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Scleroderma lung disease and β-thymosins:bronchoalveolar lavage fluid biomarkers
No full textObiettivi. Le β timosine sono un gruppo di piccoli peptidi con una massa molecolare di 5 kDa. Queste chemochine sono coinvolte nella polimerizzazione intracellulare dell’actina, ma possiedono anche numerose funzioni extracellulari e svolgono un ruolo nell’angiogenesi e nell’infiammazione. In particolare la timosina β4 (Tβ4) è un peptide ubiquitario essenzialmente intracellulare e strettamente coinvolto nella regolazione del citoscheletro inquanto è deputato a sequestrare l’actina monomerica o a rilasciarla in caso di polimerizzazione. La Tβ4 esercita, inotre, importanti funzioni regolatorie sia a livello intracellulare (i.e. signaling) sia a livello extracellulare (proprietà antinfiammatorie, proprietà favorenti la guarigione delle ulcere e l’angiogenesi). Esiste una forma sulfossidata della Tβ4, la sTβ4.
La timosina β10 (Tβ10) è invece prodotta in corso di precancerosi, cancro ed infiammazione ed ha un’azione antiangiogenetica ed è coinvolta nella modificazione della motilità cellulare. Recentemente è stata descritta la presenza delle Tβ nella saliva di soggetti sani e nel fluido crevicolare gengivale utilizzando la RP-HPLC-ESI-MS. L’obiettivo di questo studio è stato quello di valutare l’eventuale presenza delle Tβ in un altro liquido biologico, il broncolavaggio alveolare (BAL) di soggetti sani e di soggetti affetti da sclerodermia con impegno polmonare. Inoltre, per individuare un marcatore di coinvolgimento polmonare in corso di sclerodermia sono stati studiati i livelli della Tβ4, sTβ4 e della Tβ10 e le loro reciproche variazioni in pazienti con e senza alveolite al BAL. Infine le concentrazioni delle Tβ sono state correlate al coinvolgimento funzionale e radiologico del polmone.
Dato il ruolo delle β timosine nell’angiogenesi e la loro capacità di modulare il VEGF (vascular endothelial growth factor), anche i livelli di VEGF sono stati studiati nel BAL.
Metodi. 15 controlli sani e 46 pazienti affetti da sclerodermia sono stati sottoposti a broncoscopia e i BAL ottenuti sono stati analizzati con un metodo proteomico. I pazienti affetti da sclerodermia sono inoltre stati sottoposti alle prove di funzionalità respiratoria e alla TAC ad alta risoluzione del polmone al basale e dopo 12 mesi. Le Tβ nel BAL sono state identificate mediante RP-HPLC-ESI-MS, mentre i livelli di VEGF sono stati valutati con metodica ELISA.
Risultati. I livelli di Tβ4 sono risultati significativamente più elevati nei pazienti affetti da sclerodermia (0.310 +/- 0.372 μmol/L), rispetto ai controlli (0.112 +/- 0.084 μmol/L), p=0.008. Considerando i pazienti affetti da sclerodermia i livelli di sTβ4 erano significativamente più elevati nei pazienti con alveolite (0.025 +/- 0.052 μmol/L), rispetto ai pazienti senza alveolite (0.006 +/- 0.022 μmol/L), p=0.05. Ventiquattro pazienti (52.2%) presentavano un’alveolite al BAL. I pazienti che presentavano, dopo un anno di follow-up, un peggioramento dello score alveolare avevano livelli di Tβ4 più bassi. I livelli di sTβ4 correlavano con la percentuale di neutrofili al BAL (r=+0.36, p=0.013). Sebbene i livelli di Tβ10 fossero più elevati nei pazienti con sclerodermia rispetto ai controlli questa differenza non era statisticamente significativa. Inoltre vi era una correlazione indiretta tra i livelli di Tβ10 e la DLCO nei pazienti con sclerodermia (r=-0.39, p=0.009).
Sono stati inoltre evidenziati nel BAL livelli significativamente più bassi di VEGF nei pazienti sclerodermici rispetto ai controlli sani, ed in particolare nei pazienti con alveolite rispetto ai pazienti senza alveolite.
