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Removal of introns from eukaryotic messenger RNA precursors often occurs co-transcriptionally. In this issue of Cell, Fiszbein et al. report that evolutionary or tissue-specific activation of an internal exon can enhance gene expression by promoting the use of alternative transcription initiation sites.
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Precursores de RNA , Splicing de RNA , Éxons , Íntrons , RNA MensageiroRESUMO
BACKGROUND & AIMS: Liver injury after COVID-19 vaccination is very rare and shows clinical and histomorphological similarities with autoimmune hepatitis (AIH). Little is known about the pathophysiology of COVID-19 vaccine-induced liver injury (VILI) and its relationship to AIH. Therefore, we compared VILI with AIH. METHODS: Formalin-fixed and paraffin-embedded liver biopsy samples from patients with VILI (n = 6) and from patients with an initial diagnosis of AIH (n = 9) were included. Both cohorts were compared by histomorphological evaluation, whole-transcriptome and spatial transcriptome sequencing, multiplex immunofluorescence, and immune repertoire sequencing. RESULTS: Histomorphology was similar in both cohorts but showed more pronounced centrilobular necrosis in VILI. Gene expression profiling showed that mitochondrial metabolism and oxidative stress-related pathways were more and interferon response pathways were less enriched in VILI. Multiplex analysis revealed that inflammation in VILI was dominated by CD8+ effector T cells, similar to drug-induced autoimmune-like hepatitis. In contrast, AIH showed a dominance of CD4+ effector T cells and CD79a+ B and plasma cells. T-cell receptor (TCR) and B-cell receptor sequencing showed that T and B cell clones were more dominant in VILI than in AIH. In addition, many T cell clones detected in the liver were also found in the blood. Interestingly, analysis of TCR beta chain and Ig heavy chain variable-joining gene usage further showed that TRBV6-1, TRBV5-1, TRBV7-6, and IgHV1-24 genes are used differently in VILI than in AIH. CONCLUSIONS: Our analyses support that SARS-CoV-2 VILI is related to AIH but also shows distinct differences from AIH in histomorphology, pathway activation, cellular immune infiltrates, and TCR usage. Therefore, VILI may be a separate entity, which is distinct from AIH and more closely related to drug-induced autoimmune-like hepatitis. IMPACT AND IMPLICATIONS: Little is known about the pathophysiology of COVID-19 vaccine-induced liver injury (VILI). Our analysis shows that COVID-19 VILI shares some similarities with autoimmune hepatitis, but also has distinct differences such as increased activation of metabolic pathways, a more prominent CD8+ T cell infiltrate, and an oligoclonal T and B cell response. Our findings suggest that VILI is a distinct disease entity. Therefore, there is a good chance that many patients with COVID-19 VILI will recover completely and will not develop long-term autoimmune hepatitis.
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COVID-19 , Doença Hepática Crônica Induzida por Substâncias e Drogas , Hepatite Autoimune , Humanos , Vacinas contra COVID-19/efeitos adversos , SARS-CoV-2 , COVID-19/prevenção & controle , Fígado/patologia , Receptores de Antígenos de Linfócitos T , VacinaçãoRESUMO
OBJECTIVE: The possibility of combining real and virtual environments is driving the increased use of augmented reality (AR) in education, including medical training. The aim of this multicentre study was to evaluate the students' perspective on the AR-based Rheumality GO!® app as a new teaching concept, presenting six real anonymised patient cases with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA). METHODS: The study encompassed 347 undergraduate medical students (232 women and 115 men) from four medical universities in Germany (Jena, Bad Nauheim/Gießen, Nuremberg, Erlangen). The course was divided into a theoretical refresher lecture followed by six AR-based cases in each of the three indications presented in the Rheumality GO!® app. All participants evaluated the course after completion, assessing the benefit of the app from a student´s perspective using a questionnaire with 16 questions covering six subject areas. RESULTS: The use of the AR-based app Rheumality GO!® improved the understanding of pathologies in RA, PsA, and axSpA for 99% of the participants. For 98% of respondents, the concept of AR with real patient data has made a positive impact on the teaching environment. On the other hand, 82% were in favour of the use of virtual tools (e.g. AR) in addition to this conventional approach. CONCLUSION: The results of our survey showed that from medical students' perspective, an AR-based concept like the Rheumality GO!® app can complement rheumatology teaching in medical school as an effective and attractive tool though not replace bedside teaching.
