the University of Pittsburgh was also screened for anti-Sp4 autoantibodies.ResultsAnti-Sp4 autoantibodies were present in 27 (10.5%) patients with DM and 1 (3.3%) patient with RA but not in other clinical groups. In patients with DM, 96.3% of anti-Sp4 autoantibodies were detected in those with anti-TIF1γ autoantibodies. Among 26 TIF1γ-positive patients with anti-Sp4 autoantibodies, none (0%) had cancer. In contrast, among 35 TIF1γ-positive patients without anti-Sp4 autoantibodies, 5 (14%, p=0.04) had cancer. In the validation cohort, among 15 TIF1γ-positive patients with anti-Sp4 autoantibodies, 2 (13.3%) had cancer. By comparison, among 31 TIF1γ-positive patients without anti-Sp4 autoantibodies, 21 (67.7%, pConclusionsAnti-Sp4 autoantibodies appear to identify a subgroup of anti-TIF1γ-positive DM patients with lower cancer risk.

ObjectiveDiagnostic muscle biopsies are routinely immunostained for major histocompatibility complex class I (MHC-I) protein. In this study we analysed the prevalence and patterns of MHC-I immunostaining in biopsies from patients with different types of myopathies and neurogenic disorders.MethodsAll 357 diagnostic muscle biopsies processed at the Johns Hopkins Neuromuscular Pathology Laboratory from August 2013 to January 2017 were immunostained for MHC-I. The prevalence and patterns of MHC-I immunostaining were compared between patients with histologically normal muscle biopsies (n = 31), idiopathic inflammatory myopathies (IIMs; n = 170), non-inflammatory myopathies (n = 60) and neurogenic disorders (n = 96).ResultsMHC-I immunostaining was abnormal in most patients with DM (98%), sporadic IBM (sIBM; 100%), immune-mediated necrotizing myopathy (IMNM; 100%) and polymyositis (77%). In contrast, MHC-I immunostaining was less frequently present in non-inflammatory myopathies (32%) or neurogenic disorders (30%). Overall, abnormal MHC-I immunostaining had a sensitivity of 0.95 and a specificity of 0.82 for diagnosing IIMs. A focal MHC-I staining pattern was associated with IMNM, whereas a global pattern was more prevalent in sIBM and a perifascicular pattern was significantly more common in dermatomyositis. Among 18 DM biopsies without perifascicular atrophy, 50% had a perifascicular MHC-I staining pattern. Sarcoplasmic upregulation staining was more common than sarcolemmal staining across all groups.ConclusionMHC-I immunostaining was useful to distinguish IIMs from non-inflammatory myopathies or neurogenic disorders. Of note, a perifascicular MHC-I staining pattern was present only in those with DM, including half of those without perifascicular atrophy; many of these biopsies may not otherwise have been diagnostic for DM.

ObjectivesInflammatory myopathy or myositis is a heterogeneous family of immune-mediated diseases including dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Immune checkpoint inhibitors (ICI) can also cause myositis (ICI-myositis). This study was designed to define gene expression patterns in muscle biopsies from patients with ICI-myositis.MethodsBulk RNA sequencing was performed on 200 muscle biopsies (35 ICI-myositis, 44 DM, 18 AS, 54 IMNM, 16 IBM, and 33 normal muscle biopsies) and single nuclei RNA sequencing was performed on 22 muscle biopsies (7 ICI-myositis, 4 DM, 3 AS, 6 IMNM, and 2 IBM).ResultsUnsupervised clustering defined three distinct transcriptomic subsets of ICI-myositis: ICI-DM, ICI-MYO1, and ICI-MYO2. ICI-DM included patients with DM and anti-TIF1γ autoantibodies who, like DM patients, overexpressed type 1 interferon-inducible genes. ICI-MYO1 patients had highly inflammatory muscle biopsies and included all patients that developed co-existing myocarditis. ICI-MYO2 was composed of patients with predominant necrotizing pathology and low levels of muscle inflammation. The type 2 interferon pathway was activated both in ICI-DM and ICI-MYO1. Unlike the other types of myositis, all three subsets of ICI-myositis patients overexpressed genes involved in the IL6 pathway.ConclusionsWe identified three distinct types of ICI-myositis based on transcriptomic analyses. The IL6 pathway was overexpressed in all groups, the type I interferon pathway activation was specific for ICI-DM, the type 2 IFN pathway was overexpressed in both ICIDM and ICI-MYO1, and only ICI-MYO1 patients developed myocarditis.

ObjectivesMyositis is a heterogeneous family of diseases including dermatomyositis (DM), immune-mediated necrotising myopathy (IMNM), antisynthetase syndrome (AS) and inclusion body myositis (IBM). Myositis-specific autoantibodies define different subtypes of myositis. For example, patients with anti-Mi2 autoantibodies targeting the chromodomain helicase DNA-binding protein 4 (CHD4)/NuRD complex (a transcriptional repressor) have more severe muscle disease than other DM patients. This study aimed to define the transcriptional profile of muscle biopsies from anti-Mi2-positive DM patients.MethodsRNA sequencing was performed on muscle biopsies (n=171) from patients with anti-Mi2-positive DM (n=18), DM without anti-Mi2 autoantibodies (n=32), AS (n=18), IMNM (n=54) and IBM (n=16) as well as 33 normal muscle biopsies. Genes specifically upregulated in anti-Mi2-positive DM were identified. Muscle biopsies were stained for human immunoglobulin and protein products corresponding to genes specifically upregulated in anti-Mi2-positive muscle biopsies.ResultsA set of 135 genes, includingSCRT1andMADCAM1, was specifically overexpressed in anti-Mi2-positive DM muscle. This set was enriched for CHD4/NuRD-regulated genes and included genes that are not otherwise expressed in skeletal muscle. The expression levels of these genes correlated with anti-Mi2 autoantibody titres, markers of disease activity and with the other members of the gene set. In anti-Mi2-positive muscle biopsies, immunoglobulin was localised to the myonuclei, MAdCAM-1 protein was present in the cytoplasm of perifascicular fibres, and SCRT1 protein was localised to myofibre nuclei.ConclusionsBased on these findings, we hypothesise that anti-Mi2 autoantibodies could exert a pathogenic effect by entering damaged myofibres, inhibiting the CHD4/NuRD complex, and subsequently derepressing the unique set of genes defined in this study.

