Predictors of disease worsening defined by progression of organ damage in diffuse systemic sclerosis: a European Scleroderma Trials and Research (EUSTAR) analysis.

Objectives Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database. Methods Inclusion criteria were diagnosis of diffuse SSc and follow-up over 12\ub13 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression. Results Of 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model. Conclusions The use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trial

Rooting and acclimatization of micropropagated Hypericum perforatum L. native to Sicily

Hypericum perforatum L. is traditionally used as a medicinal plant because of its different bioactive compounds with documented antidepressant and antiinflammatory activities. Plantlets\u2019 mass production with high content of these secondary metabolites has been enhanced through in vitro culture but the process has often been stopped at the multiplication phase. A study was conducted in order to set up an efficient in vitro rooting and acclimatization protocol of a H. perforatum Sicilian genotype well-adapted to south Mediterranean conditions. Aseptic nodal segments were cultured onto a Murashige and Skoog (MS) basal medium supplemented with 4.44 \ub5M 6-benzyladenine for multiplication. Microshoots were then transferred onto specific culture media for in vitro rooting in order to evaluate the nutrients concentration and different auxins effect: full and half-strength hormone-free MS or supplemented with 5.7 \ub5M indole-3-acetic acid (IAA) or 4.9 \ub5M indole-3-butyric acid (IBA). Highest rooting rate was achieved on full-strength MS with IAA 5.7 \ub5M and on all half-strength MS media; higher number of roots was recorded on half-strength MS with IAA and full-strength MS with IBA 4.9 \ub5M; longest roots were measured on full-strength MS with IAA 5.7 \ub5M. Rooted plantlets were ex vitro acclimatized by transferring them into greenhouse in plastic pots filled with peat: perlite and sand: perlite mixtures (1:1, v/v) under mist: acclimatization rate was higher for rooted plantlets grown in sand:perlite substrate

Effect of weak magnetic fields on the in vitro propagation of Genista aetnensis (Raf. Ex Biv.) Dc.

Over the years, many studies have emphasized the importance of the magnetic fields (MF), used as a safe alternative choice to improve agricultural production. The induction effect of different magnetic fields varies depending on the species, explants typology, intensity of magnetic field and period of exposure. The aim of the present study was to investigate the application of a continuous magnetic field induction, at different exposure times, as a production enhancement for in vitro culture of Genista aetnensis, an endemic shrub commonly named 'Mount Etna broom'. An in vitro protocol has been settled for the conservation of the species. Plantlets cultured onto a solified Murashige and Skoog salts and vitamins medium enriched with 1.78 \u3bcM BA showed the best multiplication rate (3.5 shoot explants-1). All the plants cultured on this medium were induced by a 150 mT MF at different times (0, 1, 2, 3, 4 and 5 min) and, after 3 weeks, the multiplication rate was scored. Root production was also tested on the plantlets coming from the MF induction trial. The MF widely influenced the multiplication response of the species, increasing the number of shoots (7.2 explant-1) at 4-min induction. The magnetised plants, cultured on the same rooting medium, evidenced significant rooting percentage response (92.2%). In this article, the influence of a magnetic field is highlighted, confirming the possibility of a large scale production process

A gender gap in primary and secondary heart dysfunctions in systemic sclerosis: a EUSTAR prospective study.

OBJECTIVES: In agreement with other autoimmune diseases, systemic sclerosis (SSc) is associated with a strong sex bias. However, unlike lupus, the effects of sex on disease phenotype and prognosis are poorly known. Therefore, we aimed to determine sex effects on outcomes. METHOD: We performed a prospective observational study using the latest 2013 data extract from the EULAR scleroderma trials and research (EUSTAR) cohort. We looked at (i) sex influence on disease characteristics at baseline and (ii) then focused on patients with at least 2\u2005years of follow-up to estimate the effects of sex on disease progression and survival. RESULTS: 9182 patients with SSc were available (1321 men) for the baseline analyses. In multivariate analysis, male sex was independently associated with a higher risk of diffuse cutaneous subtype (OR: 1.68, (1.45 to 1.94); p<0.001), a higher frequency of digital ulcers (OR: 1.28 (1.11 to 1.47); p<0.001) and pulmonary hypertension (OR: 3.01 (1.47 to 6.20); p<0.003). In the longitudinal analysis (n=4499), after a mean follow-up of 4.9 (\ub12.7) years, male sex was predictive of new onset of pulmonary hypertension (HR: 2.66 (1.32 to 5.36); p=0.006) and heart failure (HR: 2.22 (1.06 to 4.63); p=0.035). 908 deaths were recorded, male sex predicted deaths of all origins (HR: 1.48 (1.19 to 1.84); p<0.001), but did not significantly account for SSc-related deaths. CONCLUSIONS: Although more common in women, SSc appears as strikingly more severe in men. Our results obtained through the largest worldwide database demonstrate a higher risk of severe cardiovascular involvement in men. These results raise the point of including sex in the management and the decision-making process

Associated autoimmune diseases in Systemic Sclerosis define a subset of patients with milder disease: results from two large cohorts of European Caucasian patients.

