Arsenic trioxide inhibits transforming growth factor-β1-induced fibroblast to myofibroblast differentiation in vitro and bleomycin induced lung fibrosis in vivo

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease of insidious onset, and is responsible for up to 30,000 deaths per year in the U.S. Excessive production of extracellular matrix by myofibroblasts has been shown to be an important pathological feature in IPF. TGF-β1 is expressed in fibrotic lung and promotes fibroblast to myofibroblast differentiation (FMD) as well as matrix deposition. Methods To identify the mechanism of Arsenic trioxide’s (ATO)’s anti-fibrotic effect in vitro, normal human lung fibroblasts (NHLFs) were treated with ATO for 24 hours and were then exposed to TGF-β1 (1 ng/ml) before harvesting at multiple time points. To investigate whether ATO is able to alleviate lung fibrosis in vivo, C57BL/6 mice were administered bleomycin by oropharyngeal aspiration and ATO was injected intraperitoneally daily for 14 days. Quantitative real-time PCR, western blotting, and immunofluorescent staining were used to assess the expression of fibrotic markers such as α-smooth muscle actin (α-SMA) and α-1 type I collagen. Results Treatment of NHLFs with ATO at very low concentrations (10-20nM) inhibits TGF-β1-induced α-smooth muscle actin (α-SMA) and α-1 type I collagen mRNA and protein expression. ATO also diminishes the TGF-β1-mediated contractile response in NHLFs. ATO’s down-regulation of profibrotic molecules is associated with inhibition of Akt, as well as Smad2/Smad3 phosphorylation. TGF-β1-induced H2O2 and NOX-4 mRNA expression are also blocked by ATO. ATO-mediated reduction in Smad3 phosphorylation correlated with a reduction of promyelocytic leukemia (PML) nuclear bodies and PML protein expression. PML-/- mouse embryonic fibroblasts (MEFs) showed decreased fibronectin and PAI-1 expression in response to TGF-β1. Daily intraperitoneal injection of ATO (1 mg/kg) in C57BL/6 mice inhibits bleomycin induced lung α-1 type I collagen mRNA and protein expression. Conclusions In summary, these data indicate that low concentrations of ATO inhibit TGF-β1-induced fibroblast to myofibroblast differentiation and decreases bleomycin induced pulmonary fibrosis.http://deepblue.lib.umich.edu/bitstream/2027.42/109463/1/12931_2013_Article_1494.pd

Arsenic trioxide inhibits transforming growth factor-β1-induced fibroblast to myofibroblast differentiation in vitro and bleomycin induced lung fibrosis in vivo

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease of insidious onset, and is responsible for up to 30,000 deaths per year in the U.S. Excessive production of extracellular matrix by myofibroblasts has been shown to be an important pathological feature in IPF. TGF-β1 is expressed in fibrotic lung and promotes fibroblast to myofibroblast differentiation (FMD) as well as matrix deposition. Methods To identify the mechanism of Arsenic trioxide’s (ATO)’s anti-fibrotic effect in vitro, normal human lung fibroblasts (NHLFs) were treated with ATO for 24 hours and were then exposed to TGF-β1 (1 ng/ml) before harvesting at multiple time points. To investigate whether ATO is able to alleviate lung fibrosis in vivo, C57BL/6 mice were administered bleomycin by oropharyngeal aspiration and ATO was injected intraperitoneally daily for 14 days. Quantitative real-time PCR, western blotting, and immunofluorescent staining were used to assess the expression of fibrotic markers such as α-smooth muscle actin (α-SMA) and α-1 type I collagen. Results Treatment of NHLFs with ATO at very low concentrations (10-20nM) inhibits TGF-β1-induced α-smooth muscle actin (α-SMA) and α-1 type I collagen mRNA and protein expression. ATO also diminishes the TGF-β1-mediated contractile response in NHLFs. ATO’s down-regulation of profibrotic molecules is associated with inhibition of Akt, as well as Smad2/Smad3 phosphorylation. TGF-β1-induced H2O2 and NOX-4 mRNA expression are also blocked by ATO. ATO-mediated reduction in Smad3 phosphorylation correlated with a reduction of promyelocytic leukemia (PML) nuclear bodies and PML protein expression. PML-/- mouse embryonic fibroblasts (MEFs) showed decreased fibronectin and PAI-1 expression in response to TGF-β1. Daily intraperitoneal injection of ATO (1 mg/kg) in C57BL/6 mice inhibits bleomycin induced lung α-1 type I collagen mRNA and protein expression. Conclusions In summary, these data indicate that low concentrations of ATO inhibit TGF-β1-induced fibroblast to myofibroblast differentiation and decreases bleomycin induced pulmonary fibrosis.http://deepblue.lib.umich.edu/bitstream/2027.42/134571/1/12931_2013_Article_1494.pd

