Herschel imaging and spectroscopy of the nebula around the luminous blue variable star WRAY 15-751

We have obtained far-infrared Herschel PACS imaging and spectroscopic observations of the nebular environment of the luminous blue variable WRAY 15-751. These images clearly show that the main, dusty nebula is a shell of radius 0.5 pc and width 0.35 pc extending outside the H-alpha nebula. They also reveal a second, bigger and fainter dust nebula, observed for the first time. Both nebulae lie in an empty cavity, likely the remnant of the O-star wind bubble formed when the star was on the main sequence. The kinematic ages of the nebulae are about 20000 and 80000 years and each nebula contains about 0.05 Msun of dust. Modeling of the inner nebula indicates a Fe-rich dust. The far-infrared spectrum of the main nebula revealed forbidden emission lines coming from ionized and neutral gas. Our study shows that the main nebula consists of a shell of ionized gas surrounded by a thin photodissociation region illuminated by an "average" early-B star. The derived abundance ratios N/O=1.0+/-0.4 and C/O=0.4+/-0.2 indicate a mild N/O enrichment. We estimate that the inner shell contains 1.7+/-0.6 Msun of gas. Assuming a similar dust-to-gas ratio for the outer nebula, the total mass ejected by WRAY 15-751 amounts to 4+/-2 Msun. The measured abundances, masses and kinematic ages of the nebulae were used to constrain the evolution of the star and the epoch at which the nebulae were ejected. Our results point to an ejection of the nebulae during the RSG evolutionary phase of an ~ 40 Msun star. The presence of multiple shells around the star suggests that the mass-loss was not a continuous ejection but rather a series of episodes of extreme mass-loss. Our measurements are compatible with the recent evolutionary tracks computed for an 40 Msun star with little rotation. They support the O-BSG-RSG-YSG-LBV filiation and the idea that high-luminosity and low-luminosity LBVs follow different evolutionary paths.Comment: 19 pages, 13 figures, accepted for publication in A&

The Herschel view of the nebula around the luminous blue variable star AG Carinae

Far-infrared Herschel PACS imaging and spectroscopic observations of the nebula around the luminous blue variable (LBV) star AG Car have been obtained along with optical imaging in the Halpha+[NII] filter. In the infrared light, the nebula appears as a clumpy ring shell that extends up to 1.2 pc with an inner radius of 0.4 pc. It coincides with the Halpha nebula, but extends further out. Dust modeling of the nebula was performed and indicates the presence of large grains. The dust mass is estimated to be ~ 0.2 Msun. The infrared spectrum of the nebula consists of forbidden emission lines over a dust continuum. Apart from ionized gas, these lines also indicate the existence of neutral gas in a photodissociation region that surrounds the ionized region. The abundance ratios point towards enrichment by processed material. The total mass of the nebula ejected from the central star amounts to ~ 15 Msun, assuming a dust-to-gas ratio typical of LBVs. The abundances and the mass-loss rate were used to constrain the evolutionary path of the central star and the epoch at which the nebula was ejected, with the help of available evolutionary models. This suggests an ejection during a cool LBV phase for a star of ~ 55 Msun with little rotation.Comment: accepted for publication in A&

Short-term effects of angiotensin receptor-neprilysin inhibitors on diastolic strain and tissue doppler parameters in heart failure patients with reduced ejection fraction: A pilot trial

