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Deep learning has demonstrated significant potential in advancing state of the art in many problem domains, especially those benefiting from automated feature extraction. Yet, the methodology has seen limited adoption in the field of ligand-based virtual screening (LBVS) as traditional approaches typically require large, target-specific training sets, which limits their value in most prospective applications. Here, we report the development of a neural network architecture and a learning framework designed to yield a generally applicable tool for LBVS. Our approach uses the molecular graph as input and involves learning a representation that places compounds of similar biological profiles in close proximity within a hyperdimensional feature space; this is achieved by simultaneously leveraging historical screening data against a multitude of targets during training. Cosine distance between molecules in this space becomes a general similarity metric and can readily be used to rank order database compounds in LBVS workflows. We demonstrate the resulting model generalizes exceptionally well to compounds and targets not used in its training. In three commonly employed LBVS benchmarks, our method outperforms popular fingerprinting algorithms without the need for any target-specific training. Moreover, we show the learned representation yields superior performance in scaffold hopping tasks and is largely orthogonal to existing fingerprints. Summarily, we have developed and validated a framework for learning a molecular representation that is applicable to LBVS in a target-agnostic fashion, with as few as one query compound. Our approach can also enable organizations to generate additional value from large screening data repositories, and to this end we are making its implementation freely available at https://github.com/totient-bio/gatnn-vs.
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Algoritmos , Redes Neurais de Computação , Bases de Dados Factuais , Ligantes , Estudos ProspectivosRESUMO
Motivation: Several tools exist to count Mendelian violations in family trios by comparing variants at the same genomic positions. This naive variant comparison, however, fails to assess regions where multiple variants need to be examined together, resulting in reduced accuracy of existing Mendelian violation checking tools. Results: We introduce VBT, a trio concordance analysis tool, which identifies Mendelian violations by approximately solving the 3-way variant matching problem to resolve variant representation differences in family trios. We show that VBT outperforms previous trio comparison methods by accuracy. Availability and implementation: VBT is implemented in C++ and source code is available under GNU GPLv3 license at the following URL: https://github.com/sbg/VBT-TrioAnalysis.git. Supplementary information: Supplementary data are available at Bioinformatics online.
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Genoma , Genômica , Software , Genoma/genética , Genômica/métodosRESUMO
BACKGROUND: Stiff Person Syndrome (SPS) is an under-diagnosed disorder that affects mobility and the quality of life of affected patients. The aim of the study is to describe the natural history of SPS, the extent of accumulated disability and the associated clinical and immunological features in patients followed for up to 8 years in a single center. METHODS: Our collective cohort included 57 SPS patients. Additionally, 32 of these patients were examined every 6 months for a two-year period in a longitudinal study protocol, to assess disease progression using quantitative measures of stiffness and heightened sensitivity. RESULTS: The most frequent initial symptom was leg stiffness, followed by paraspinal muscle rigidity and painful spasms in 95% of the patients. Although none of the patients required assistance for ambulation during the first 2 years of disease onset, 46 patients (80%) lost the ability to walk independently during our follow-up, despite symptomatic medications. In the longitudinal cohort, the number of stiff areas increased (p < 0.0001), consistent with worsening functional status and quality of life. High-titer anti-GAD antibodies were present in serum and CSF with elevated intrathecal GAD-specific IgG synthesis, but they did not correlate with clinical severity or progression. CONCLUSIONS: This large study on SPS patients, combining an eight-year follow-up at a single center by the same leading neurologist and his team, is the first to provide longitudinal data in a large patient subgroup using objective clinical measures. One of the main findings is that SPS is a progressive disease leading to physical disability over time.