Background: Neurodegenerative diseases, such as Parkinson’s disease, are heterogeneous disorders with multifactorial nature involving impaired bioenergetics; that are on the rise with the increasing global population and average lifespan. Without definite therapeutic options, both stem regenerative medicine and bioenergetics have been proposed as promising therapeutic targets in the neurologic field. The rationale of the present study was to assess human derived adipose stem cells (hASC) potential to transdifferentiate into neuronal-like cells (NhASC and neurospheres), as well as to explore hASC bioenergetic profile. Methods: To this purpose, hASC derived from the forearm of both healthy controls and clinical diagnosed Parkinson’s disease patients (PD) were included in this study and transdifferentiated through neuronal induction. Results: Morphological, growth features and neuronal protein expression markers of differentiated neuron-like NhASC and neurospheres were achieved. Increased MAP-2 neuronal marker protein expression upon neuronal induction (pConclusions: We have confirmed the capability of transdifferentiation to neuronal-like profile of hASC derived from the forearem of human subjects and characterized the bioenergetic oxidative profile of hASC. Despite the latter did not lead to significant differential respiration profiles, trends to suboptimal maximal respiratory capacity in PD were found. The neuronal induction leading to positive neuronal protein expression markers is a relevant issue that encourages the suitability of the NhASC models in neurodegeneration.

BackgroundGanciclovir/valganciclovir is currently indicated during the first 6 months of life in symptomatic children with congenital cytomegalovirus (CMV) infection. However, this treatment may have the potential to induce mitochondrial toxicity due to off-target inhibition of DNA-polymerases. Similar anti-HIV drugs have been associated with mitochondrial toxicity but this has never been explored in CMV.ObjectiveTo determine the potential mitochondrial toxicity profile at the genetic, functional and biogenesis level in peripheral blood mononuclear cells from a cohort of newborns and infants with symptomatic congenital CMV infection (treated with valganciclovir, untreated and uninfected controls).DesignLongitudinal, observational and controlled study.Setting and patientsSubjects were recruited at the tertiary referral Hospital Sant Joan de Déu and experiments were conducted at IDIBAPS-Hospital Clínic of Barcelona, Spain. CMV-infected newborns underwent comprehensive monthly clinical follow-up.MethodsMitochondrial parameters, audiometry and neurological assessment were measured at baseline, 3–6 and 12 months after inclusion in the study. The Kruskal-Wallis test for k-independent samples and Friedman tests for repeated measurements were applied.ResultsComplex IV, citrate synthase enzymatic activities and mtDNA remained preserved in congenital CMV-infected infants treated with valganciclovir compared with controls (p>0.05 in all cases).ConclusionsNo evidence of mitochondrial toxicity was found in infants treated with valganciclovir for congenital CMV.

Síndrome de Pearson; Aminocil-ARNt sintetasa mitocondrial; Nova variant patògena Síndrome de Pearson; Aminocil-ARNt sintetasa mitocondrial; Nueva variante patógena Pearson’s syndrome; Mitochondrial aminocyl-tRNA synthetase; Novel pathogenic variant Pathogenic variants in the mitochondrial tyrosyl-tRNA synthetase gene (YARS2) were associated with myopathy, lactic acidosis, and sideroblastic anemia (MLASA). However, patients can present mitochondrial myopathy, with exercise intolerance and muscle weakness, leading from mild to lethal phenotypes. Genes implicated in mtDNA replication were studied by Next Generation Sequencing (NGS) and whole exome sequence with the TruSeq Rapid Exome kit (Illumina, San Diego, CA, USA). Mitochondrial protein translation was studied following the Sasarman and Shoubridge protocol and oxygen consumption rates with Agilent Seahorse XF24 Analyzer Mitostress Test, (Agilent, Santa Clara, CA, USA). We report two siblings with two novel compound heterozygous pathogenic variants in YARS2 gene: a single nucleotide deletion in exon 1, c.314delG (p.(Gly105Alafs*4)), which creates a premature stop codon in the amino acid 109, and a single nucleotide change in exon 5 c.1391T>C (p.(Ile464Thr)), that cause a missense variant in amino acid 464. We demonstrate the pathogenicity of these new variants associated with reduced YARS2 mRNA transcript, reduced mitochondrial protein translation and dysfunctional organelle function. These pathogenic variants are responsible for late onset MLASA, herein accompanied by pancreatic insufficiency, observed in both brothers, clinically considered as Pearson’s syndrome. Molecular study of YARS2 gene should be considered in patients presenting Pearson’s syndrome characteristics and MLASA related phenotypes. This work was supported by the Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias and cofounded with ERDF funds (Grant No. FIS PI15/01428, FIS PMP15/00025 PI18/00498, PI19/01772, and the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER).

