Daviddueholm6222

Pathological changes in the biomechanical environment are implicated in the progression of idiopathic pulmonary fibrosis (IPF). Stiffened matrix augments fibroblast proliferation and differentiation and activates TGF-β1 (transforming growth factor-β1). Stiffened matrix impairs the synthesis of the antifibrogenic lipid mediator prostaglandin E2 (PGE2) and reduces the expression of the rate-limiting prostanoid biosynthetic enzyme cyclooxygenase-2 (COX-2). We now show that prostaglandin E synthase (PTGES), the final enzyme in the PGE2 biosynthetic pathway, is expressed at lower levels in the lungs of patients with IPF. We also show substantial induction of COX-2, PTGES, prostaglandin E receptor 4 (EP4), and cytosolic phospholipase A2 (cPLA2) expression in human lung fibroblasts cultured in soft collagen hydrogels or in spheroids compared with conventional culture on stiff plastic culture plates. Induction of COX-2, cPLA2, and PTGES expression in spheroid cultures was moderately inhibited by the p38 mitogen-activated protein kinase inhibitor SB203580. The induction of prostanoid biosynthetic enzyme expression was accompanied by an increase in PGE2 levels only in non-IPF-derived fibroblast spheroids. Our study reveals an extensive dysregulation of prostanoid biosynthesis and signaling pathways in IPF-derived fibroblasts, which are only partially abrogated by culture in soft microenvironments.Rationale Exercise capacity predicts mortality in pulmonary arterial hypertension (PAH), but limited data exist on the routine use of maximal exercise testing.Objectives This study evaluates a simple-to-perform maximal test (the incremental shuttle walking test) and its use in risk stratification in PAH.Methods Consecutive patients with pulmonary hypertension were identified from the ASPIRE (Assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre) registry (2001-2018). Thresholds for levels of risk were identified at baseline and tested at follow-up, and their incorporation into current risk stratification approaches was assessed.Results Of 4,524 treatment-naive patients with pulmonary hypertension who underwent maximal exercise testing, 1,847 patients had PAH. A stepwise reduction in 1-year mortality was seen between levels 1 (≤30 m; 32% mortality) and 7 (340-420 m; 1% mortality) with no mortality for levels 8-12 (≥430 m) in idiopathic and connective tissue disease-related PAH. Thresholds derived at baseline of ≤180 m (>10%; high risk), 190-330 m (5-10%; intermediate risk), and ≥340 m ( less then 5%; low risk of 1-yr mortality) were applied at follow-up and also accurately identified levels of risk. Thresholds were incorporated into the REVEAL (Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management) 2.0 risk score calculator and French low-risk approach to risk stratification, and distinct categories of risk remained.Conclusions We have demonstrated that maximal exercise testing in PAH stratifies mortality risk at baseline and follow-up. This study highlights the potential value of the incremental shuttle walking test as an alternative to the 6-minute walking test, combining some of the advantages of maximal exercise testing and maintaining the simplicity of a simple-to-perform field test.

WHO mortality statistics overlook land motor-vehicle accident (LMVA)-related drowning. The aim of the study was to provide an overview of the prevalence and trends of fatal LMVA-related drowning in Finland, plus the main crash settings, victims' demographic characteristics, and contributing factors leading to such deaths.

A descriptive, retrospective, population-based study of drowning deaths associated with LMVA among Finnish residents of all ages, 1971-2013. LMVA-related drownings and applicable variables were extracted from the Statistics Finland (SF) mortality database by cross-analysis of ICD injury- and external cause-of-death codes.

During the study period, 538 LMVAs leading to drowning occurred among Finnish residents (2.5/1 000 000/year; 4.9% of all unintentional drownings, 3.7% of all LMVA). Three main settings, ones responsible for over 95% of LMVA-related drownings, were recognized traffic vehicle accidents involving a passenger car; non-traffic vehicle accident involving a snowmobile; and non-traffic accidents involving agricultural, industrial, or construction vehicles. Akti1/2 was a contributing factor for death in > 40% of the victims, whereas severe injuries were reported in less than 6%.

Because transport safety is crucial to prevent any vehicle entering the water, placing LMVA-related drowning in the category of transport accidents is warranted. #link# Once the vehicle becomes submersed, however, prevention measures to avoid death by drowning remains decisive.