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BACKGROUND: SARS-CoV-2 replicates efficiently in the upper airways of humans and produces high loads of virus RNA and, at least in the initial phase after infection, many infectious virus particles. Studying virus ultrastructure, such as particle integrity or presence of spike proteins, and effects on their host cells in patient samples is important to understand the pathogenicity of SARS-CoV-2. METHODS: Suspensions from swab samples with a high load of virus RNA (Ct < 20) were sedimented by desktop ultracentrifugation and prepared for thin section electron microscopy using a novel method which is described in detail. Embedding was performed in Epon or in LR White resin using standard or rapid protocols. Thin sections were examined using transmission electron microscopy. RESULTS: Virus particles could be regularly detected in the extracellular space, embedded in a background of heterogenous material (e.g. vesicles and needle-like crystals), and within ciliated cells. Morphology (i.e. shape, size, spike density) of virus particles in the swab samples was very similar to particle morphology in cell culture. However, in some of the samples the virus particles hardly revealed spikes. Infected ciliated cells occasionally showed replication organelles, such as double-membrane vesicles. The most common cells in all samples were keratinocytes from the mucosa and bacteria. CONCLUSIONS: The new method allows the ultrastructural visualization and analysis of coronavirus particles and of infected host cells from easy to collect naso/oropharyngeal patient swab samples.
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COVID-19 , SARS-CoV-2 , Humanos , Manejo de Espécimes/métodos , Microscopia Eletrônica de Transmissão , RNARESUMO
RNA-binding proteins (RBPs) are crucial factors of post-transcriptional gene regulation and their modes of action are intensely investigated. At the center of attention are RNA motifs that guide where RBPs bind. However, sequence motifs are often poor predictors of RBP-RNA interactions in vivo. It is hence believed that many RBPs recognize RNAs as complexes, to increase specificity and regulatory possibilities. To probe the potential for complex formation among RBPs, we assembled a library of 978 mammalian RBPs and used rec-Y2H matrix screening to detect direct interactions between RBPs, sampling > 600 K interactions. We discovered 1994 new interactions and demonstrate that interacting RBPs bind RNAs adjacently in vivo. We further find that the mRNA binding region and motif preferences of RBPs deviate, depending on their adjacently binding interaction partners. Finally, we reveal novel RBP interaction networks among major RNA processing steps and show that splicing impairing RBP mutations observed in cancer rewire spliceosomal interaction networks. The dataset we provide will be a valuable resource for understanding the combinatorial interactions of RBPs with RNAs and the resulting regulatory outcomes.
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Proteínas de Ligação a RNA/metabolismo , RNA/metabolismo , Técnicas do Sistema de Duplo-Híbrido , Animais , Humanos , Camundongos , Mutação , Neoplasias/genética , Motivos de Nucleotídeos , Ligação Proteica , RNA/química , Fatores de Processamento de RNA/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genéticaRESUMO
A 69-year-old male patient with seropositive erosive rheumatoid arthritis (RA) presented to our clinic due to progressive dyspnea. High-resolution computed tomography (HRCT) and immunological bronchioalveolar lavage revealed ground-glass opacities and a lymphocytic alveolitis caused by interstitial lung disease (ILD) in RA. Considering previous forms of treatment, disease-modifying antirheumatic drug (DMARD) treatment was switched to tofacitinib. Tofacitinib treatment demonstrated a 33% reduction in ground-glass opacities by artificial intelligence-based quantification of pulmonary HRCT over the course of 6 months, which was associated with an improvement in dyspnea symptoms. In conclusion, tofacitinib represents an effective anti-inflammatory therapeutic option in the treatment of RA-ILD.