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Rigidez Muscular Espasmódica , Estudos de Coortes , Progressão da Doença , Humanos , Qualidade de VidaRESUMO
OBJECTIVE: In stiff person syndrome (SPS), an antibody-mediated impaired γ-aminobutyric acidergic (GABAergic) neurotransmission is believed to cause muscle stiffness and spasms. Most patients improve with GABA-enhancing drugs and intravenous immunoglobulin, but some respond poorly and remain disabled. The need for more effective therapy prompted a trial with the anti-CD20 monoclonal antibody rituximab. METHODS: This was a placebo-controlled randomized trial of rituximab (2 biweekly infusions of 1g each). The primary outcome was a change in stiffness scores at 6 months. Secondary outcomes were changes in heightened-sensitivity and quality of life scores. Enrolling 24 patients was calculated to detect 50% change in stiffness scores. RESULTS: Randomization was balanced for age, sex, disease duration, and glutamic acid decarboxylase autoantibody titers. No significant changes were noted at 6 months after treatment in all outcomes. Specifically, no differences were noted in the stiffness index, the primary outcome, or sensitivity scores, the secondary outcome, at 3 or 6 months. Quality of life scores improved significantly (p < 0.01) at 3 months in both groups, but not at 6 months, denoting an early placebo effect. Blinded self-assessment rating of the overall stiffness for individual patients revealed improvement in 4 patients in each group. At 6 months, improvement persisted in 1 patient in the placebo group versus 3 of 4 in the rituximab group, where these meaningful improvements were also captured by video recordings. INTERPRETATION: This is the largest controlled trial conducted in SPS patients and demonstrates no statistically significant difference in the efficacy measures between rituximab and placebo. Rituximab's lack of efficacy could be due to a considerable placebo effect; insensitivity of scales to quantify stiffness, especially in the less severely affected patients; or drug effectiveness in only a small patient subset. Ann Neurol 2017;82:271-277.
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Rituximab/uso terapêutico , Rigidez Muscular Espasmódica/tratamento farmacológico , Autoanticorpos/sangue , Método Duplo-Cego , Feminino , Glutamato Descarboxilase/imunologia , Humanos , Fatores Imunológicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Rigidez Muscular Espasmódica/sangue , Resultado do TratamentoRESUMO
BACKGROUND: Seronegative ocular myasthenia gravis (OMG) is diagnosed by ocular symptoms with supporting SFEMG, typically of frontalis or extensor digitorum muscles. We aimed to determine the sensitivity and specificity of orbicularis oculi SFEMG to diagnose and exclude myasthenia gravis and predict response to therapy. METHODS: Orbicularis oculi SFEMG studies were conducted in 142 consecutive patients with symptoms and/or findings of OMG and negative AChR antibody during the period of 5 years. Retrospective chart review was conducted 2 years after the SFEMG to determine whether treatments were given and responses to treatment. RESULTS: Orbicularis oculi SFEMG was abnormal in 31 patients and normal in 111 patients. Twenty-nine patients with abnormal SFEMG were treated, and 25 had a good response. Twenty-four patients with normal SFEMG received treatment; none responded to treatment or developed generalized myasthenia. CONCLUSION: An abnormal orbicularis oculi SFEMG in patients with seronegative OMG has a high predictive value for response to therapy. Our study findings may affect the treatment decisions in practice and aid better management of myasthenic patients.
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Eletromiografia/métodos , Músculos Faciais , Miastenia Gravis/diagnóstico , Adolescente , Pálpebras , Feminino , Humanos , Masculino , Músculo Esquelético , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Critical illness polyneuropathy (CIN) and critical illness myopathy (CIM), together "ICU-Acquired weakness (ICUAW)," occur frequently in septic patients. One of the proposed mechanisms for ICUAW includes prolonged inactivation of sodium channels. Propofol, used commonly in patients with acute respiratory failure (ARF), primarily acts via enhancement of GABAergic transmission but may also increase sodium channel inactivation, suggesting a potential interaction. METHODS: Electronic medical records and EMG reports of patients with ICUAW and a diagnosis of either sepsis, septicaemia, severe sepsis, or septic shock, concurrent with a diagnosis of acute respiratory failure (ARF), were retrospectively analyzed in a single center university hospital. RESULTS: 74 cases were identified (50.0% men, age 58±14 years), and compared to age- and sex-matched controls. Of these, 51 (69%) had CIN, 19 (26%) had CIM, and 4 (5%) had both. Propofol exposure was significantly higher in patients with ICUAW compared to controls (63.5% vs. 33.8%, p<0.001). The odds ratio of developing ICUAW with propofol exposure was 3.4 (95% CI:1.7-6.7, p<0.001). Patients with ICUAW had significantly more days in hospital (59±44 vs. 30±23) and ICU (38±26 vs. 17±13), days dependent on mechanical ventilation (27±21 vs. 13±16), and rates of tracheostomy (79.7% vs. 36.5%) and gastrostomy (75.7% vs. 25.7%) (all p<0.001). They also received a significantly higher number of distinct intravenous antibiotics, cumulative days of antibiotic therapy, and exposure to vasopressors and paralytics. CONCLUSIONS: Propofol exposure may increase the risk of ICUAW in septic patients. An interaction through sodium channel inactivation is hypothesized.