Background Mitochondrial diseases (MD) are genetic metabolic disorders that impair normal mitochondrial structure or function. The aim of this study was to investigate the status of circulating cell-free mitochondrial DNA (ccfmtDNA) in cerebrospinal fluid (CSF), together with other biomarkers (growth differentiation factor-15 [GDF-15], alanine, and lactate), in a cohort of 25 patients with a molecular diagnosis of MD. Methods Measurement of ccfmtDNA was performed by using droplet digital PCR. Results The mean copy number of ccfmtDNA was approximately 6 times higher in the MD cohort compared to the control group; patients with mitochondrial deletion and depletion syndromes (MDD) had the higher levels. We also detected the presence of both wild-type mtDNA and mtDNA deletions in CSF samples of patients with single deletions. Patients with MDD with single deletions had significantly higher concentrations of GDF-15 in CSF than controls, whereas patients with point mutations in mitochondrial DNA presented no statistically significant differences. Additionally, we found a significant positive correlation between ccfmtDNA levels and GDF-15 concentrations (r = 0.59, P = 0.016). Conclusion CSF ccfmtDNA levels are significantly higher in patients with MD in comparison to controls and, thus, they can be used as a novel biomarker for MD research. Our results could also be valuable to support the clinical outcome assessment of MD patients.

Idiopathic Parkinson’s disease (iPD) and type 2 diabetes mellitus (T2DM) are chronic, multisystemic, and degenerative diseases associated with aging, with eventual epidemiological co-morbidity and overlap in molecular basis. This study aims to explore if metabolic and mitochondrial alterations underlie the previously reported epidemiologic and clinical co-morbidity from a molecular level. To evaluate the adaptation of iPD to a simulated pre-diabetogenic state, we exposed primary cultured fibroblasts from iPD patients and controls to standard (5 mM) and high (25 mM) glucose concentrations to further characterize metabolic and mitochondrial resilience. iPD fibroblasts showed increased organic and amino acid levels related to mitochondrial metabolism with respect to controls, and these differences were enhanced in high glucose conditions (citric, suberic, and sebacic acids levels increased, as well as alanine, glutamate, aspartate, arginine, and ornithine amino acids; p-values between 0.001 and 0.05). The accumulation of metabolites in iPD fibroblasts was associated with (and probably due to) the concomitant mitochondrial dysfunction observed at enzymatic, oxidative, respiratory, and morphologic level. Metabolic and mitochondrial plasticity of controls was not observed in iPD fibroblasts, which were unable to adapt to different glucose conditions. Impaired metabolism and mitochondrial activity in iPD may limit energy supply for cell survival. Moreover, reduced capacity to adapt to disrupted glucose balance characteristic of T2DM may underlay the co-morbidity between both diseases. Conclusions: Fibroblasts from iPD patients showed mitochondrial impairment, resulting in the accumulation of organic and amino acids related to mitochondrial metabolism, especially when exposed to high glucose. Mitochondrial and metabolic defects down warding cell plasticity to adapt to changing glucose bioavailability may explain the comorbidity between iPD and T2DM., This work was supported by funds from the Integrated Projects of Excellence PIE14/00061 and the Fondo de Investigaciones Sanitarias of the Instituto de Salud Carlos III (ISCIII) (grant numbers PI1800498 and PI1800451), the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), all initiatives of ISCIII and FEDER (‘Una manera de hacer Europa’), as well as Fundació Privada Cellex and Suports a Grups de Recerca (grant code 2017 SGR 893) and CERCA programs from the Generalitat de Catalunya. Maria de Maeztu Unit of Excellence funded our institution (Institute of Neurosciences, University of Barcelona) as consolidated excellence centre (MDM-2017-0729, Ministry of Science, Innovation and Universities). Two grants from the Spanish government allowed facility maintenance (SAF2017-85877-R from CGR and both SAF2015-69944-R and PID2019-111669RB-I00 from JCFC)

Magnetic resonance imaging (MRI) is considered the most sensitive and specific imaging technique for the detection of muscle diseases related to myopathies. Since 2008, the use of whole-body MRI (WBMRI) to evaluate myopathies has improved due to technical advances such as rolling table platform and parallel imaging, which enable rapid assessment of the entire musculoskeletal system with high-quality images. WBMRI protocols should include T1-weighted and short-tau inversion recovery (STIR), which provide the basic pulse sequences for studying myopathies, in order to detect fatty infiltration/muscle atrophy and muscle edema, respectively. High signal intensity in T1-weighted images shows chronic disease with fatty infiltration, whereas high signal intensity in STIR indicates an acute stage with muscle edema. Additional sequences such as diffusion-weighted imaging (DWI) can be readily incorporated into routine WBMRI study protocols. Contrast-enhanced sequences have not been done. This article reviews WBMRI as an imaging method to evaluate different myopathies (idiopathic inflammatory, dystrophic, non-dystrophic, metabolic, and channelopathies). WBMRI provides a comprehensive estimate of the total burden with a single study, seeking specific distribution patterns, including clinically silent involvement of muscle areas. Furthermore, WBMRI may help to select the "target muscle area" for biopsy during patient follow-up. It may be also be used to detect related and non-related pathological conditions, such as tumors.