Because transport safety is crucial to prevent any vehicle entering the water, placing LMVA-related drowning in the category of transport accidents is warranted. Once the vehicle becomes submersed, however, prevention measures to avoid death by drowning remains decisive.Cancer stem cells (CSCs) proliferate extensively and drive tumor metastasis and recurrence. CSCs have been identified in over 20 cancer types to date, but it remains unknown how to target and eliminate CSCs in vivo. Aldehyde dehydrogenase (ALDH) is a marker that has been used extensively for isolating CSCs. Here we present a novel approach to target and reduce the frequency of ALDHhigh CSCs by vaccination against ALDH. link2 We have identified ALDH1-A1 and ALDH1-A3 epitopes from CSCs and developed synthetic high-density lipoprotein nanodiscs for vaccination against ALDHhigh CSCs. Nanodiscs increased antigen trafficking to lymph nodes and generated robust ALDH-specific T cell responses. Nanodisc vaccination against ALDHhigh CSCs combined with anti-PD-L1 therapy exerted potent antitumor efficacy and prolonged animal survival in multiple murine models. Overall, this is the first demonstration of a simple nanovaccine strategy against CSCs and may lead to new avenues for cancer immunotherapy against CSCs.Neutron reflectometry has been used to measure the surface excesses and structures of hydrophobically modified polyacrylamide polymers (HMPAMs) at the air-water (A-W) interface. The HMPAMs were based on a range of commercially available PAM, which were modified by the N-alkylation of the amide group to give an N-C n D2n+1 hydrophobic group with n = 8, 12, and 16 at levels of 0.5, 1, 2, 4, and 6 mol %. A further HMPAM was synthesized in two isotopic forms with either N-C n D2n+1 or N-C n H2n+1 as hydrophobes. For moderate- and high MW species the near surface structure at the A-W interface consists of two layers. All the hydrophobic units are in these two layers as well as a large fraction of backbone units, often amounting to a total volume comparable to that of the hydrophobes. The outer layer next to air contains no water, but the residual volume in the inner layer is filled with water. A further large fraction of the backbone units also form a diffuse third layer extending a substantial distance into the srporation of a low charge on the polymers (about 1 charge per 100 backbone units). The presence of such a charge in PAM can arise from hydrolysis of some amide to carboxylate and was known to be present for one of the polymers. The extra structural information obtained by NR on these HMPAMs combined with more recent measurements of the state of ionization in polyacrylates (PAA) allowed us to reinterpret earlier ST and X-ray reflection results on hydrophobically modified HMPAANa containing a similar level of 1 and 2 mol % C12H25 hydrophobes. The Gibbs equation again accounted quantitatively for the ST behavior by using the correct state of ionization of the polymer. Although the adsorption of hydrophobic groups in HMPAANa is about one-tenth of that for the corresponding HMPAM, the ST drops more quickly to lower values for HMPAANa because of its higher level of dissociation, which increases the magnitude of the slope in the Gibbs plot.Surfactants in aqueous solutions self-assemble in the presence of salt, to form long, flexible, wormlike micelles (WLM). WLM solutions exhibit viscoelastic properties and are used in many applications, such as for cosmetic products, drag reduction, and hydraulic fracturing. Understanding the coalescence stability of bubbles in WLM solutions is important for the development of WLM based products that require a stable dispersion of bubbles. In this paper, we investigate the thin film drainage dynamics leading up to the coalescence of bubbles at flat WLM solution-air interfaces. The salts and surfactant type and concentrations were chosen so as to have the viscoelastic properties of the tested WLM solutions span over 2 orders of magnitude in moduli and relaxation times. The various stages in drainage and coalescence, the formation of a thick region at the apex (a dimple), the thinning and washout of this dimple, and the final stages of drainage before rupture, are modified by the viscoelasticity of the wormlike micellar solutions. As a result of the unique viscoelastic properties of the WLM solutions, we also observe a number of interesting fluid dynamic phenomena during the drainage processes including elastic recoil, thin film ripping, and single-step terminal drainage.Deferoxamine mesylate (DFO) is an FDA-approved, hexadentate iron chelator routinely used to alleviate systemic iron burden in thalassemia major and sickle cell patients. Iron accumulation in these disease states results from the repeated blood transfusions required to manage these conditions. Iron accumulation has also been implicated in the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD), and secondary injury following intracerebral hemorrhage (ICH). Chelation of brain iron is thus a promising therapeutic strategy for improving behavioral outcomes and slowing neurodegeneration in the aforementioned disease states, though the effectiveness of DFO treatment is limited on several accounts. link3 Systemically administered DFO results in nonspecific toxicity at high doses, and the drug's short half-life leads to low patient compliance. Mixed reports of DFO's ability to cross the blood-brain barrier (BBB) also appear in literature. These limitations necessitate novel DFO formulations prior to the drug similar results, and some complex formulations have been developed to improve permeability across the BBB. However, despite the success in preclinical models, clinical translation is limited with most clinical evidence investigating DFO treatment in ICH patients, where high-dose treatment has proven dangerous and dosing regimens are not consistent across studies. DFO is a strong drug candidate for managing neurodegeneration in the aging population, but before it can be routinely implemented as a therapeutic agent, dosing regimens must be standardized, and brain DFO content following drug administration must be understood and controlled via novel formulations.As an important damping way of the light absorption of plasmonic nanoparticles, the d-sp interband transition within the short wavelength regime has been recently drawing attentions in photochemistry. Compared with the intraband Landau damping, the d-sp interband transition excited carriers have larger populations and longer relaxation times, which is promising to match the photochemical reactions in time scale. Here, we propose a novel approach to the growth of plasmonic gold nanoparticles more efficiently promoted by d-sp interband transition excited charge carriers than by plasmon excited carriers. It is founded that photochemical growth of plasmonic gold nanoparticles can be modulated by engineering the electrochemical potential of precursor using different surfactants. From the distribution of surfactant on a single gold nanoparticle revealed by nanoscale resolved IR mapping, a reasonable photochemical reaction mechanism mediated by d-sp interband excitation is suggested. The results highlight the importance of d-sp interband transition excited carriers in photochemical reactions especially for materials science.