Conclusioni. In questo studio per la prima volta sono stati studiati la presenza e i livelli di Tβ (Tβ4, sTβ4 e Tβ10) nel BAL di soggetti sani e in pazienti sclerodermici con impegno polmonare. Mentre la Tβ4 è costitutivamente espressa nel polmone, la sTβ4 e la Tβ10 sono espresse solo in alcuni pazienti e in alcuni controlli sani. Gli elevati livelli di Tβ4 nei pazienti sclerodermici rispetto ai controlli suggerisce la Tβ4 come un possibile marcatore di patologia; mentre le diverse concentrazioni di sTβ4 nei pazienti con alveolite rispetto ai pazienti senza alveolite suggeriscono che questa molecola sia un possibile biomarcatore di stress ossidativo e di danno polmonare, vista anche la correlazione tra i livelli di sTβ4 e la percentuale di neutrofili.
La correlazione tra i livelli di Tβ10 e la DLCO, invece, suggerisce un possibile ruolo inibitorio della Tβ10 sulla permeabilità alveolo-capillare. Quindi questi risultati indicano un possibile coinvolgimento di questi piccoli fattori paracrini nella patogenesi della malattia sclerodermica e che la Tβ4 possa avere un ruolo cito-protettivo nel danno tissutale del coinvolgimento polmonare sclerodermico. La presenza del prodotto di ossidazione della Tβ4, la sTβ4, sembra invece rispecchiare la presenza di uno stato infiammatorio, caratteristico dell’alveolite.
I bassi livelli di VEGF nel BAL dei pazienti con alveolite sclerodermica confermano il possibile ruolo del VEGF nel mantenere l’omeostasi alveolo-capillare del polmone e la correlazione inversa tra il VEGF e la sTβ4 è suggestivo del ruolo contrapposto delle due molecole nel processo alveolitico.Objective. The role of β-thymosins (Tβ4, Tβ4 sulfoxide [sTβ4], Tβ10) in cytoscheleton rearrangement, angiogenesis, fibrosis and reparative process suggests a possible involvement of these peptides in the pathogenesis of systemic sclerosis (SSc). The aims of the study were to demonstrate the presence of Tβ4, sTβ4 and Tβ10 in bronchoalveolar lavage fluid (BALF) of SSc patients with interstitial lung disease (ILD) and to correlate their levels with the biologic, functional and radiological parameters of the lung involvement and to the progression of ILD. Considering the role of β-thymosins in the angiogenetic process and in modulation of vascular endothelial growth factor (VEGF) production, also the VEGF BAL levels were investigated.
Patients and Methods. Tβ4, sTβ4, Tβ10 were determined by HPLC-ESI-MS in BALF samples of 46 SSc patients with ILD and of 15 control subjects. VEGF levels were evaluated by ELISA.
Results. Tβ4 levels were significantly higher in SSc patients than in controls (SSc: 0.310 +/- 0.372 μmol/L vs controls: 0.112 +/- 0.084 μmol/L, p=0.008). Nevertheless, lower BALF Tβ4 levels were found in the SSc patients with significantly worsening in the alveolar score on HRCT after one-year follow-up. In SSc cohort, patients with alveolitis presented higher BAL levels of sTβ4 (0.025 +/- 0.052 μmol/L) than SSc patient without alveolitis (0.006 +/- 0.022 μmol/L), p=0.05. Higher sTβ4 BALF levels correlated with the smoking habits, the presence of alveolitis, the BALF neutrophil percentage count, an inverted BALF CD4/CD8 ratio, and a lower forced vital capacity. Tβ10 levels directly correlated with the BALF lymphocyte percentage count and inversely with the carbon monoxide diffusing capacity. Furthermore SSc patients presented lower BAL VEGF levels compared to controls, principally the SSc patients with alveolitis.
Conclusion. In this study for the first time the presence of Tβ4, its sulfoxide form and Tβ10 in human BALF has been described and the results suggested the possible involvement of these paracrine factors in the pathogenesis of scleroderma lung disease. As described in other studies, Tβ4 seems to have a protective role against tissue damage even in SSc lung disease and its oxidation product sTβ4 seems to mirror the presence of an inflammatory condition. The correlation between Tβ10 and DLCO suggests an inhibitory role of Tβ10 in the alveolar capillary permeability, while the inverse correlation between VEGF levels and sTβ4 levels implies a opposite role of these two molecules
Sixth-month remission as a predictor for twelve-month remission in polymyalgia rheumatica
Full text linkObjectives: To investigate clinical and laboratory prognostic factors of remission after one year of follow-up in patients with polymyalgia rheumatica (PMR) treated with low-dose prednisone.