ObjectivesMyositis is a heterogeneous family of diseases that includes dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM), inclusion body myositis (IBM), polymyositis and overlap myositis. Additional subtypes of myositis can be defined by the presence of myositis-specific autoantibodies (MSAs). The purpose of this study was to define unique gene expression profiles in muscle biopsies from patients with MSA-positive DM, AS and IMNM as well as IBM.MethodsRNA-seq was performed on muscle biopsies from 119 myositis patients with IBM or defined MSAs and 20 controls. Machine learning algorithms were trained on transcriptomic data and recursive feature elimination was used to determine which genes were most useful for classifying muscle biopsies into each type and MSA-defined subtype of myositis.ResultsThe support vector machine learning algorithm classified the muscle biopsies with >90% accuracy. Recursive feature elimination identified genes that are most useful to the machine learning algorithm and that are only overexpressed in one type of myositis. For example, CAMK1G (calcium/calmodulin-dependent protein kinase IG), EGR4 (early growth response protein 4) and CXCL8 (interleukin 8) are highly expressed in AS but not in DM or other types of myositis. Using the same computational approach, we also identified genes that are uniquely overexpressed in different MSA-defined subtypes. These included apolipoprotein A4 (APOA4), which is only expressed in anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) myopathy, and MADCAM1 (mucosal vascular addressin cell adhesion molecule 1), which is only expressed in anti-Mi2-positive DM.ConclusionsUnique gene expression profiles in muscle biopsies from patients with MSA-defined subtypes of myositis and IBM suggest that different pathological mechanisms underly muscle damage in each of these diseases.

Background and objective Statin-associated autoimmune myopathy (SAAM) with anti-HMGCR antibodies has recently been described. Several specific immunoassays are in use to detect HMGCR antibodies. In the course of systematic autoantibody screening we recognized a new distinct IFL staining pattern on rat liver sections that regularly coincided with anti-HMGCR antibodies. In this study we investigated whether this new IFL pattern is specifically associated to statin-associated autoimmune myopathy and corresponds to anti-HMGCR antibodies. Patients and methods Twenty-three patients positive for anti-HMGCR antibodies (14 diagnosed with SAAM) were investigated for anti-HMGCR antibodies by two ELISA assays and confirmed by immmunoblot. HMGCR associated liver IFL pattern (HALIP) was detected by indirect IFL and the reactivity against HMGCR was confirmed by immunoabsorption using purified human HMGCR antigen. 90 patients with other autoimmune diseases and 45 non-autoimmune statin treated patients were studied as controls. Results 21 out of 23 (91%) anti-HMGCR positive patients were HALIP positive. The staining was completely and specifically removed by immunoabsorption with human purified HMGCR. None of the control sera from autoimmune patients or non-autoimmune statin treated subjects was positive for HALIP. Statistical concordance between HALIP and anti-HMGCR antibody specific tests was 98.7%, kappa 0.95. Conclusions A new and distinct IFL staining pattern (HALIP) is associated to HMGCR associated myopathy. Absorption and concordance studies indicate that the antigen recognized in the liver by HALIP is HMGCR or a closely related protein. Awareness of this new pattern can help to detect HMGCR autoantibodies in statin treated patients tested for autoimmune serology.

La pseudocirrosis hepática se define como los cambios morfológicos hepáticos que asemejan una cirrosis hepática sin serlo. La causa más frecuente es el carcinoma de mama metastásico. Se trata de un diagnóstico infrecuente y de mal pronóstico, si bien la incidencia de este fenómeno podría estar actualmente en aumento. Como ocurre en la cirrosis, pueden aparecer complicaciones derivadas de la hipertensión portal, por lo que será importante identificar y tratar estos pacientes. Describimos aquí un caso de recidiva de carcinoma de mama en forma de pseudocirrosis hepática a los 9 años del diagnóstico inicial.

En la linea de las investigaciones sobre los efectos de Twitter sobre la configuracion de la opinion publica, se analizan las caracteristicas del debate generado a raiz de la presentacion de la Ley del referendum de Cataluna. Se trabajo con dos muestras (n1: 260.866 tweets y retweets y n2: 1.681 tweets) que permitieron estudiar, por un lado, la morfologia de la red de retweets (RT) y la obtencion de los perfiles –lideres de influencia, constructores y puentes– que en ella se dibujan y, por otro, la conceptualizacion de la situacion politica por parte de aquellos usuarios que lideran la mencionada red. Los resultados muestran un porcentaje significativo (32%) de usuarios de las esferas publicas perifericas entre los lideres de influencia, frente al 68% perteneciente a la esfera publica central. Ambos se configuran como lideres de dos comunidades altamente polarizadas ideologicamente a favor y en contra de esta Ley, lo cual se aleja del ideal de deliberacion.

To evaluate the clinical manifestations, long-term clinical outcome and longitudinal pulmonary function in a large cohort of Spanish patients with anti-Jo1 antibodies.We retrospectively analyzed the clinical data and lung function parameters of 148 anti-Jo1 patients recruited from a multicentre registry including 18 Spanish hospitals. A composite endpoint was defined, comprising death due to respiratory failure directly related to antisynthetase syndrome (ASS), the need for long-term oxygen therapy or lung transplantation.Median follow-up was 78.3 months. Clinical presentation patterns at onset are as follows: isolated interstitial lung disease (ILD) (32.4%), isolated myositis (26.9%), concomitant myositis and ILD (22.8%), and isolated polyarthritis (17.9%). Myositis with ILD was the most frequent final clinical phenotype (67.6%). In most ASS patients, ILD was a non-progressive disease, tending to stabilize with therapy. The endpoint was reached in a significantly larger number of ILD patients with dyspnea at onset than those with paucisymptomatic or asymptomatic forms (p = 0.01). A steady FVC decrease was the hallmark of patients with end-stage lung disease. Estimated survival rates were 87.7% and 75.4% at 5 and 10 years, respectively. Cancer (p = 0.02) and advanced age at ASS diagnosis (p0.0001) were related to poorer survival. Mortality was significantly higher than in the general Spanish population, with a standardised mortality ratio (95% CI) of 4.03 (2.79-5.64).Anti-Jo1 ASS is a heterogeneous syndrome. ILD in ASS under immunosuppressive therapy is mainly a non-progressive disease. Dyspnea at ILD onset and a steady FVC decrease over time were related to a poorer respiratory prognosis.

