39 research outputs found
Data on CUX1 isoforms in idiopathic pulmonary fibrosis lung and systemic sclerosis skin tissue sections
This data article contains complementary figures related to the
research article entitled, “Transforming growth factor-β-induced
CUX1 isoforms are associated with fibrosis in systemic sclerosis
lung fibroblasts” (Ikeda et al. (2016) [2], http://dx.doi.org/10.1016/j.
bbrep.2016.06.022), which presents that TGF-β increased CUX1
binding in the proximal promoter and enhancer of the COL1A2 and
regulated COL1. Further, in the scleroderma (SSc) lung and diffuse
alveolar damage lung sections, CUX1 localized within the α-
smooth muscle actin (α-SMA) positive cells (Fragiadaki et al., 2011)
[1], “High doses of TGF-beta potently suppress type I collagen via
the transcription factor CUX1” (Ikeda et al., 2016) [2]. Here we
show that CUX1 isoforms are localized within α-smooth muscle
actin-positive cells in SSc skin and idiopathic pulmonary fibrosis
(IPF) lung tissue sections. In particular, at the granular and prickle
cell layers in the SSc skin sections, CUX1 and α-SMA are colocalized.
In addition, at the fibrotic loci in the IPF lung tissue
sections, CUX1 localized within the α-smooth muscle actin (α-
SMA) positive cells
Design, synthesis and antiparasitic evaluation of click phospholipids
A library of seventeen novel ether phospholipid analogues, containing 5-membered heterocyclic rings (1,2,3-triazolyl, isoxazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl) in the lipid portion were designed and synthesized aiming to identify optimised miltefosine analogues. The compounds were evaluated for their in vitro antiparasitic activity against Leishmania infantum and Leishmania donovani intracellular amastigotes, against Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the substituents of the heterocyclic ring (tail) and the oligomethylene spacer between the head group and the heterocyclic ring was found to affect the activity and toxicity of these compounds leading to a significantly improved understanding of their structure\u2013activity relationships. The early ADMET profile of the new derivatives did not reveal major liabilities for the potent compounds. The 1,2,3-triazole derivative 27 substituted by a decyl tail, an undecyl spacer and a choline head group exhibited broad spectrum antiparasitic activity. It possessed low micromolar activity against the intracellular amastigotes of two L. infantum strains and T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes, while its cytotoxicity concentration (CC50) against THP-1 macrophages ranged between 50 and 100 \ub5M. Altogether, our work paves the way for the development of improved ether phospholipid derivatives to control neglected tropical diseases
Predictors of morbidity and mortality in early systemic sclerosis: Long-term follow-up data from a single-centre inception cohort
Objectives: To determine predictors of morbidity and mortality in systemic sclerosis (SSc) in a long-term follow-up of an inception cohort of early SSc patients. Methods: We evaluated clinical manifestations, laboratory and lung function tests at disease onset as predictors of morbidity and mortality in 3rd, 6th and 9th year in SSc patients recruited within 12 months of disease onset. Results: A total of 115 SSc patients (97 women, mean age 48.1 ± 13.5 years, 54 diffuse subtype) were included. In multivariate regression analysis, predictors at disease onset for the presence of pulmonary fibrosis in 6th year of follow-up were diffuse subtype (OR: 4.4, p = 0.033), digital ulcers (OR: 7.9, p = 0.014) and esophageal involvement (OR: 4.79, p = 0.038). Arrythmias at disease onset predicted pulmonary hypertension (OR: 6.05, p = 0.022), while age (OR: 1.12, p = 0.002) and anti-Scl70 (OR: 4.3, p = 0.038) predicted arrhythmias in 6th year. During a follow-up of 101.8 ± 48.5 months, 23/115 patients died. Cox proportional hazard models analysis revealed 6 independent predictors of mortality present at disease onset: age at disease onset (45–59 years (HR: 3.0, p = 0.098), ≥60 years (HR: 4.3, p = 0.073), male gender (HR: 3.63, p = 0.025), diffuse subtype (HR: 2.83, p = 0.095), pulmonary fibrosis (HR: 3.7, p = 0.032), echocardiography-diagnosed pulmonary hypertension (HR = 7.49, p = 0.008) and DLCO < 60% (HR: 3.17, p = 0.035). Mortality rates at 3 and 6 years were 14% and 24% for patients with 3 independent predictors and 46% and 53% for patients with 4–6 predictors, respectively. Conclusion: Clinical phenotypes at disease onset may predict morbidity and mortality in SSc and guide treatment decisions. © 2018 Elsevier B.V
Anti-TNFα treatment for recalcitrant ulcerative necrobiosis lipoidica diabeticorum: A case report and review of the literature
Introduction Necrobiosis lipoidica diabeticorum (NLD) is a rare degenerative connective tissue disorder associated with diabetes mellitus, which usually presents with red papules or plaques with raised edges and occasional ulceration. Ulcerating NLD is notoriously difficult to treat. We present a young patient with ulcerative NLD who was successfully treated with the anti-TNFα agent infliximab. Case presentation is followed by a review of therapeutic TNFα blockade in NLD. Case presentation A 17-year old woman with type 1 diabetes since the age of 8, presented with a long-standing and extensively ulcerated and infected NLD lesion on her left shin. After achieving better glycemic control and treating her for infection of the wound, several NLD treatments failed to help, including corticosteroids and hyperbaric oxygen. She was treated successfully with 4 monthly sessions of 5 mg/kg body weight intravenous infliximab, achieving complete resolution of ulceration. Discussion A multitude of available treatments have been suggested for NLD over the past decades, based on two axes, one through wound healing and the other through immunosuppression. Anti-TNFα agents are relatively new drugs that brought a revolution in chronic inflammatory diseases and have been on the rise as novel potential treatments for NLD. Three out of the five available anti-TNFα agents have been safely tested so far, both topically and systematically, with mostly favorable results. Conclusion Intravenous infliximab was successful in the treatment of recalcitrant ulcerating NLD in our patient. Taken together with an increasing number of similar reports revealing a pathogenetic role of TNFα in NLD, we suggest that anti-TNFα agents are promising drugs in the management of this condition. © 2016 Elsevier Inc. All rights reserved