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Unidades de Terapia Intensiva/tendências , Debilidade Muscular/induzido quimicamente , Debilidade Muscular/epidemiologia , Propofol/efeitos adversos , Síndrome do Desconforto Respiratório/epidemiologia , Sepse/epidemiologia , Adulto , Idoso , Estudos de Coortes , Estado Terminal/epidemiologia , Estado Terminal/terapia , Registros Eletrônicos de Saúde/tendências , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Síndrome do Desconforto Respiratório/terapia , Fatores de Risco , Sepse/terapia , Canais de Sódio/fisiologiaRESUMO
The age-specific differences in the genetic mechanisms of myeloid leukemogenesis have been observed and studied previously. However, NGS technology has provided a possibility to obtain a large amount of mutation data. We analyzed DNA samples from 20 childhood (cAML) and 20 adult AML (aAML) patients, using NGS targeted sequencing. The average coverage of high-quality sequences was 2981 × per amplicon. A total of 412 (207 cAML, 205 aAML) variants in the coding regions were detected; out of which, only 122 (62 cAML and 60 aAML) were potentially protein-changing. Our results confirmed that AML contains small number of genetic alterations (median 3 mutations/patient in both groups). The prevalence of the most frequent single gene AML associated mutations differed in cAML and aAML patient cohorts: IDH1 (0 % cAML, 5 % aAML), IDH2 (0 % cAML, 10 % aAML), NPM1 (10 % cAML, 35 % aAML). Additionally, potentially protein-changing variants were found in tyrosine kinase genes or genes encoding tyrosine kinase associated proteins (JAK3, ABL1, GNAQ, and EGFR) in cAML, while among aAML, the prevalence is directed towards variants in the methylation and histone modifying genes (IDH1, IDH2, and SMARCB1). Besides uniform genomic profile of AML, specific genetic characteristic was exclusively detected in cAML and aAML.
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Biomarcadores Tumorais/genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia Mieloide Aguda/genética , Mutação/genética , Transcriptoma , Adulto , Criança , Biologia Computacional , Feminino , Humanos , Leucemia Mieloide Aguda/classificação , Masculino , Nucleofosmina , Reação em Cadeia da Polimerase , PrognósticoRESUMO
BACKGROUND: Mechanisms of inflammation and protein accumulation are crucial in inclusion body myositis (IBM). Recent evidence demonstrated that intravenous immunoglobulin failed to suppress cell-stress mediators in IBM. Here we studied the molecular changes in skeletal muscle biopsies from patients with IBM before and after treatment with alemtuzumab. METHODS: Relevant inflammatory and degeneration-associated markers were assessed by quantitative-PCR and immunohistochemistry in repeated muscle biopsy specimens from patients with IBM, which had been treated in a previously published uncontrolled proof-of-concept trial with alemtuzumab. RESULTS: There were no significant changes of the mRNA expression levels of the pro-inflammatory chemokines CXCL-9, CCL-4, and the cytokines IFN-γ, TGF-ß, TNF-α, and IL-1ß. Similarly, the degeneration-associated molecules ubiquitin, APP and αB-crystallin did not substantially change. Although no overall beneficial treatment effect was noted except for a 6-month stabilization, some patients experienced a transient improvement in muscle strength. In such responders, a trend towards reduced expression of inflammatory markers was noted. In contrast, the expression remained unchanged in the others who did not experience any change. The expression levels of IL-1ß and MHC-I correlated with the positive clinical effect. By immunohistochemistry, some inflammatory mediators like CD8, CXCL-9, and MHC-I were downmodulated. However, no consistent changes were noted for ubiquitin, nitrotyrosin and ß-amyloid. CONCLUSIONS: Alemtuzumab showed a trend towards downregulation of the expression of some inflammatory molecules in skeletal muscle of IBM patients but has no effect on several crucial markers of cell stress and degeneration. The data are helpful to explain the molecular treatment effects of future lymphocyte-targeted immunotherapies in IBM.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Inflamação/patologia , Miosite de Corpos de Inclusão/tratamento farmacológico , Alemtuzumab , Biópsia , Citocinas/metabolismo , Humanos , Imuno-Histoquímica , Imunoterapia/métodos , Força Muscular/efeitos dos fármacos , Músculo Esquelético/metabolismoRESUMO