A 39-year-old caucasian man presented to our hospital in Barcelona with fever, dry cough, headache and weight loss of 4 kg. Symptoms started 5 days after returning from a 21-day travel to Malaysia. His physical examination was unremarkable except for a splenomegaly. Laboratory tests showed mild elevation of transaminases, elevated levels of lactate dehydrogenase (468 UI/L) and a normal blood cell count. Blood cultures, thick and thin blood smear and serologic tests for dengue, chikungunya, HIV, cytomegalovirus, Epstein-Barr virus, herpes virus 6, parvovirus B19, Toxoplasma spp and Rickettsia conorii were negative.

[Background]: Intrauterine growth restriction (IUGR) is associated with cardiovascular remodeling persisting into adulthood. Mitochondrial bioenergetics, essential for embryonic development and cardiovascular function, are regulated by nuclear effectors as sirtuins. A rabbit model of IUGR and cardiovascular remodeling was generated, in which heart mitochondrial alterations were observed by microscopic and transcriptomic analysis. We aimed to evaluate if such alterations are translated at a functional mitochondrial level to establish the etiopathology and potential therapeutic targets for this obstetric complication. [Methods]: Hearts and placentas from 16 IUGR-offspring and 14 controls were included to characterize mitochondrial function. [Results]: Enzymatic activities of complexes II, IV and II + III in IUGR-hearts (−11.96 ± 3.16%; −15.58 ± 5.32%; −14.73 ± 4.37%; p, This work was supported by Fondo de Investigación Sanitaria [FIS PI12/01199, PI15/00817, PI15/00903 and PI15/00130], CIBERER (an initiative of ISCIII) and InterCIBER [PIE1400061] granted by Instituto de Salud Carlos III and cofinanced by the Fondo Europeo de Desarrollo Regional de la Unión Europea “Una manera de hacer Europa”; Suports a Grups de Recerca [SGR893/2017] and CERCA Programme from the Generalitat de Catalunya; CONACyT; Fundació La Marató de TV3 [87/C/2015]; Fundació Cellex; and “la Caixa” Foundation.

Introduction: Musculoskeletal manifestations are well-recognized side effects of treatment with statins. New advances in this field have appeared in recent years. This review focuses on the diagnosis of these conditions and their underlying pathogenesis, in particular immune-mediated necrotizing myopathy.Areas covered: Clinical phenotypes including rhabdomyolysis, myalgia and/or mild hyperCKemia, self-limited toxin statin myopathy, and immune-mediated necrotizing myopathy are herein described. Therapeutic recommendations and a diagnostic algorithm in statin-associated myopathy are also proposed. The etiology and pathogenesis of statin-induced myopathy has mainly focused on the anti-HMGCR antibodies and the responsibility of the immune-mediated necrotizing myopathy is discussed. The fact that patients who have not been exposed to statins may develop statin-associated autoimmune myopathy with anti-HMGCR antibodies is also addressed. The literature search strategy included terms identified by searches of PubMed between 1969 and December 2017. The search terms myositis', statin-induced autoimmune myopathy', immune-mediate necrotizing myopathy', statins', muscular manifestations', and anti-HMGCR antibodies' were used.Expert commentary: Full characterization of the known phenotypes of statin toxicity and the specific role of the anti-HMGCR in those exposed and not exposed (i.e. juvenile forms) to statins and in some types of neoplasms is of paramount relevance.

Idiopathic inflammatory myopathies are a heterogeneous group of rare autoimmune diseases characterized by symmetric proximal muscle weakness and inflammatory infiltrates on muscle biopsy. A meticulously collected combination of clinical, serological, and pathological data is essential to correctly diagnose and classify myositis patients, often a considerable challenge for clinicians. This article provides a comprehensive overview of the most useful tools for the diagnosis and follow-up of patients with myositis. Capillaroscopy, serological biomarkers (particularly the autoantibody profile) and imaging techniques, such as muscle magnetic resonance and chest ultrasound, are of great aid in diagnosing, classifying and managing these patients. Relevant clinical scenarios, such as interstitial lung disease, associated cancer and pregnancy are also addressed in this review. Myositis registries, identification of new autoantibodies, and genetic studies will enhance our understanding of the pathogenesis of these conditions and help to define new diagnostic and therapeutic approaches.

Background HIV infection and HAART trigger genetic and functional mitochondrial alterations leading to cell death and adverse clinical manifestations. Mitochondrial dynamics enable mitochondrial turnover and degradation of damaged mitochondria, which may lead to apoptosis. Objectives To evaluate markers of mitochondrial dynamics and apoptosis in pregnancies among HIV-infected women on HAART and determine their potential association with obstetric complications. Methods This controlled, single-site, observational study without intervention included 26 HIV-infected pregnant women on HAART and 18 control pregnancies and their newborns. Maternal PBMCs and neonatal cord blood mononuclear cells (CBMCs) were isolated at the first trimester of gestation and at delivery. The placenta was homogenized at 5% w/v. Mitochondrial dynamics, fusion events [mitofusin 2 (Mfn2)/β-actin] and fission events [dynamin-related protein 1 (Drp1/β-actin)] and apoptosis (caspase 3/β-actin) were assessed by western blot analysis. Results Obstetric complications were significantly more frequent in pregnancies among HIV-infected women [OR 5.00 (95% CI 1.21-20.70)]. Mfn2/β-actin levels in PBMCs from controls significantly decreased during pregnancy (202.13 ± 57.45%), whereas cases maintained reduced levels from the first trimester of pregnancy and no differences were observed in CBMCs. Mfn2/β-actin and Drp1/β-actin contents significantly decreased in the placenta of cases. Caspase 3/β-actin levels significantly increased during pregnancy in PBMCs of cases (50.00 ± 7.89%), remaining significantly higher than in controls. No significant differences in caspase 3/β-actin content of neonatal CBMCs were observed, but there was a slight increased trend in placenta from cases. Conclusions HIV- and HAART-mediated mitochondrial damage may be enhanced by decreased mitochondrial dynamics and increased apoptosis in maternal and placental compartments but not in the uninfected fetus. However, direct effects on mitochondrial dynamics and implication of apoptosis were not demonstrated in adverse obstetric outcomes.