Atherosclerosis is not accelerated in rheumatoid arthritis of low activity or remission, regardless of antirheumatic treatment modalities
Objectives. RA associates with increased cardiovascular disease (CVD) morbidity and mortality due to accelerated atherosclerosis, attributed to both classical risk factors and chronic inflammation. The aim of this study was to test the hypothesis that effective disease control over 3 years modifies acceleration of atherosclerosis in RA. Methods. Consecutive, non-diabetic RA patients previously examined by ultrasonography for subclinical atherosclerosis were re-evaluated after 3.2 (0.2) years, provided that they were in remission/low disease activity (DAS28<3.2) for at least 75% of this period. Patients (n = 139) were demographically matched with 139 non-diabetic, non-RA control individuals studied in parallel. Results. Patients and controls (mean age of 56 years at baseline) had a comparable burden of classical CVD risk factors. Patients' pulse wave velocity (reflecting arterial stiffness) changed by 0.07 m/s/year and left carotid intima-media thickness (reflecting wall hypertrophy) increased by 0.009 mm/year; formation of new atheromatic plaques in carotid and/or femoral arterial beds occurred in 22%. Multivariate analysis after correcting for all classical CVD risk factors and anti-hypertensive/lipid-lowering therapies demonstrated no significant differences between patients and controls in any of the subclinical atherosclerosis indices. Changes in all atherosclerosis indices from baseline to end of follow-up were comparable between those 56 patients treated with biologic DMARDs and their demographically matched patients treated with synthetic DMARDs. Conclusion. Effective disease control may abrogate any RA-specific effect on the progression of atherosclerosis regardless of treatment. Whether early and sustained RA control translates to the CVD outcomes expected in the general population should be examined in prospective studies. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved
A pilot study of endothelial dysfunction and aortic stiffness after interleukin-6 receptor inhibition in rheumatoid arthritis
Interleukin (IL)-6 is a pleiotropic proinflammatory cytokine involved in
the pathogenesis of both atherosclerosis and rheumatoid arthritis. The
role of the IL-6/IL-6 receptor pathway in the documented acceleration of
atherosclerosis in rheumatoid arthritis has not been examined. In a
non-randomized prospective pilot study we asked whether endothelial
dysfunction, defined as impaired flow mediated dilatation (FMD), and
aortic stiffness, assessed by pulse wave velocity (PWV) improve after 3
and 6 monthly therapeutic infusions of the anti-IL-6 receptor antibody
tocilizumab for active rheumatoid arthritis. We found that FMD increased
from 3.3 +/- 0.8 to 4.4 +/- 1.2 to 5.2 +/- 1.9% (p = 0.003), whereas
PWV decreased from 8.2 +/- 1.2 to 7.7 +/- 1.3 to 7.0 +/- 1.0 m/s (p <
0.001). Whether these beneficial arterial changes are direct effects of
the IL-6/IL-6 receptor pathway inhibition, maintained over time and
translate into better clinical outcome warrants further studies. (C)
2011 Elsevier Ireland Ltd. All rights reserved
Improvement of vascular endothelial function using the oral endothelin receptor antagonist Bosentan in patients with systemic sclerosis
Objective. Increased endothelin activity may play a role in the
pathogenesis of vascular injury, a primary feature of systemic sclerosis
(SSc; scleroderma). Our goal was to test the hypothesis that treatment
with the oral endothelin receptor antagonist bosentan might improve
vascular endothelial function in SSc patients.
Methods. A 4-week, prospective, parallel-group study compared 12 SSc
patients who did not receive bosentan treatment with 12 patients who did
receive treatment (125 mg/day) for pulmonary hypertension and/or digital
ulcers. There were no differences in demographic and clinical
characteristics or medications between the 2 groups. Baseline
endothelial dysfunction was documented by decreased brachial artery
ultrasound-derived flow-mediated dilation (FMD%; <5.5). Pulse wave
analysis, venous occlusion plethysmography, and measurement of serum
vascular markers were performed in parallel.
Results. FMD%, the main end point, increased significantly from a mean
+/- SD of 3.1 +/- 13% to 8.4 +/- 2.6% after 4 weeks of bosentan
treatment (P < 0.001, compared with a change from 2.4 +/- 1.6% to 2.4
+/- 2.2% in control patients). Arterial blood pressure,
endothelium-independent vascular function, augmentation index,
peripheral flow reserve, as well as circulating intercellular adhesion
molecule 1, E-selectin, vascular endothelial growth factor, and
endothelin 1 were not significantly affected by bosentan treatment. In
patients continuously treated for 4 months, during which the dosage of
bosentan remained at 125 mg/day (n = 5) or increased to 250 mg/day (n =
5), the 4-week results remained unchanged.
Conclusion. Small doses of bosentan improve endothelial function without
affecting hemodynamic parameters or endothelial activation-related
processes, thus supporting a direct, reversible effect of endothelin in
SSc-associated vascular injury. A long-term, controlled trial to examine
the potentially global clinical benefit of endothelin receptor blockade
in patients with early SSc may be warranted