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BACKGROUND: Nuclear endosperm development is a common mechanism among Angiosperms, including Arabidopsis. During nuclear development, the endosperm nuclei divide rapidly after fertilization without cytokinesis to enter the syncytial phase, which is then followed by the cellularized phase. The endosperm can be divided into three spatial domains with distinct functions: the micropylar, peripheral, and chalazal domains. Previously, we identified two putative small invertase inhibitors, InvINH1 and InvINH2, that are specifically expressed in the micropylar region of the syncytial endosperm. In addition, ectopically expressing InvINH1 in the cellularized endosperm led to a reduction in embryo growth rate. However, it is not clear what are the upstream regulators responsible for the specific expression of InvINHs in the syncytial endosperm. RESULTS: Using protoplast transient expression system, we discovered that a group of type I MADS box transcription factors can form dimers to activate InvINH1 promoter. Promoter deletion assays carried out in the protoplast system revealed the presence of an enhancer region in InvINH1 promoter, which contains several consensus cis-elements for the MADS box proteins. Using promoter deletion assay in planta, we further demonstrated that this enhancer region is required for InvINH1 expression in the syncytial endosperm. One of the MADS box genes, AGL62, is a key transcription factor required for syncytial endosperm development. Using promoter-GFP reporter assay, we demonstrated that InvINH1 and InvINH2 are not expressed in agl62 mutant seeds. Collectively, our data supports the role of AGL62 and other type I MADS box genes as the upstream activators of InvINHs expression in the syncytial endosperm. CONCLUSIONS: Our findings revealed several type I MADS box genes that are responsible for activating InvINH1 in the syncytial endosperm, which in turn regulates embryo growth rate during early stage of seed development.
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Proteínas de Arabidopsis/genética , Arabidopsis/genética , Endosperma/metabolismo , Regulação da Expressão Gênica de Plantas , Peptídeos e Proteínas de Sinalização Intercelular , Proteínas de Domínio MADS/genética , beta-Frutofuranosidase/antagonistas & inibidores , Arabidopsis/enzimologia , Endosperma/genética , Elementos Facilitadores Genéticos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Domínio MADS/metabolismo , Regiões Promotoras Genéticas , Protoplastos/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Precise modification and processing of rRNAs are required for the production of ribosomes and accurate translation of proteins. Small nucleolar ribonucleoproteins (snoRNPs) guide the folding, modification, and processing of rRNAs and are thus critical for all eukaryotic cells. Bcd1, an essential zinc finger HIT protein functionally conserved in eukaryotes, has been implicated as an early regulator for biogenesis of box C/D snoRNPs and controls steady-state levels of box C/D snoRNAs through an unknown mechanism. Using a combination of genetic and biochemical approaches, here we found a conserved N-terminal motif in Bcd1 from Saccharomyces cerevisiae that is required for interactions with box C/D snoRNAs and the core snoRNP protein, Snu13. We show that both the Bcd1-snoRNA and Bcd1-Snu13 interactions are critical for snoRNP assembly and ribosome biogenesis. Our results provide mechanistic insight into Bcd1 interactions that likely control the early steps of snoRNP maturation and contribute to the essential role of this protein in maintaining the steady-state levels of snoRNAs in the cell.
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Mutação , Proteínas de Ligação a RNA/genética , Ribonucleoproteínas Nucleares Pequenas/genética , Ribonucleoproteínas Nucleolares Pequenas/genética , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Sequência de Bases , Sobrevivência Celular/genética , Sequência Conservada/genética , Ligação Proteica , Proteínas de Ligação a RNA/metabolismo , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Ribonucleoproteínas Nucleolares Pequenas/metabolismo , Ribossomos/genética , Ribossomos/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Dedos de Zinco/genéticaAssuntos
Eosinofilia , Fasciite , Eosinofilia/diagnóstico , Fasciite/diagnóstico por imagem , Seguimentos , Humanos , UltrassonografiaRESUMO
OBJECTIVES: Rheumatoid arthritis (RA) is associated with an increased risk for osteoporosis and osteoporotic fractures. Since the treatment of RA has improved significantly in recent years, we can expect RA-associated osteoporosis to decrease with good disease control. Therefore, we conducted a retrospective study to investigate whether the frequency of osteoporosis and osteoporotic fractures has changed during 24 years in RA. METHODS: We analysed the data of 1.086 RA patients from the time of the first osteological assessment with bone mineral density (BMD) measurement and collection of osteologically important data during the years 1996 and 2019 at our clinic. According to the treatment period, the patients were divided into cohort 1 (investigation between 1996 and 2004; n=539) and cohort 2 (investigation between 2005 and 2019; n=547). The data of the two cohorts were compared, and predictors of BMD were analysed by linear regression analysis. RESULTS: Prevalence of osteoporosis (28.3% vs 48.4%; p<0.001) as well as osteoporotic peripheral fractures (11.5% vs 21%; p<0.001) and vertebral fractures (6.6% vs 10.9%; p=0.011) were significantly lower and treatment with biologicals (19.7% vs 5.0%; p<0.001) significantly more common and glucocorticoid use was significantly less common (p=0.005) in cohort 2. In RA patients with a disease duration of more than 2 years, BMD was significantly higher under treatment with biologicals (p<0.001) despite increased cumulative glucocorticoid dosages (p<0.001). CONCLUSION: Our study showed a significant decline in osteoporosis and osteoporotic fractures in RA for 24 years. This positive effect is associated with the more frequent use of biologicals in the years between 2005 and 2019.