Patients with inborn errors of metabolism (IEMs) have become an emerging and challenging group in the adult healthcare system whose needs should be known in order to implement appropriate policies and to adapt adult clinical departments. We aimed to analyze the clinical characteristics of adult patients with IEMs who attend the most important Spanish hospitals caring for these conditions. A cohort study was conducted in 500 patients, categorized by metabolic subtype according to pathophysiological classification. The most prevalent group of IEMs was amino acid disorders, with 108 (21.6%) patients diagnosed with phenylketonuria. Lysosomal storage disorders were the second group, in which 32 (6.4%) and 25 (5%) patients had Fabry disease and Gaucher disease respectively. The great clinical heterogeneity, the significant delay in diagnosis after symptom onset, the existence of some degree of physical dependence in a great number of patients, the need for a multidisciplinary and coordinated approach, and the lack of specific drug treatment are common features in this group of conditions.

We quantified the immune histiocytic Langerhans cells (LCs) in skin biopsy samples of patients with distal small fiber neuropathy (SFN). Patients were divided according to the presence or absence of neuropathic pain (burning pain) assessed by a visual analogue scale (VAS). We studied 13 diabetic patients (pain-DSFN), 7 nondiabetic patients (pain-SFN) who reported relevant neuropathic pain (VAS ≥ 3), and 6 nondiabetic patients without neuropathic pain (no-pain-SFN). Using double immunofluorohistochemistry with the PGP 9.5 and the langerin/CD207, we quantified the intraepidermal nerve fibers density (IENFD) and LCs per square millimeter in the epidermis. A group of 10 skin samples from healthy subjects served as controls. Confocal analysis was performed to evaluate LC PGP 9.5-immunoreactivity. We found a mean value of 334.3LC/mm(2) in controls, 310.2LC/mm(2) in no-pain-SFN, 329.6LC/mm(2) in pain-SFN and 484.3LC/mm(2) in pain-DSFN (analysis of variance; P=.01). In patients, analysis of covariance adjusted by different covariables showed that the presence of diabetes (F=5.2, P=.03) was associated with an increased number of LC/mm(2). There was a negative correlation between the IENFD and the number of LCs (r(2)=-0.13, P=.03). No statistically significant differences were found among groups of subjects either for the co-localization or for the number of LCs that were PGP 9.5-immunoreactive (analysis of variance; P>.05). These results indicate that patients with neuropathic pain in the context of SFN, specially those who had diabetes (DSFN), had an increased number of LCs in the epidermis that may play a role in the generation or maintenance of neuropathic pain.

We present a novel approach to quantify skin innervation by measuring the PGP 9.5 immunoreactive (PGP-ir) fluorescence corresponding to axons within the epidermis and dermis. The skin biopsies from 35 controls and 45 small fiber neuropathy (SFN) patients were included. In 50-μm free-floating sections, we determined the intraepidermal nerve fiber density (IENFD) by direct fluorescence visualization and captured 2-μm thick individual optical sections using the same confocal microscope and magnification. We measured the fluorescence of the PGP-ir axons in both, epidermal and dermal area by using the ImageJ software. There was good interobserver and intraobserver reliability of PGP-ir measures, similar than for IENFD. The PGP-ir axons were found decreased in patients with SFN (1.1‰ and 9.0‰ respectively for epidermal and dermal area in contrast to 2.2‰ and 16.0‰, respectively to controls). The area under the ROC curve was 0.90 for the IENFD, 0.84 for epidermal PGP-ir axons and 0.70 for dermal PGP-ir axons. There was a positive correlation between the IENFD and the PGP-ir axons at epidermis (Spearman Rho=0.66, p

This study analyzed the relationship between the density of intraepidermal nerve fibers (IENF) and the characteristics of either nociceptive laser-evoked potentials (LEPs) or contact heat-evoked potentials (CHEPs) in patients with painful sensory polyneuropathy with the aim to determine which parameters of LEPs and CHEPs more reliably reflect IENF loss. A total of 96 patients and 35 healthy volunteers took part in the study. Based on clinical examination, nerve conduction tests, and quantitative sensory testing, we identified 52 patients with small-fiber neuropathy (SFN), 40 with mixed (small-fiber and large-fiber) neuropathy (MFN), and 4 who were excluded from the analysis because of no evidence of involvement of small fibers. The latency of the N2 was delayed for both LEPs and CHEPs in patients with MFN and for CHEPs only in patients with SFN. The amplitude of the vertex N2/P2 potential was similarly reduced in both types of neuropathy, but LEPs were more frequently absent than CHEPs in MFN patients (68% vs 40%). In general, latency and amplitude of LEPs and CHEPs were well correlated with IENF density. SFN patients were characterized by abnormal EPs and slightly decreased but morphologically abnormal IENF. MFN patients were characterized by frequently absent LEPs and CHEPs and a rather severe IENF loss. The correlation between nociceptive evoked potentials (laser-evoked potentials and contact heat-evoked potentials) and skin biopsy aids in the diagnosis of painful neuropathies.