Methods: In this observational study, in a monocentric Italian Rheumatology Unit, we enrolled eighty-one consecutive PMR patients. Clinical and laboratory tests were performed every 3 months. Clinical remission was defined as the lack of symptoms, while laboratory remission was defined as erythrocyte sedimentation rate ≤40 mm/h and C-reactive protein (CRP) ≤0.5 mg/dl.
Results: Thirty-eight patients reached complete (clinical and laboratory) remission after 12 months of follow-up. A significant lower percentage of complete remission was seen in female gender compared to male (33.9 % vs. 78.2%, p=0.0001) at univariate analysis. No significant differences were found at baseline according to response to therapy during follow-up, while CRP values at the sixth month were significantly lower in patients who reached complete remission after one year (median: 0.4 mg/dl vs. 1 mg/dl, p=0.017). CRP<0.5 mg/dl at 6 months was independently associated with complete remission at 12 months in the multivariate analysis.
Conclusions: The sixth month of therapy is a target for the management of PMR because it can help to identify patients at greater risk of exacerbations, who may benefit from a tighter follow-up and more aggressive therapeutic strategy. Higher CRP values at 6 months appear to be associated with a higher risk of longer steroid therapy
Sixth-month remission as a predictor for twelve-month remission in polymyalgia rheumatica
No full textObjectives: To investigate clinical and laboratory prognostic factors of remission after one year of follow-up in patients with polymyalgia rheumatica (PMR) treated with low-dose prednisone. Methods: In this observational study, in a monocentric Italian Rheumatology Unit, we enrolled eighty-one consecutive PMR patients. Clinical and laboratory tests were performed every 3 months. Clinical remission was defined as the lack of symptoms, while laboratory remission was defined as erythrocyte sedimentation rate ≤40 mm/h and C-reactive protein (CRP) ≤0.5 mg/dl. Results: Thirty-eight patients reached complete (clinical and laboratory) remission after 12 months of follow-up. A significant lower percentage of complete remission was seen in female gender compared to male (33.9 % vs. 78.2%, p=0.0001) at univariate analysis. No significant differences were found at baseline according to response to therapy during follow-up, while CRP values at the sixth month were significantly lower in patients who reached complete remission after one year (median: 0.4 mg/dl vs. 1 mg/dl, p=0.017). CRP<0.5 mg/dl at 6 months was independently associated with complete remission at 12 months in the multivariate analysis. Conclusions: The sixth month of therapy is a target for the management of PMR because it can help to identify patients at greater risk of exacerbations, who may benefit from a tighter follow-up and more aggressive therapeutic strategy. Higher CRP values at 6 months appear to be associated with a higher risk of longer steroid therapy
QTc interval prolongation in Systemic Sclerosis: Correlations with clinical variables and arrhythmic risk
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Interstitial Lung Disease Associated With Autoimmune Rheumatic Diseases: Checklists for Clinical Practice
Full text linkBackground: Interstitial lung diseases (ILDs) are often associated with rheumatic diseases. Their early diagnosis and management are not only difficult, but also crucial, because they are associated with major morbidity and mortality and can be the first cause of death in autoimmune rheumatic diseases (ARDs).Objectives: By using methodologies, such as Nominal Group Technique (NGT) and Delphi Survey, the aims of this study were (1) to measure consensus between pulmonologists, radiologists, and rheumatologists experienced in the management of ARD-ILD; (2) to highlight the importance of a multidisciplinary approach; and (3) to provide clinicians with a practical tool aimed at improving the prompt recognition and follow-up of ILD associated with ARDs and of any possible rheumatic conditions underlying ILD.Results: During the NGT round, the Steering Committee defined 57 statements to be used in the Delphi survey. A total of 78 experts participated in the Delphi survey, namely 28 pulmonologists, 33 rheumatologists, and 17 radiologists. During this round, consensus on agreement was reached in 47 statements, while disagreement was not reached in any statements. A secondary questionnaire was drafted by the Steering Committee to obtain clearer indications on ILD-ARD "red-flags" and follow-up. Delphi Panelists took part also in the second-questionnaire survey. Answers from both surveys were used to draft two checklists of "red flags" sign or symptom suggestive of ILD and ARD, respectively, and two checklists on identification and monitoring of rheumatoid arthritis (RA) and systemic sclerosis (SSc) ILD.Limitations: This study is a consensus work, which cannot produce empiric data, and is limited to the Italian scenario.Conclusions: This work showed a high level of agreement, but also shows some divergent opinions between different experts. This underlines the importance of a multidisciplinary approach. Eventually, we believe the drafted checklists can help clinicians in the diagnosis and follow-up of ILD-ARD
Correspondence to 'Gender gap in rheumatology: speaker representation at annual conferences' by Monga and Liew-gender discrepancies at annual EULAR congresses: towards the gap narrowing
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What can we learn from rapidly progressive interstitial lung disease related to anti-MDA5 dermatomyositis in the management of COVID-19?