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Artrite Reumatoide , Densidade Óssea , Osteoporose , Fraturas por Osteoporose , Humanos , Artrite Reumatoide/complicações , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/tratamento farmacológico , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/prevenção & controle , Osteoporose/epidemiologia , Osteoporose/etiologia , Osteoporose/complicações , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Prevalência , Adulto , Antirreumáticos/uso terapêutico , Fatores de RiscoRESUMO
OBJECTIVES: Inflammatory rheumatic diseases (IRD) are often associated with interstitial lung disease (ILD). The aim of the present study was to establish a correlation between the findings on HRCT and the immunological bronchoalveolar lavage (BAL). METHODS: The study included 74 patients with newly diagnosed IRD and evidence of ILD on HRCT with the following pattern: ground-glass opacities (GGO), non-specific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP). Patients with other HRCT pattern were excluded. No patient received any immunosuppressive therapy. In addition to HRCT, immunological BAL was performed and the American Thoracic Society clinical practice guideline were used to define BAL patterns (lymphocytic cellular pattern, neutrophilic cellular pattern, eosinophilic cellular pattern and unspecified pattern). RESULTS: The main HRCT patterns were NSIP (47.3%), GGO (33.8%), and UIP (18.9%). BAL patterns showed the following distribution: 41.9% lymphocytic cellular pattern, 23.0% neutrophilic cellular pattern, 18.9% eosinophilic cellular pattern, and 16.2% unspecific cellular pattern. Placing these data in the context of the HRCT findings, the lymphocytic cellular BAL pattern (48%) was most commonly BAL pattern associated with GGO pattern in HRCT, whereas neutrophilic and lymphocytic cellular BAL patterns were the dominant feature in NSIP and UIP. CONCLUSION: In patients with new-onset IRD and ILD, inflammatory pulmonary changes are predominate, reflected by GGO on HRCT and a mainly lymphocytic cell profile in the immunological BAL. In NSIP or UIP on HRCT, the percentages of lymphocytes and neutrophils were higher in BAL fluid, representing a fibrotic component in addition to the inflammation. Consequently, patients with evidence of GGO on HRCT should primarily be treated with anti-inflammatory/immunosuppressive therapy, whereas in patients with NSIP and UIP a combination of anti-inflammatory and anti-fibrotic agents would be the appropriate treatment.
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Líquido da Lavagem Broncoalveolar , Doenças Pulmonares Intersticiais , Doenças Reumáticas , Tomografia Computadorizada por Raios X , Humanos , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/diagnóstico , Feminino , Masculino , Tomografia Computadorizada por Raios X/métodos , Pessoa de Meia-Idade , Doenças Reumáticas/diagnóstico por imagem , Doenças Reumáticas/imunologia , Idoso , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Adulto , Lavagem Broncoalveolar/métodosRESUMO
An 83-year-old male patient presented due to a 3-week history of swelling of the tongue with tongue pain on eating, yellowish plaques, and a gray-brown lesion in the anterior portion of the tongue. Sudden loss of vision in the left eye and temporal headache occurred 3 days before presentation. Due to elevated Creactive protein, sonography of the supraaortic arteries as well as positron emission tomography/computed tomography was performed. Imaging revealed inflammation of the great arteries as well as a halo sign on ultrasound of the temporal artery. Thus, a diagnosis of giant cell arteritis with necrosis of the tongue was made. Immunosuppressive therapy with glucocorticoids was initiated. Necrosis of the tongue is a rare manifestation of giant cell arteritis that requires immediate immunosuppressive therapy to prevent further complications to the tongue (e.g., complete necrosis of the tongue, superinfection, tongue amputation).