Estudio descriptivo y retrospectivo de una serie de 35 pacientes con miopatia inflamatoria idiopatica, que a partir de la recogida de variables clinicas, de laboratorio y patologicas, se propone los siguientes objetivos: caracterizar a este grupo de enfermedades, clasificar a los pacientes en subgrupos en funcion de criterios histopatologicos y caracterizar los distintos subgrupos analizando que variables permiten diferenciar mejor cada categoria.

We report the case of a 45-year-old patient who presented with acute dilated cardiomyopathy. During admission the patient was consecutively diagnosed with cryoglobulinaemic vasculitis and beriberi. In both diseases, cardiac involvement may occur as dilated cardiomyopathy. Thiamin deficiency was the final cause for the severe cardiac manifestations (cardiac acute beriberi or Shoshin syndrome), which returned to normal after thiamin supplementation.

Currently, 2',3'-dideoxyinosine (ddI) is used in AIDS therapy. To investigate the possible myotoxicity of ddI in patients infected with human immunodeficiency virus (HIV), we examined the effect of ddI in vitro in tissue cultures of skeletal muscles of rats exposed to ddI at doses equivalent to plasma ddI levels obtained in the treatment of HIV patients. Control cultures were exposed to normal saline and zidovudine (AZT). After 4 weeks no changes were noted in the ddI and normal saline cultures, but AZT cultures showed abnormal accumulation of mitochondria. The creatine kinase values in culture supernatants were all normal. We also reviewed the clinical, nutritional and biological parameters, AZT and ddI dosage, and histochemical findings in muscle specimens of 14 HIV patients receiving ddI therapy. All patients had previously received AZT. The mean cumulative dose of ddI was 91.6 gm. Two patients had myalgia, 9 muscle atrophy, and 13 weakness. All patients were malnourished. Five patients had mitochondrial myopathy related to AZT, 4 had ddI-associated neuropathy and 2 patients had only selective type 2 fiber atrophy. One patient had necrotizing vasculitis, one had scattered necrotic fibers and type 2 fiber atrophy and 2 had a normal muscle biopsy. On the basis of the results, we have been unable to implicate ddI as a cause of skeletal myopathy.

Erdheim-Chester disease (EC) is a rare form of non-Langerhans' cell histiocytosis. It is characterized by the xanthomatous infiltration of tissues with foamy CD68+/CD1a- histiocytes. We report a series of 12 patients diagnosed with EC.We reviewed the clinical, pathological and therapeutic aspects of 12 cases diagnosed with EC at 7 tertiary teaching hospitals in Spain. Patients were included if tissue infiltration by histiocytes CD68+/CD1a- could be demonstrated in an appropriate clinical setting.Twelve patients (7 male) were included. Median follow-up was 36 months (IQR: 20-84). The median age at the time of clinical onset and pathological diagnosis was 49 (IQR: 28-61) and 56 years (IQR: 37-62), respectively. In 6 cases multiples biopsies were performed (skin, muscle, testicular) previous to diagnosis, which was confirmed in 3 cases after a carefully review of pathological tissues. Neurological involvement was independently associated with mortality (P.05). Characteristic long bone osteosclerosis was detected in 9 patients.EC is a multisystemic and heterogeneous clinicopathological condition. A high index of suspicion and fluent communication between clinicians and pathologists is necessary to achieve a correct diagnosis.

Background Antisynthetase syndrome (ASS) can be a life-threatening condition. Patients with ASS in the context of idiopathic inflammatory myositis (IIM) have been described to have a worse prognosis compared to patients either with dermatomyositis (DM) or polymyositis (PM) alone. Objectives To evaluate survival and mortality in a large cohort of Spanish patients with anti-Jo1 ASS and compare it with mortality rates of Spanish general population. Methods From March 2011 to June 2014 we conducted a national multicentre study, including retrospective and prospective data, among members of the GEAS-IIM Group of the SEMI. Clinicians from 18 Spanish centers participated in the development of a registry of patients with Anti-Jo1 ASS. For data collection a specific electronic database including broad information about demographic and clinical data was developed. Continuous variables were compared by the t-student or non-parametric Mann-Whitney tests when appropriated, while X2 test were used to compare categorical variables. The Kaplan-Meier method and long-rank tests were used to compare survival between groups. The standardized mortality ratio (SMR) was calculated using the Spanish mortality registry. Results were expressed with its 95% interval confiance (IC). Results A total of 148 anti-Jo1 ASS patients, 90 women (60.8%), were included in the study. Mean (SD) age at diagnosis was 50.8 (16) years. Range follow-up was 1.3 to 412 months [mean (SD) 95 (76.4) months], with only 12 patients with a follow-up fewer than 12 months. Fifteen percent of patients had ILD as the unique main ASS clinical manifestation, other 15% had myositis and 69.3% had both ILD and myositis. Thirty seven patients (25%) died after a median follow-up of 70.3 months (range 4.9 – 308 months). The SMR (95%IC) was 4.77 (3.31-6.67). Main causes of death included respiratory failure (6.8%), cancer (6.1%), infection (4.1%), myositis (2.7%) and acute cardiovascular events (1.3%). A directly ASS-related death were considered in 18 patients (46.6%). Estimated survival rate (95% IC) was 87.5% (81.6% - 93.4%) and 75.4% (66.4% - 84.4%) at 5 and 10 years respectively. Median survival rate (95% IC) was 20.3 years (13.8-26.8 years). No difference in survival was found between patients with myositis (DM or PM) and those with ILD without associated myopathy. The presence of cancer (p=0.02) and an advanced age at ASS diagnosis (p Conclusions Mortality in ASS patients is four-fold and a half higher than in the general population. Mortality can be directly attributed to ASS in near a half of the cases. Respiratory failure, cancer and infection are the main causes of death. Estimated survival rate at 10 years is around 75%. References Marie I. Morbidity and mortality in adult polymyositis and dermatomyositis. Curr Rheumatol Rep.2012;14:275-285. Disclosure of Interest None declared