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(AS) TNF-alpha blockade induces a reversible but transient effect on endothelial dysfunction in patients with long-standing severe rheumatoid arthritis.
No full textConsiderable evidence indicates that patients with rheumatoid arthritis (RA) are at greater risk of developing atherosclerosis and cardiovascular disease. Recent studies support the predictive ability of endothelial function measures for subsequent atherosclerotic events. We have investigated the effects of infliximab, a chimeric monoclonal anti-tumor necrosis factor (TNF) antibody, on endothelial vasodilation, measured by brachial ultrasonography and on the levels of inflammatory biomarkers and adhesion molecules in ten consecutive patients with severe long-standing RA, despite methotrexate therapy, during the loading phase of infliximab therapy. Flow-mediated dilation (FMD) in RA patients at baseline was significantly impaired compared with healthy controls (7.71 +/- 2.78% vs 14.91 +/- 6.41%; p = 0.008) and improved significantly after infliximab infusion (12.63 +/- 1.63% vs 7.71 +/- 2.78%; p = 0.005). At baseline, a statistically significant correlation between C-reactive protein levels and FMD was found (r = -0.69, p = 0.026). However, this improvement was transitory, as FMD values returned to baseline values before each infliximab infusion at weeks 2, 6 and 14. There were no significant differences in baseline brachial artery diameter between visits, although at each time, the diameter was increased. According to European League Against Rheumatism response criteria, all ten patients were good responders. No significant differences were observed in intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, vascular endothelial growth factor and E-selectin plasma levels before and after each infusions. This study demonstrates that endothelial dysfunction is a reversible phenomenon in RA. The addition of anti-TNFalpha treatment reduces inflammatory symptoms in patients with severe RA. The improvement of endothelial function during the loading phase of therapy is transitory, suggesting an enhanced and persistent TNF-alpha generation within the arterial wall
Computer-aided quantification of interstitial lung disease from high resolution computed tomography images in systemic sclerosis: correlation with visual reader-based score and physiologic tests
No full textObjective. To evaluate the performance of a computerized-aided method (CaM) for quantification of interstitial lung disease (ILD) in patients with systemic sclerosis and to determine its correlation with the conventional visual reader-based score (CoVR) and the pulmonary function tests (PFTs). Methods. Seventy-nine patients were enrolled. All patients underwent chest high resolution computed tomography (HRCT) scored by two radiologists adopting the CoVR. All HRCT images were then analysed by a CaM using a DICOM software. The relationships among the lung segmentation analysis, the readers, and the PFTs results were calculated using linear regression analysis and Pearson's correlation. Receiver operating curve analysis was performed for determination of CaM extent threshold. Results. A strong correlation between CaM and CoVR was observed (P < 0.0001). The CaM showed a significant negative correlation with forced vital capacity (FVC) (P < 0.0001) and the single breath carbon monoxide diffusing capacity of the lung (DLco) (P < 0.0001). A CaM optimal extent threshold of 20% represented the best compromise between sensitivity (75.6%) and specificity (97.4%). Conclusions. CaM quantification of SSc-ILD can be useful in the assessment of extent of lung disease and may provide reliable tool in daily clinical practice and clinical trials
Troponin in Stable Ischemic Heart Disease and Diabetes
No full textTroponin in Stable Ischemic Heart Disease and Diabete
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