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Lung involvement is the most common and serious organ manifestation in patients with inflammatory rheumatic disease (IRD). The type of pulmonary involvement can differ, but the most frequent is interstitial lung disease (ILD). The clinical manifestations of IRD-ILD and severity can vary from subclinical abnormality to dyspnea, respiratory failure, and death. Consequently, early detection is of significant importance. Pulmonary function test (PFT) including diffusing capacity of the lungs for carbon monoxide (DLCO), and forced vital capacity (FVC) as well as high-resolution computed tomography (HRCT) are the standard tools for screening and monitoring of ILD in IRD-patients. Especially, the diagnostic accuracy of HRCT is considered to be high. Magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) allow both morphological and functional assessment of the lungs. In addition, biomarkers (e.g., KL-6, CCL2, or MUC5B) are being currently evaluated for the detection and prognostic assessment of ILD. Despite the accuracy of HRCT, invasive diagnostic methods such as bronchoalveolar lavage (BAL) and lung biopsy are still important in clinical practice. However, their therapeutic and prognostic relevance remains unclear. The aim of this review is to give an overview of the individual methods and to present their respective advantages and disadvantages in detecting and monitoring ILD in IRD-patients in the clinical routine.
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Mutations in regulatory mechanisms that control gene expression contribute to phenotypic diversity and thus facilitate the adaptation of microbes and other organisms to new niches. Comparative genomics can be used to infer rewiring of regulatory architecture based on large effect mutations like loss or acquisition of transcription factors but may be insufficient to identify small changes in noncoding, intergenic DNA sequence of regulatory elements that drive phenotypic divergence. In human-derived Vibrio cholerae, the response to distinct chemical cues triggers production of multiple transcription factors that can regulate the type VI secretion system (T6), a broadly distributed weapon for interbacterial competition. However, to date, the signaling network remains poorly understood because no regulatory element has been identified for the major T6 locus. Here we identify a conserved cis-acting single nucleotide polymorphism (SNP) controlling T6 transcription and activity. Sequence alignment of the T6 regulatory region from diverse V. cholerae strains revealed conservation of the SNP that we rewired to interconvert V. cholerae T6 activity between chitin-inducible and constitutive states. This study supports a model of pathogen evolution through a noncoding cis-regulatory mutation and preexisting, active transcription factors that confers a different fitness advantage to tightly regulated strains inside a human host and unfettered strains adapted to environmental niches. IMPORTANCE Organisms sense external cues with regulatory circuits that trigger the production of transcription factors, which bind specific DNA sequences at promoters ("cis" regulatory elements) to activate target genes. Mutations of transcription factors or their regulatory elements create phenotypic diversity, allowing exploitation of new niches. Waterborne pathogen Vibrio cholerae encodes the type VI secretion system "nanoweapon" to kill competitor cells when activated. Despite identification of several transcription factors, no regulatory element has been identified in the promoter of the major type VI locus, to date. Combining phenotypic, genetic, and genomic analysis of diverse V. cholerae strains, we discovered a single nucleotide polymorphism in the type VI promoter that switches its killing activity between a constitutive state beneficial outside hosts and an inducible state for constraint in a host. Our results support a role for noncoding DNA in adaptation of this pathogen.
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Sistemas de Secreção Tipo VI , Vibrio cholerae , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Humanos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Sistemas de Secreção Tipo VI/genética , Sistemas de Secreção Tipo VI/metabolismo , Vibrio cholerae/metabolismoRESUMO
Up to now, there is only limited information available on a possible relationship between clinical characteristics and the mineralization of metacarpal bones and finger joint space distance (JSD) in patients with psoriatic arthritis (PsA). Computerized digital imaging techniques like digital X-ray radiogrammetry (DXR) and computer-aided joint space analysis (CAJSA) have significantly improved the structural analysis of hand radiographs and facilitate the recognition of radiographic damage. The objective of this study was to evaluate clinical features which potentially influence periarticular mineralization of the metacarpal bones and finger JSD in PsA-patients. 201 patients with PsA underwent computerized measurements of the metacarpal bone mineral density (BMD) with DXR and JSD of all finger joints by CAJSA. DXR-BMD and JSD were compared with clinical features such as age and sex, disease duration, C-reactive protein (CRP) as well as treatment with prednisone and disease-modifying antirheumatic drugs (DMARDs). A longer disease duration and an elevated CRP value were associated with a significant reduction of DXR-BMD, whereas JSD-parameters were not affected by both parameters. DXR-BMD was significantly reduced in the prednisone group (-0.0383 g/cm²), but prednisone showed no impact on finger JSD. Patients under the treatment with bDMARDs presented significant lower DXR-BMD (-0.380 g/cm²), JSDMCP (-0.0179 cm), and JSDPIP (-0.0121 cm) values. Metacarpal BMD was influenced by inflammatory activity, prednisone use, and DMARDs. In contrast, finger JSD showed only a change compared to baseline therapy. Therefore, metacarpal BMD as well as finger JSD represent radiographic destruction under different aspects.