The forearm ischemic exercise test (FIET) with serial lactate determinations is used worldwide for the screening of McArdle's disease and other glucogenosis. Yet there is no uniformity with regard to the intensity of the work and the ischemia time. The aim of this study was to standardize the test conditions in normal people and to check its efficacy in our population.In a first stage, we included 9 healthy persons in whom four different conditions were applied regarding the cuff pressure and ischemia time. In a second stage, 5 previously known McArdle disease patients, 30 normal individuals and 25 patients with a diagnosis of myopathy other than glucogenosis underwent FIET with the conditions standardized in the first stage.The best curve profile was obtained with a cuff pressure 20 mm Hg above systolic blood pressure and with exercise until fatigue o cramps without time limitation. With a cut-point at 200% of the basal values of ammonium and lactate, the sensitivity and specificity of FIET were 100% and 96%, respectively, for McArdle's disease. No major side effects were recorded in any case.Conditions of FIET have been standardized. Taking into account the high sensitivity and specificity of the test, its use should be considered in the screening of anaerobic metabolic myopathies.

Background Pompe´s disease is an inherited metabolic myopathy caused by deficiency of the lysosomal enzyme acid α-glucosidase. In adults, it may be misdiagnosed as other chronic muscle disease such as limb girdle muscular dystrophy or polymyositis (PM), among others. Until now diagnosis was difficult and substitutive treatment not available, but recently the development of enzymatic methods using dried blood spots (DBS) on filter paper as a simple, quick and inexpensive first test, as well as the approval of enzyme replacement therapy, have substantially changed the patients perspectives. Objectives To check for Pompe’s disease in a series of adult patients diagnosed with myopathy of unknown etiology (MUE), PM or with asymptomatic hyperCKemia. Methods Patients with high values or creatin kinase (>1000 UI/L) recruited from a general routine laboratory and patients diagnosed with PM or MUE attended in a specialized myopathies outpatient clinic from 2 tertiary University Hospitals in Barcelona during the period of 1 year (from january 2012 to january 2013) were evaluated. The diagnosis of both PM and MUE was reached after a full pathologic analysis including histochemistry and immunohistochemistry on muscle biopsies was performed. We included another group of patients with well-known myopathy as a control group. In all patients, acid α-glucosidase activity in DBS was the method employed for screening and positive cases were then confirmed by enzymatic activity in purified lymphocytes and genetic testing. Results One-hundred twenty-four patients (78 female), with a median age (SD) of 53.6 yrs (17.6) were analysed. Polymyositis was diagnosed in 25 patients, hyper CK in 9, and MUE in 50. Other well-known myopathies such as mitochondrial myopathies, dystrophinopathies, dysferlinopathies, and McArdle disease were diagnosed in the remaining 40 (control group). Eight patients (3 with polymyositis, 2 with hyperCKemia and 3 with MUE tested positive for DBS to Pompe´s disease. Only one patient from the group of MUE was confirmed to be positive for Pompe´s disease by enzymatic and genetic testing. Conclusions Pompe’s disease may be an underdiagnosed disease in patients with myopathy of uncertain origin and it should be included in the differential diagnosis in these patients. Positivity to DBS required enzymatic and genetic confirmation. References Van der Ploeg AT, Reuser AJ. Lysosomal Storage Diseases 2. Pompe´s diseases. Lancet 2008;372:1342-53. van der Beek NA, de Vries JM, Hagemans ML, et al. Clinical features and predictor for disease natural progression in adults with Pompe disease: a nationwide prospective observational study. Orphanet Journal of Rare Diseases 2012, doi: 10.1186/1750-1172-7-88. Disclosure of Interest None Declared

Ethanol consumption may produce acute or chronic changes in striated skeletal muscle in a dose-dependent manner. The physiopathological mechanisms for such changes are probably related to alterations in membrane fluidity, channels, pumps and ionic transients, depression of muscle contractility, protein synthesis and genetic problems. In patients with alcoholic myopathies, multiorgan involvement is frequent and reversibility is only partially achieved by abstinence.

To determine the significance of type II fiber atrophy in alcoholic myopathy and its relationship with ethanol-related diseases a prospective study was carried out in 100 chronic alcoholics who showed clinical suspicion of skeletal myopathy. Measurement of muscle strength, laboratory analysis, nutritional assessment and open biopsy of deltoid muscle were performed in each case, as well as electrophysiological testing for peripheral neuropathy. Hepatic ultrasonography and liver biopsy, echocardiography and radionuclide cardiac scanning were carried out in selected subjects. According to histomorphometric analysis, type II fiber atrophy was found in 33 cases (33%), being selective for type II B fiber in 23 (70%). Skeletal myopathy was diagnosed in 61 cases, alcoholic cardiomyopathy in 26, peripheral neuropathy in 23 and cirrhosis in 12. Patients with type II fiber atrophy had a significantly higher total lifetime dose of ethanol, presented a greater incidence of skeletal myopathy and peripheral neuropathy, and exhibited significantly lower values of percentage of ideal body weight and lean body mass than their counterparts. However, the only independent factors for developing type II fiber atrophy were the coexistence of caloric malnutrition (p = 0.004) and the presence of skeletal myopathy (p = 0.043). Selective type II fiber atrophy is a non-specific finding in alcohol-induced muscle damage appearing, overall, in the patients with caloric malnutrition as well as in those with histologic evidence of myopathy.