The existence of a potential primary central nervous system lymphoma-specific genomic signature that differs from the systemic form of diffuse large B cell lymphoma (DLBCL) has been suggested, but is still controversial. We investigated 19 patients with primary DLBCL of central nervous system (DLBCL CNS) using the TruSeq Amplicon Cancer Panel (TSACP) for 48 cancer-related genes. Next generation sequencing (NGS) analyses have revealed that over 80% of potentially protein-changing mutations were located in eight genes (CTNNB1, PIK3CA, PTEN, ATM, KRAS, PTPN11, TP53 and JAK3), pointing to the potential role of these genes in lymphomagenesis. TP53 was the only gene harboring mutations in all 19 patients. In addition, the presence of mutated TP53 and ATM genes correlated with a higher total number of mutations in other analyzed genes. Furthermore, the presence of mutated ATM correlated with poorer event-free survival (EFS) (p = 0.036). The presence of the mutated SMO gene correlated with earlier disease relapse (p = 0.023), inferior event-free survival (p = 0.011) and overall survival (OS) (p = 0.017), while mutations in the PTEN gene were associated with inferior OS (p = 0.048). Our findings suggest that the TP53 and ATM genes could be involved in the molecular pathophysiology of primary DLBCL CNS, whereas mutations in the PTEN and SMO genes could affect survival regardless of the initial treatment approach.
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Neoplasias do Sistema Nervoso Central/genética , Linfoma Difuso de Grandes Células B/genética , Mutação , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Oncogênicas/genéticaRESUMO
BACKGROUND: Although human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) affect mitochondrial DNA (mtDNA) content and function, comprehensive evaluations of their effects on mitochondria in muscle, adipose tissue, and blood cells are limited. METHODS: Mitochondrial DNA quantification, mitochondrial genome sequencing, and gene expression analysis were performed on muscle, adipose tissue, and peripheral blood mononuclear cell (PBMC) samples from untreated HIV-positive patients, HIV-positive patients receiving nucleoside reverse transcriptase inhibitor (NRTI)-based ART, and HIV-negative controls. RESULTS: The adipose tissue mtDNA/nuclear DNA (nDNA) ratio was increased in untreated HIV-infected patients (ratio, 353) and decreased in those receiving ART (ratio, 162) compared with controls (ratio, 255; P < .05 for both comparisons); the difference between the 2 HIV-infected groups was also significant (P = .002). In HIV-infected participants, mtDNA/nDNA in adipose tissue correlated with the level of activation (CD38+ /HLA-DR+) for CD4+ and CD8+ lymphocytes. No significant differences in mtDNA content were noted in muscle or PMBCs among groups. Exploratory DNA microarray analysis identified differential gene expression between patient groups, including a subset of adipose tissue genes. CONCLUSIONS: HIV infection and ART have opposing effects on mtDNA content in adipose tissue; immune activation may mediate the effects of HIV, whereas NRTIs likely mediate the effects of ART.
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Tecido Adiposo/efeitos dos fármacos , Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade , DNA Mitocondrial/metabolismo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Mitocôndrias/efeitos dos fármacos , Adolescente , Adulto , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Músculos/efeitos dos fármacos , Adulto JovemRESUMO
Stiff person syndrome (SPS) is a disabling autoimmune central nervous system disorder characterized by progressive muscle rigidity and gait impairment with superimposed painful spasms that involve axial and limb musculature, triggered by heightened sensitivity to external stimuli. Impaired synaptic GABAergic inhibition resulting from intrathecal B-cell-mediated clonal synthesis of autoantibodies against various presynaptic and synaptic proteins in the inhibitory neurons of the brain and spinal cord is believed to be an underlying pathogenic mechanism. SPS is most often idiopathic, but it can occur as a paraneoplastic condition. Despite evidence that anti-GAD and related autoantibodies impair GABA synthesis, the exact pathogenic mechanism of SPS is not fully elucidated. The strong association with several MHC-II alleles and improvement of symptoms with immune-modulating therapies support an autoimmune etiology of SPS. In this review, we discuss the clinical spectrum, neurophysiological mechanisms, and therapeutic options, including a rationale for agents that modulate B-cell function in SPS.