Immunohistochemical localization of low density lipoprotein receptor-related protein 1 and α2-Macroglobulin in retinal and choroidal tissue of proliferative retinopathies

The immunolocalization of the low density lipoprotein receptor-related protein 1 (LRP1) and its ligand α 2-Macroglobulin (α2M) was examined in tissues from human donor eyes of normal, diabetic and sickle cell disease subjects. Streptavidin alkaline phosphatase immunohistochemistry was performed with a mouse anti-human LRP1 and rabbit anti-human α2M antibodies. Retinal and choroidal blood vessels were labeled with mouse anti-human CD34 antibody in adjacent tissue sections. Mean scores for immunostaining from the pathological and control eyes were statistically compared.LRP1 immunoreactivity was very weak to negative in the neural retina of normal subjects except in scattered astrocytes. LRP1 expression in diabetic eyes was detected in the internal limiting membrane (ILM), astrocytes, inner photoreceptor matrix, choriocapillaris and choroidal stroma. The ligand α2M, however, was limited mainly to blood vessel walls, some areas of the inner nuclear layer (INL), photoreceptors, RPE-Bruch's membrane-choriocapillaris complex, intercapillary septa, and choroidal stroma. In sickle cell eyes, avascular and vascular retina as well as choroidal neovascularization (CNV) were analyzed. In avascular areas, LRP1 immunoreactivity was in innermost retina (presumably ILM, astrocytes, and Muller cells) and INL as well as RPE-Bruch's membrane-choriocapillaris complex and choroidal stroma α2M was very weak in avascular peripheral retina compared to vascularized areas and limited to stroma in choroid. In contrast, in areas with CNV, LRP1 immunoreactivity was significantly decreased in overlying retina and in RPE-Bruch's membrane and choroidal stroma compared to the controls, while α2M was elevated in RPE-Bruch's membrane near CNV compared to normal areas in sickle cell choroid. The mean scores revealed that LRP1 and α2M in neural retina were significantly elevated in astrocytes and ILM in diabetic eyes (p ≤ 0.05), whereas in sickle cell eyes scores were elevated in ILM and INL (p ≤ 0.05). In addition, α2M immunoreactivity was in photoreceptors in both ischemic retinopathies. In choroid, the patterns of LRP1 and α2M expression were different and not coincident.This is the first demonstration of the presence of LRP1 and α2M in human proliferative retinopathies. Elevated LRP1 expression in sickle cell neural retina and diabetic inner retina and choroid suggests that LRP1 plays an important role in ischemic neovascular diseases. © 2010 Elsevier Ltd.Fil: Barcelona, Pablo Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Luna, J. D.. Fundación VER. Departamento de Oftalmología; ArgentinaFil: Chiabrando, Gustavo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Juarez, P. C.. Fundación VER. Departamento de Oftalmología; ArgentinaFil: Bhutto IA. University Johns Hopkins; Estados UnidosFil: McLeod, D. S.. University Johns Hopkins; Estados UnidosFil: Sanchez, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Lutty, G. A.. University Johns Hopkins; Estados Unido

The relative age effect on physical fitness in preschool children

The aim of the present study was to investigate the existence of a relative age effect (RAE) on physical fitness of preschoolers. Anthropometry and physical fitness were assessed in 3147 children (3–5 years old) using the PREFIT battery. Based on the birth year, participants were divided into 3year groups (3-, 4- and 5-years). Within each year group, 4quarter groups were created: quarter 1, preschoolers born from January to March; quarter 2, from April to June; quarter 3, from July to September; quarter 4, from October to December. The MANCOVA analysis revealed a main effect of year group (Wilks’ λ = 0.383; F10,5996 = 369.64; p < 0.001, ηp 2 = 0.381) and of quarter (Wilks’ λ = 0.874; F15,8276.6 = 27.67; p < 0.001; ηp 2 = 0.044) over the whole battery of tests. To the best of our knowledge, this is the first study to report the existence of RAE at the preschool stage. In general, performance improved as the relative age increased (i.e., those born in quarter 1 performed better than those in the other quarters). Individualization strategies should be addressed within the same academic year not only in elementary or secondary years but also in preschoolers