OBJECTIVES: To measure the prevalence of, and factors associated with, left ventricular (LV) dysfunction in systemic sclerosis (SSc). METHODS: The EUSTAR database was first searched. A case-control study of a patient subset was then performed to further identify independent factors associated with LV dysfunction by simple and multiple regression. RESULTS: Of 7073 patients, 383 (5.4%) had an LV ejection fraction (EF) of <55%. By multiple regression analysis, age, sex, diffuse cutaneous disease, disease duration, digital ulcerations, renal and muscle involvement, disease activity score, pulmonary fibrosis and pulmonary arterial hypertension were associated with LV dysfunction. In the second phase, 129 patients with SSc with LVEF <55% were compared with 256 patients with SSc with normal LVEF. Male sex (OR 3.48; 95% CI 1.74 to 6.98), age (OR 1.03; 95% CI 1.01 to 1.06), digital ulcerations (OR 1.91; 95% CI 1.05 to 3.50), myositis (OR 2.88; 95% CI 1.15 to 7.19) and use of calcium channel blockers (OR 0.41; 95% CI 0.22 to 0.74) were independent factors associated with LV dysfunction. CONCLUSION: The prevalence of LV dysfunction in SSc is 5.4%. Age, male gender, digital ulcerations, myositis and lung involvement are independently associated with an increased prevalence of LV dysfunction. Conversely, the use of calcium channel blockers may be protective

Prevalence of the different types of pulmonary hypertension in systemic sclerosis: Results from two large samples of European Caucasians And meta-analysis of five studies.

To measure the prevalence of different types of pulmonary hypertension (PH) and to identify patients with systemic sclerosis (SSc) at highest risk in a multicenter European sample, with a metaanalysis of relevant studies. METHODS: Consecutive patients with SSc recruited at 11 French and Italian centers underwent detailed evaluations, including Doppler echocardiography, chest computed tomography, pulmonary function tests, and right-heart catheterization (RHC), to detect the presence and causes of PH. A metaanalysis was performed, including data from 4 other studies. RESULTS: Among 206 patients in whom it was suspected, PH was confirmed by RHC in 83 patients (7%). Precapillary PH was found in 64 patients (5%), of whom 42 had pulmonary arterial hypertension (PAH) and 22 had PH secondary to interstitial lung disease (ILD). RHC identified 17 patients (1%) with postcapillary PH secondary to left-heart disease. Patients with DLCO/alveolar volume < 70% were more likely to have precapillary PH (87.5% vs 42%; p < 0.0001). Precapillary and postcapillary PH were associated with advanced age (68 \ub1 14 vs 59 \ub1 12 yrs, p < 0.0001, and 74 \ub1 16 vs 61.5 \ub1 10 yrs, p < 0.0001, respectively). The metaanalysis of 3818 patients showed a prevalence of precapillary PH of 9% (95% CI 6%-12%) and identified advanced age, longer disease duration, and limited cutaneous disease subset as risk factors for this condition. CONCLUSION: The prevalence of precapillary PH in our multicenter study of SSc was 5%, and in the metaanalysis 9%. Our observations support use of RHC to confirm the presence of precapillary PH suspected by noninvasive testing. We also identified patients at high risk who should be carefully monitored

Prediction of pulmonary hypertension related to systemic sclerosis bu an index based on simple clinical observations

To develop a score to estimate the risk of developing pulmonary hypertension (PH) in patients with systemic sclerosis (SSc). METHODS: We first examined the prevalence and characteristics of precapillary PH confirmed by right-heart catheterization in a cross-sectional (derivation) sample of 1,165 SSc patients, and we developed a risk prediction score (RPS) based on simple clinical observations associated with PH. We next prospectively tested the 3-year predictive power of the "Cochin RPS" in a separate (validation) sample of 443 patients presenting with PH-free SSc at baseline. RESULTS: In the derivation sample, age, forced vital capacity, and diffusing capacity for carbon monoxide/alveolar volume were independently associated with the presence of PH and were used to create the Cochin RPS. PH developed during followup in 20 patients in the validation sample. The area under the receiver operating characteristic curve of the Cochin RPS was 0.87 (95% confidence interval 0.79-0.95). With a cutoff value of 2.73, patients at risk of PH during followup could be identified with 89.5% sensitivity and 74.1% specificity. PH occurred in 0.6% of patients in the lowest 2 quintiles of the Cochin RPS, in 1.7% of patients in the third and fourth quintiles, and in 17.1% of patients in the highest quintile (P35-fold higher risk of developing PH compared with patients in the 2 lowest quintiles (P=0.001). CONCLUSION: Using routine clinical observations, we developed a simple score that accurately predicted the risk of PH in SSc