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Eletrofisiologia , Doenças da Medula Espinal/imunologia , Doenças da Medula Espinal/fisiopatologia , Rigidez Muscular Espasmódica/imunologia , Rigidez Muscular Espasmódica/fisiopatologia , Autoanticorpos , Glutamato Descarboxilase/imunologia , Humanos , Ácido gama-Aminobutírico/metabolismoRESUMO
Inflammatory myopathies, in short, myositis, are heterogeneous disorders that are characterized by inflammation of skeletal muscle and weakness of arms and legs. Research over the past few years has led to a new understanding regarding the pathogenesis of myositis. The new insights include different pathways of the innate and adaptive immune response during the pathogenesis of myositis. The importance of non-inflammatory mechanisms such as cell stress and impaired autophagy has been recently described. New target-specific drugs for myositis have been developed and are currently being tested in clinical trials. In this review, we discuss the mechanisms of action of pharmacological standards in myositis and provide an outlook of future treatment approaches.
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Dermatomiosite , Miosite de Corpos de Inclusão , Miosite , Dermatomiosite/patologia , Dermatomiosite/terapia , Humanos , Inflamação/patologia , Músculo Esquelético/patologia , Miosite/tratamento farmacológico , Miosite/patologia , Miosite de Corpos de Inclusão/patologia , Miosite de Corpos de Inclusão/terapiaRESUMO
The rise of machine learning (ML) has created an explosion in the potential strategies for using data to make scientific predictions. For physical scientists wishing to apply ML strategies to a particular domain, it can be difficult to assess in advance what strategy to adopt within a vast space of possibilities. Here we outline the results of an online community-powered effort to swarm search the space of ML strategies and develop algorithms for predicting atomic-pairwise nuclear magnetic resonance (NMR) properties in molecules. Using an open-source dataset, we worked with Kaggle to design and host a 3-month competition which received 47,800 ML model predictions from 2,700 teams in 84 countries. Within 3 weeks, the Kaggle community produced models with comparable accuracy to our best previously published 'in-house' efforts. A meta-ensemble model constructed as a linear combination of the top predictions has a prediction accuracy which exceeds that of any individual model, 7-19x better than our previous state-of-the-art. The results highlight the potential of transformer architectures for predicting quantum mechanical (QM) molecular properties.
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Ciência do Cidadão/métodos , Ciência do Cidadão/tendências , Previsões/métodos , Algoritmos , Participação da Comunidade , Humanos , Aprendizado de Máquina/tendências , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Modelos EstatísticosRESUMO
OBJECTIVE: Report a double-blind, placebo-controlled study of rituximab in patients with anti-MAG demyelinating polyneuropathy (A-MAG-DP). METHODS: Twenty-six patients were randomized to four weekly infusions of 375 mg/m(2) rituximab or placebo. Sample size was calculated to detect changes of > or = 1 Inflammatory Neuropathy Course and Treatment (INCAT) leg disability scores at month 8. IgM levels, anti-MAG titers, B cells, antigen-presenting cells, and immunoregulatory T cells were monitored every 2 months. RESULTS: Thirteen A-MAG-DP patients were randomized to rituximab and 13 to placebo. Randomization was balanced for age, electrophysiology, disease duration, disability scores, and baseline B cells. After 8 months, by intention to treat, 4 of 13 rituximab-treated patients improved by > or = 1 INCAT score compared with 0 of 13 patients taking placebo (p = 0.096). Excluding one rituximab-randomized patient who had normal INCAT score at entry, and thus could not improve, the results were significant (p = 0.036). The time to 10m walk was significantly reduced in the rituximab group (p = 0.042) (intention to treat). Clinically, walking improved in 7 of 13 rituximab-treated patients. At month 8, IgM was reduced by 34% and anti-MAG titers by 50%. CD25+CD4+Foxp3+ regulatory cells significantly increased by month 8. The most improved patients were those with high anti-MAG titers and most severe sensory deficits at baseline. INTERPRETATION: Rituximab is the first drug that improves some patients with A-MAG-DP in a controlled study. The benefit may be exerted by reducing the putative pathogenic antibodies or by inducing immunoregulatory T cells. The results warrant confirmation with a larger trial.