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Antirreumáticos , Artrite Psoriásica , Artrite Reumatoide , Humanos , Artrite Psoriásica/diagnóstico por imagem , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/complicações , Artrite Reumatoide/tratamento farmacológico , Prednisona/uso terapêutico , Antirreumáticos/uso terapêutico , Densidade Óssea , Absorciometria de FótonRESUMO
BACKGROUND: Giant cell arteritis (GCA) with the involvement of extracranial vessels is increasingly coming into focus. Isolated aortic involvement in the acute phase of GCA is probably more frequent than estimated because only a minority of patients show typical symptoms. 18F-fluorodeoxyglucose positron emission tomography/CT (PET/CT) is a reliable imaging tool to diagnose patients with extracranial GCA. The aim of this retrospective study was to quantify arterial involvement at the onset of a newly diagnosed GCA by PET/CT and to evaluate the influence of glucocorticoid (GC) treatment on the diagnostic performance of this imaging technique. METHODS: The study included 60 patients with GCA at the onset of a GCA. All patients had undergone a PET/CT scan. 44 patients were GC naïve and 16 patients received GC. RESULTS: The most affected arteries were the ascending aorta (72%), followed by the brachiocephalic trunk (62%), aortic arch (60%) and descending aorta (60%). The aorta and its branches showed an inflammatory involvement in 83.3% of patients. A singular affection of the aorta and the brachiocephalic trunk was revealed in 20% of cases. GC-naïve patients (95.5%) had more frequently affected arteries compared with GC-treated patients (50%). CONCLUSION: Our study showed the frequent involvement of the thoracic aorta and brachiocephalic trunk in patients with GCA using PET/CT. Since these vascular compartments cannot be visualised by ultrasound, we advocate screening imaging of the aorta with PET/CT when GCA is suspected. Because the use of GC is associated with a marked decrease in the inflamed vascular segment in GCA, PET/CT should be performed as soon as possible.
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Arterite de Células Gigantes , Artérias , Fluordesoxiglucose F18 , Arterite de Células Gigantes/diagnóstico por imagem , Arterite de Células Gigantes/tratamento farmacológico , Glucocorticoides/efeitos adversos , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Estudos RetrospectivosRESUMO
BACKGROUND: Interstitial lung disease (ILD) is a severe pulmonary complication in inflammatory rheumatic diseases (IRD) and associated with significantly increased morbidity and mortality. That is why ILD screening at a very early stage, at the onset of IRD, is essential. The objective of the present study was to evaluate the diagnostic value and utility of a stepwise approach as a potential ILD screening tool in patients with newly diagnosed IRD. METHODS: Consecutively, 167 IRD patients were enrolled. To homogenize the study cohort, an age and gender matching was performed. The case-control study included 126 patients with new onset of IRD (mainly connective tissue diseases [CTD], small vessel vasculitis, and myositis). We applied a stepwise screening algorithm in which all patients underwent pulmonary function testing (PFT) and/or additional chest radiography. If there was at least one abnormal finding, pulmonary high-resolution computed tomography (HRCT) was subsequently performed. RESULTS: With our stepwise diagnostic approach, we identified 63 IRD patients with ILD (ILD group) and 63 IRD patients without ILD (non-ILD group). A reduced diffusing capacity for carbon monoxide (DLCO) < 80% showed a sensitivity of 83.6% and a specificity of 45.8% compared to chest X-ray with 64.2% and 73.6%, respectively, in detecting ILD. The combination of reduced DLCO and chest X-ray revealed a sensitivity of 95.2% and a specificity of 38.7%. The highest sensitivity (95.2%) and specificity (77.4%) were observed for the combination of reduced DLCO, chest X-ray, and pulmonary HRCT. The most common pulmonary abnormalities on HRCT were ground-glass opacities (GGO; 36.5%), followed by non-specific interstitial pneumonia (NSIP; 31.8%) and usual interstitial pneumonia (UIP; 9.5%). CONCLUSIONS: The combination of reduced DLCO (< 80%), chest X-ray, and pulmonary HRCT yielded the highest sensitivity and specificity in detecting ILD at the onset of IRD. Therefore, this stepwise approach could be a new screening algorithm to identify IRD patients with pulmonary involvement already at the time of the initial IRD diagnosis.