OBJECTIVE: Although sacubitril/valsartan has recently shown its long-term benefits on morbidity and mortality in symptomatic patients with chronic heart failure with reduced ejection fraction (HFrEF), its short-term effects on diastolic function remain uncertain. We sought to assess 30-day effects of sacubitril/valsartan on left ventricular (LV) diastolic paremeters determined by speckle tracking and tissue Doppler imaging (STI and TDI respectively) as well as their association with functional capacity change evaluated by peak oxygen uptake (VO2max) in stable patients with symptomatic HFrEF. METHODS: A total of 35 patients (aged 61 ± 9 years) eligible for sacubitril/valsartan underwent a complete two-dimension (2D) echocardiographic study and a cardiopulmonary exercise test at baseline and 30 days after the initiation of therapy. RESULTS: Significant improvements in ratio of trans-mitral inflow early diastolic velocity E to mitral annulus early diastolic velocity E' (ΔΕ//Ε' = -35.9%, p = 0.001), peak early diastolic strain rate SRE (ΔSRE = +22.5%, p = 0.024) and ratio E/SRE (ΔE/SRE = -33.2%, p = 0.025) were observed after 1-month therapy. Compared with baseline, VO2max also increased significantly by 16.7 % (p = 0.001). Baseline E/SRE and ΔE/SRE were the strongest independent predictors of VO2max improvement (beta = -0.43, p = 0.004 and beta = 0.45, p = 0.021 respectively) in the multivariate analysis. CONCLUSION: Sacubitril/valsartan was associated with early improvement in LV diastolic function determined by TDI and 2D STI. Baseline E/SRE was stronger than standard echocardiographic parameters in predicting the early benefit of sacubitril/valsartan therapy

Herschel observations of nebulae ejected by massive evolved stars

We have obtained far-infrared Herschel PACS imaging and spectroscopic observations of nebulae associated to massive evolved stars. The study of these nebulae is crucial to understand the evolution of these stars as it can reveal the mass-loss history. The infrared images along with available data at other wavelengths give a complete view of their morphology. The dust modeling provides the dust parameters, such as the temperature, the mass and the composition of dust. The spectroscopic analysis provides the gas C,N,O abundances and mass. Based on these observations, the evolutionary status of the star at the time of the nebula ejection can be constrained. We present here selected results of an ongoing exhaustive study of nebulae around low- and high-luminosity LBVs (AG Car, HR Car, WRAY 15-751, G79.29+0.46, HD168625), WN stars (NGC6888, M1-67, He3-519) and Of stars (NGC6164/5)

RBCK1‐related disease: A rare multisystem disorder with polyglucosan storage, auto‐inflammation, recurrent infections, skeletal, and cardiac myopathy—Four additional patients and a review of the current literature

In this article, we report four new patients, from three kindreds, with pathogenic variants in RBCK1 and a multisystem disorder characterised by widespread polyglucosan storage. We describe the clinical presentation of progressive skeletal and cardiac myopathy, combined immunodeficiencies and auto‐inflammation, illustrate in detail the histopathological findings in multiple tissue types, and report muscle MRI findings

Identification of Novel Inhibitors of Dietary Lipid Absorption Using Zebrafish

Pharmacological inhibition of dietary lipid absorption induces favorable changes in serum lipoprotein levels in patients that are at risk for cardiovascular disease and is considered an adjuvant or alternative treatment with HMG-CoA reductase inhibitors (statins). Here we demonstrate the feasibility of identifying novel inhibitors of intestinal lipid absorption using the zebrafish system. A pilot screen of an unbiased chemical library identified novel compounds that inhibited processing of fluorescent lipid analogues in live zebrafish larvae. Secondary assays identified those compounds suitable for testing in mammals and provided insight into mechanism of action, which for several compounds could be distinguished from ezetimibe, a drug used to inhibit cholesterol absorption in humans that broadly inhibited lipid absorption in zebrafish larvae. These findings support the utility of zebrafish screening assays to identify novel compounds that target complex physiological processes

A Review of Time Courses and Predictors of Lipid Changes with Fenofibric Acid-Statin Combination

Fibrates activate peroxisome proliferator activated receptor α and exert beneficial effects on triglycerides, high-density lipoprotein cholesterol, and low density lipoprotein subspecies. Fenofibric acid (FA) has been studied in a large number of patients with mixed dyslipidemia, combined with a low- or moderate-dose statin. The combination of FA with simvastatin, atorvastatin and rosuvastatin resulted in greater improvement of the overall lipid profile compared with the corresponding statin dose. The long-term efficacy of FA combined with low- or moderate- dose statin has been demonstrated in a wide range of patients, including patients with type 2 diabetes mellitus, metabolic syndrome, or elderly subjects. The FA and statin combination seems to be a reasonable option to further reduce cardiovascular risk in high-risk populations, although trials examining cardiovascular disease events are missing

Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis

Introduction: Rheumatoid arthritis (RA) is a T-cell-mediated systemic autoimmune disease, characterized by synovium inflammation and articular destruction. Bone marrow mesenchymal stem cells (MSCs) could be effective in the treatment of several autoimmune diseases. However, there has been thus far no report on umbilical cord (UC)-MSCs in the treatment of RA. Here, potential immunosuppressive effects of human UC-MSCs in RA were evaluated. Methods: The effects of UC-MSCs on the responses of fibroblast-like synoviocytes (FLSs) and T cells in RA patients were explored. The possible molecular mechanism mediating this immunosuppressive effect of UC-MSCs was explored by addition of inhibitors to indoleamine 2,3-dioxygenase (IDO), Nitric oxide (NO), prostaglandin E2 (PGE2), transforming growth factor beta 1 (TGF-beta 1) and interleukin 10 (IL-10). The therapeutic effects of systemic infusion of human UC-MSCs on collagen-induced arthritis (CIA) in a mouse model were explored. Results: In vitro, UC-MSCs were capable of inhibiting proliferation of FLSs from RA patients, via IL-10, IDO and TGF-beta 1. Furthermore, the invasive behavior and IL-6 secretion of FLSs were also significantly suppressed. On the other hand, UC-MSCs induced hyporesponsiveness of T cells mediated by PGE2, TGF-beta 1 and NO and UC-MSCs could promote the expansion of CD4(+) Foxp3(+) regulatory T cells from RA patients. More importantly, systemic infusion of human UC-MSCs reduced the severity of CIA in a mouse model. Consistently, there were reduced levels of proinflammatory cytokines and chemokines (TNF-alpha, IL-6 and monocyte chemoattractant protein-1) and increased levels of the anti-inflammatory/regulatory cytokine (IL-10) in sera of UC-MSCs treated mice. Moreover, such treatment shifted Th1/Th2 type responses and induced Tregs in CIA. Conclusions: In conclusion, human UC-MSCs suppressed the various inflammatory effects of FLSs and T cells of RA in vitro, and attenuated the development of CIA in vivo, strongly suggesting that UC-MSCs might be a therapeutic strategy in RA. In addition, the immunosuppressive activitiy of UC-MSCs could be prolonged by the participation of Tregs.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000287517000020&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701RheumatologySCI(E)PubMed64ARTICLE6R2101

Long-Lived Plasma Cells and Memory B Cells Produce Pathogenic Anti-GAD65 Autoantibodies in Stiff Person Syndrome

Stiff person syndrome (SPS) is a rare, neurological disorder characterized by sudden cramps and spasms. High titers of enzyme-inhibiting IgG autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GAD65) are a hallmark of SPS, implicating an autoimmune component in the pathology of the syndrome. Studying the B cell compartment and the anti-GAD65 B cell response in two monozygotic twins suffering from SPS, who were treated with the B cell-depleting monoclonal anti-CD20 antibody rituximab, we found that the humoral autoimmune response in SPS is composed of a rituximab-sensitive part that is rapidly cleared after treatment, and a rituximab-resistant component, which persists and acts as a reservoir for autoantibodies inhibiting GAD65 enzyme activity. Our data show that these potentially pathogenic anti-GAD65 autoantibodies are secreted by long-lived plasma cells, which may either be persistent or develop from rituximab-resistant memory B lymphocytes. Both subsets represent only a fraction of anti-GAD65 autoantibody secreting cells. Therefore, the identification and targeting of this compartment is a key factor for successful treatment planning of SPS and of similar autoimmune diseases