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Anticorpos Monoclonais/uso terapêutico , Doenças Desmielinizantes/imunologia , Imunoglobulina M/sangue , Fatores Imunológicos/uso terapêutico , Glicoproteína Associada a Mielina/imunologia , Polineuropatias/imunologia , Idoso , Anticorpos Monoclonais Murinos , Linfócitos B/efeitos dos fármacos , Doenças Desmielinizantes/complicações , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Polineuropatias/complicações , Rituximab , Vazamento Acidental em Seveso , Linfócitos T/efeitos dos fármacos , Resultado do TratamentoRESUMO
Sporadic inclusion-body myositis (sIBM) is the most common disabling, adult-onset, inflammatory myopathy histologically characterized by intense inflammation and vacuolar degeneration. In spite of T cell-mediated cytotoxicity and persistent, clonally expanded and antigen-driven endomysial T cells, the disease is resistant to immunotherapies. Alemtuzumab is a humanized monoclonal antibody that causes an immediate depletion or severe reduction of peripheral blood lymphocytes, lasting at least 6 months. We designed a proof-of-principle study to examine if one series of Alemtuzumab infusions in sIBM patients depletes not only peripheral blood lymphocytes but also endomysial T cells and alters the natural course of the disease. Thirteen sIBM patients with established 12-month natural history data received 0.3 mg/kg/day Alemtuzumab for 4 days. The study was powered to capture > or =10% increase strength 6 months after treatment. The primary end-point was disease stabilization compared to natural history, assessed by bi-monthly Quantitative Muscle Strength Testing and Medical Research Council strength measurements. Lymphocytes and T cell subsets were monitored concurrently in the blood and the repeated muscle biopsies. Alterations in the mRNA expression of inflammatory, stressor and degeneration-associated molecules were examined in the repeated biopsies. During a 12-month observation period, the patients' total strength had declined by a mean of 14.9% based on Quantitative Muscle Strength Testing. Six months after therapy, the overall decline was only 1.9% (P < 0.002), corresponding to a 13% differential gain. Among those patients, four improved by a mean of 10% and six reported improved performance of daily activities. The benefit was more evident by the Medical Research Council scales, which demonstrated a decline in the total scores by 13.8% during the observation period but an improvement by 11.4% (P < 0.001) after 6 months, reaching the level of strength recorded 12 months earlier. Depletion of peripheral blood lymphocytes, including the naive and memory CD8+ cells, was noted 2 weeks after treatment and persisted up to 6 months. The effector CD45RA(+)CD62L(-) cells, however, started to increase 2 months after therapy and peaked by the 4th month. Repeated muscle biopsies showed reduction of CD3 lymphocytes by a mean of 50% (P < 0.008), most prominent in the improved patients, and reduced mRNA expression of stressor molecules Fas, Mip-1a and alphaB-crystallin; the mRNA of desmin, a regeneration-associated molecule, increased. This proof-of-principle study provides insights into the pathogenesis of inclusion-body myositis and concludes that in sIBM one series of Alemtuzumab infusions can slow down disease progression up to 6 months, improve the strength of some patients, and reduce endomysial inflammation and stressor molecules. These encouraging results, the first in sIBM, warrant a future study with repeated infusions
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Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Imunossupressores/uso terapêutico , Miosite de Corpos de Inclusão/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Alemtuzumab , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos/efeitos adversos , Biópsia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Feminino , Seguimentos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imunossupressores/efeitos adversos , Mediadores da Inflamação/metabolismo , Contagem de Linfócitos , Depleção Linfocítica/métodos , Masculino , Pessoa de Meia-Idade , Força Muscular/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Miosite de Corpos de Inclusão/imunologia , Miosite de Corpos de Inclusão/patologia , Miosite de Corpos de Inclusão/fisiopatologia , RNA Mensageiro/genética , Recuperação de Função Fisiológica , Resultado do TratamentoRESUMO
BACKGROUND: Stiff-person syndrome (SPS) is a rare autoimmune disorder that leads to progressively worsening stiffness and spasm of thoracic and proximal-limb musculature. Dyspnea has been reported but not analyzed in patients with SPS. MATERIALS AND METHODS: For this prospective study, 17 patients were recruited from a university-based neurology clinic. History and exam were performed, demographic information collected and available imaging reviewed. Dyspnea was assessed using vertical visual analog scales (VAS), the University of California San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) and dyspnea "descriptors". Standardized assessments of SPS severity were performed by an experienced neurologist. Forced vital capacity (FVC) spirometric analysis was performed on all patients. RESULTS: Fifteen of 17 patients complained of dyspnea, including dyspnea at rest, with exertion, and disturbing sleep. A restrictive pattern was the most common abnormality noted on spirometry. FVC (râ¯=â¯-0.67; P < 0.01) and forced expiratory volume in 1-second (FEV1) (râ¯=â¯-0.76; P < 0.01) percent predicted correlated with dyspnea measured by VAS over the preceding 2 weeks. Pulmonary function did not correlate with UCSB-SOBQ or standardized measures of SPS severity. CONCLUSIONS: Dyspnea in SPS is common and occurs at rest with exertion and disturbs sleep. The finding of restrictive physiology and correlation between pulmonary function variables and dyspnea support the hypothesis that thoracic cage constriction by rigidity and/or spasm of the muscles of the trunk causes or contributes to the sensation of dyspnea. The possibility of diaphragmatic involvement requires further study.