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Doenças Pulmonares Intersticiais , Doenças Reumáticas , Estudos de Casos e Controles , Humanos , Pulmão/diagnóstico por imagem , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/etiologia , Testes de Função Respiratória , Estudos Retrospectivos , Doenças Reumáticas/complicações , Doenças Reumáticas/diagnósticoRESUMO
The apicomplexan parasite Toxoplasma gondii forms bradyzoite-containing tissue cysts that cause chronic and drug-tolerant infections. However, current in vitro models do not allow long-term culture of these cysts to maturity. Here, we developed a human myotube-based in vitro culture model of functionally mature tissue cysts that are orally infectious to mice and tolerate exposure to a range of antibiotics and temperature stresses. Metabolomic characterization of purified cysts reveals global changes that comprise increased levels of amino acids and decreased abundance of nucleobase- and tricarboxylic acid cycle-associated metabolites. In contrast to fast replicating tachyzoite forms of T. gondii these tissue cysts tolerate exposure to the aconitase inhibitor sodium fluoroacetate. Direct access to persistent stages of T. gondii under defined cell culture conditions will be essential for the dissection of functionally important host-parasite interactions and drug evasion mechanisms. It will also facilitate the identification of new strategies for therapeutic intervention.
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Fibras Musculares Esqueléticas , Toxoplasma , Animais , Interações Hospedeiro-Parasita , Humanos , Metaboloma , Camundongos , Fibras Musculares Esqueléticas/parasitologia , Toxoplasma/metabolismoRESUMO
BACKGROUND: Coexistence of atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) is common, affecting morbidity and prognosis. This study evaluates outcome after cryoballoon ablation for AF in HFpEF compared with patients without heart failure. METHODS: A total of 102 AF patients with left ventricular ejection fraction ≥50% undergoing cryoballoon ablation were prospectively enrolled. Baseline evaluation included echocardiography, stress echocardiography, 6-minute walk test, biomarkers, and quality of life assessment (Short-Form-36). Procedural parameters and clinical, functional and echocardiographic end points at follow-up ≥12 months after AF ablation were compared between patients with and without HFpEF. RESULTS: Patients with HFpEF (n=24) were older (median, 74 years versus 65 years; P=0.001) more often female (83% versus 28%; P<0.001) and characterized by more pronounced AF-related symptoms (median European Heart Rhythm Association score 3 versus 2; P<0.001), higher left atrial pressures (median, 14 mm Hg versus 10 mm Hg; P=0.008), reduced left atrial-appendage velocity (median, 36 cm/s versus 59 cm/s; P<0.001), and reduced distance in the 6-minute walk test (median, 488 m versus 539 m; P<0.001). Patients with HFpEF more often experienced AF recurrence (57% versus 23%; P=0.003), repeat AF ablation (39% versus 14%; P=0.01) and AF-related rehospitalization (26% versus 7%; P=0.016). Heart failure symptoms and elevated cardiac biomarkers persisted, even in patients with HFpEF with successful rhythm control at follow-up. Echocardiographic follow-up showed progression of adverse left atrial remodeling and no relevant improvement in diastolic function in HFpEF. Quality of life improved in patients without HFpEF, whereas patients with HFpEF still exhibited a lower physical component summary score (median, 41.5 versus 53.4; P<0.004). CONCLUSIONS: Patients with HFpEF constitute a distinct subgroup with elevated risk for AF recurrence after cryoballon ablation. Functional hallmarks of HFpEF persist, irrespective of rhythm status at follow-up. Future research is needed to optimize treatment strategies in patients with HFpEF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04317911.