Effect of the radiochemical impurities of 99mTc-MIBI on the diagnostic quality of the images in nuclear medicine

En este trabajo se analiza la confiabilidad del método de control de pureza radioquímica del 99mTc-MIBI utilizado en los servicios de medicina nuclear y se discute la influencia de la mayor existencia de impurezas radioquímicas en la calidad diagnóstica de las imágenes obtenidas.This work analyzes the reliability of the radiochemical purity control method of 99mTc-MIBI used in nuclear medicine services and the influence of the greater presence of radiochemical impurities in the diagnostic quality of the obtained images.Fil: Guisande Donadio, Sabrina Natali. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Física; ArgentinaFil: Sanchez, J.. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Física; ArgentinaFil: Garavaglia, L.. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Física; ArgentinaFil: Rozanskas, S.. Cimed; ArgentinaFil: Dopta, G.. Instituto de Cardiología La Plata; ArgentinaFil: Pertusi, K.. Instituto de Cardiología la Plata; ArgentinaFil: Sanz, V.. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Física; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Mele, A.. Instituto de Cardiología La Plata; ArgentinaFil: Illanes, L.. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Física; ArgentinaFil: Chain, Cecilia Yamil. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; Argentin

Magnetic and chemical nonuniformity in Ga[1-x]Mn[x]As films as probed by polarized neutron and x-ray reflectometry

We have used complementary neutron and x-ray reflectivity techniques to examine the depth profiles of a series of as-grown and annealed Ga[1-x]Mn[x]As thin films. A magnetization gradient is observed for two as-grown films and originates from a nonuniformity of Mn at interstitial sites, and not from local variations in Mn at Ga sites. Furthermore, we see that the depth-dependent magnetization can vary drastically among as-grown Ga[1-x]Mn[x]As films despite being deposited under seemingly similar conditions. These results imply that the depth profile of interstitial Mn is dependent not only on annealing, but is also extremely sensitive to initial growth conditions. We observe that annealing improves the magnetization by producing a surface layer that is rich in Mn and O, indicating that the interstitial Mn migrates to the surface. Finally, we expand upon our previous neutron reflectivity study of Ga[1-x]Mn[x]As, by showing how the depth profile of the chemical composition at the surface and through the film thickness is directly responsible for the complex magnetization profiles observed in both as-grown and annealed films.Comment: Now Published in Physical Review

Preserving Mobility in Older Adults with Physical Frailty and Sarcopenia : Opportunities, Challenges, and Recommendations for Physical Activity Interventions

One of the most widely conserved hallmarks of aging is a decline in functional capabilities. Mobility loss is particularly burdensome due to its association with negative health outcomes, loss of independence and disability, and the heavy impact on quality of life. Recently, a new condition, physical frailty and sarcopenia, has been proposed to define a critical stage in the disabling cascade. Physical frailty and sarcopenia are characterized by weakness, slowness, and reduced muscle mass, yet with preserved ability to move independently. One of the strategies that have shown some benefits in combatting mobility loss and its consequences for older adults is physical activity. Here, we describe the opportunities and challenges for the development of physical activity interventions in people with physical frailty and sarcopenia. The aim of this article is to review age-related physio(patho)logical changes that impact mobility in old age and to provide recommendations and procedures in accordance with the available literature.Peer reviewe

The Astropy Problem

The Astropy Project (http://astropy.org) is, in its own words, "a community effort to develop a single core package for Astronomy in Python and foster interoperability between Python astronomy packages." For five years this project has been managed, written, and operated as a grassroots, self-organized, almost entirely volunteer effort while the software is used by the majority of the astronomical community. Despite this, the project has always been and remains to this day effectively unfunded. Further, contributors receive little or no formal recognition for creating and supporting what is now critical software. This paper explores the problem in detail, outlines possible solutions to correct this, and presents a few suggestions on how to address the sustainability of general purpose astronomical software

Effect of a Nutrition Supplement and Physical Activity Program on Pneumonia and Walking Capacity in Chilean Older People: A Factorial Cluster Randomized Trial

Alan Dangour and colleagues report results from the CENEX (Cost-effectiveness Evaluation of a Nutritional supplement and EXercise program for older people) trial, which evaluates a nutritional and exercise program aiming to prevent pneumonia and physical decline in Chilean people