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Dispneia/diagnóstico , Rigidez Muscular Espasmódica/diagnóstico , Adulto , Idoso , Dispneia/fisiopatologia , Dispneia/terapia , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Espirometria , Rigidez Muscular Espasmódica/fisiopatologia , Rigidez Muscular Espasmódica/terapia , Capacidade VitalRESUMO
The human reference genome serves as the foundation for genomics by providing a scaffold for alignment of sequencing reads, but currently only reflects a single consensus haplotype, thus impairing analysis accuracy. Here we present a graph reference genome implementation that enables read alignment across 2,800 diploid genomes encompassing 12.6 million SNPs and 4.0 million insertions and deletions (indels). The pipeline processes one whole-genome sequencing sample in 6.5 h using a system with 36 CPU cores. We show that using a graph genome reference improves read mapping sensitivity and produces a 0.5% increase in variant calling recall, with unaffected specificity. Structural variations incorporated into a graph genome can be genotyped accurately under a unified framework. Finally, we show that iterative augmentation of graph genomes yields incremental gains in variant calling accuracy. Our implementation is an important advance toward fulfilling the promise of graph genomes to radically enhance the scalability and accuracy of genomic analyses.
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Genoma Humano/genética , Genômica/métodos , Humanos , Polimorfismo de Nucleotídeo Único/genética , Alinhamento de Sequência/métodos , Análise de Sequência de DNA/métodos , Deleção de Sequência/genética , Sequenciamento Completo do Genoma/métodosAssuntos
Antineoplásicos/uso terapêutico , Linfoma Cutâneo de Células T/tratamento farmacológico , Rigidez Muscular Espasmódica/tratamento farmacológico , Feminino , Humanos , Imunossupressores/uso terapêutico , Linfoma Cutâneo de Células T/complicações , Pessoa de Meia-Idade , Rigidez Muscular Espasmódica/complicaçõesRESUMO
BACKGROUND: Hereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive, adult onset, non-inflammatory neuromuscular disorder with no effective treatment. The causative gene, GNE, codes for UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, which catalyzes the first two reactions in the synthesis of sialic acid. Reduced sialylation of muscle glycoproteins, such as alpha-dystroglycan and neural cell adhesion molecule (NCAM), has been reported in HIBM. METHODS: We treated 4 HIBM patients with intravenous immune globulin (IVIG), in order to provide sialic acid, because IgG contains 8 micromol of sialic acid/g. IVIG was infused as a loading dose of 1 g/kg on two consecutive days followed by 3 doses of 400 mg/kg at weekly intervals. RESULTS: For all four patients, mean quadriceps strength improved from 19.0 kg at baseline to 23.2 kg (+22%) directly after IVIG loading to 25.6 kg (+35%) at the end of the study. Mean shoulder strength improved from 4.1 kg at baseline to 5.9 kg (+44%) directly after IVIG loading to 6.0 kg (+46%) at the end of the study. The composite improvement for 8 other muscle groups was 5% after the initial loading and 19% by the end of the study. Esophageal motility and lingual strength improved in the patients with abnormal barium swallows. Objective measures of functional improvement gave variable results, but the patients experienced improvements in daily activities that they considered clinically significant. Immunohistochemical staining and immunoblotting of muscle biopsies for alpha-dystroglycan and NCAM did not provide consistent evidence for increased sialylation after IVIG treatment. Side effects were limited to transient headaches and vomiting. CONCLUSION: The mild benefits in muscle strength experienced by HIBM patients after IVIG treatment may be related to the provision of sialic acid supplied by IVIG. Other sources of sialic acid are being explored as treatment options for HIBM.