Toll-like receptor 4 (TLR4) and TLR2 were shown to be activated by saturated fatty acids (SFAs) but inhibited by docosahexaenoic acid (DHA). However, one report suggested that SFA-induced TLR ...activation in cell culture systems is due to contaminants in BSA used for solubilizing fatty acids. This report raised doubt about proinflammatory effects of SFAs. Our studies herein demonstrate that sodium palmitate (C16:0) or laurate (C12:0) without BSA solubilization induced phosphorylation of inhibitor of nuclear factor-κB α, c-Jun N-terminal kinase (JNK), p44/42 mitogen-activated-kinase (ERK), and nuclear factor-κB subunit p65, and TLR target gene expression in THP1 monocytes or RAW264.7 macrophages, respectively, when cultured in low FBS (0.25%) medium. C12:0 induced NFκB activation through TLR2 dimerized with TLR1 or TLR6, and through TLR4. Because BSA was not used in these experiments, contaminants in BSA have no relevance. Unlike in suspension cells (THP-1), BSA-solubilized C16:0 instead of sodium C16:0 is required to induce TLR target gene expression in adherent cells (RAW264.7). C16:0-BSA transactivated TLR2 dimerized with TLR1 or TLR6 and through TLR4 as seen with C12:0. These results and additional studies with the LPS sequester polymixin B and in MyD88−/− macrophages indicated that SFA-induced activation of TLR2 or TLR4 is a fatty acid-specific effect, but not due to contaminants in BSA or fatty acid preparations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on treatment with stereotactic body radiotherapy (SBRT) for patients with early-stage non-small-cell ...lung cancer. ASCO has a policy and set of procedures for endorsing and/or adapting clinical practice guidelines that have been developed by other professional organizations. Methods The ASTRO Evidence-Based Guideline for Stereotactic Body Radiotherapy for Early-Stage Non-Small-Cell Lung Cancer was reviewed for developmental rigor by methodologists. An ASCO Expert Panel updated the literature search and reviewed the guideline content and recommendations. Results The ASCO Expert Panel determined that the recommendations from the ASTRO guideline, published in 2017, are clear, thorough, and based on the most relevant scientific evidence. ASCO statements and minor modifications were added to enhance the applicability of the ASTRO guideline for the broader ASCO audience. Recommendations For standard operative risk patients with stage I NSCLC, SBRT is not recommended outside of a clinical trial. Lobectomy with systematic lymph node evaluation remains the recommended treatment, although a sublobar resection may be considered in select clinical scenarios. Recommendations are provided regarding the use of SBRT in high operative risk patients and for inoperative patients, including in challenging scenarios where tumors are: centrally located, > 5 cm in diameter, lacking tissue diagnosis, synchronous primary or multifocal, second primary after pneumonectomy, proximal to or involved with mediastinal structures, abutting the chest wall, or recurring after previous treatment. Qualifying statements are included to provide further guidance for implementation, and the importance of a discussion of treatment options among members of the multidisciplinary cancer care team is emphasized. Additional information is available at: www.asco.org/thoracic-cancer-guidelines and www.asco.org/guidelineswiki .
Acylcarnitines activate proinflammatory signaling pathways Rutkowsky, Jennifer M; Knotts, Trina A; Ono-Moore, Kikumi D ...
American journal of physiology: endocrinology and metabolism,
06/2014, Volume:
306, Issue:
12
Journal Article
Peer reviewed
Open access
Incomplete β-oxidation of fatty acids in mitochondria is a feature of insulin resistance and type 2 diabetes mellitus (T2DM). Previous studies revealed that plasma concentrations of medium- and ...long-chain acylcarnitines (by-products of incomplete β-oxidation) are elevated in T2DM and insulin resistance. In a previous study, we reported that mixed D,L isomers of C12- or C14-carnitine induced an NF-κB-luciferase reporter gene in RAW 264.7 cells, suggesting potential activation of proinflammatory pathways. Here, we determined whether the physiologically relevant L-acylcarnitines activate classical proinflammatory signaling pathways and if these outcomes involve pattern recognition receptor (PRR)-associated pathways. Acylcarnitines induced the expression of cyclooxygenase-2 in a chain length-dependent manner in RAW 264.7 cells. L-C14 carnitine (5-25 μM), used as a representative acylcarnitine, stimulated the expression and secretion of proinflammatory cytokines in a dose-dependent manner. Furthermore, L-C14 carnitine induced phosphorylation of JNK and ERK, common downstream components of many proinflammatory signaling pathways including PRRs. Knockdown of MyD88, a key cofactor in PRR signaling and inflammation, blunted the proinflammatory effects of acylcarnitine. While these results point to potential involvement of PRRs, L-C14 carnitine promoted IL-8 secretion from human epithelial cells (HCT-116) lacking Toll-like receptors (TLR)2 and -4, and did not activate reporter constructs in TLR overexpression cell models. Thus, acylcarnitines have the potential to activate inflammation, but the specific molecular and tissue target(s) involved remain to be identified.
Multi-walled carbon nanotubes (MWNT) and tungsten disulphide nanotubes (WS
2
-INT) have been widely used to improve the strength and toughness of composite materials. The mechanisms of such ...improvements are extensively studied, but it is not often clear what prompts a specific reinforcement mechanism to work. In this work we prepared two similar systems reinforced with different nanofillers (MWNT and WS
2
-INT). Using in situ optical microscopy and post-fracture electron microscopy, we established that using different nanofillers results in a different type of fracture and a different reinforcement mechanism. When compared to non-reinforced composites both systems showed significant improvements in both strength and fracture toughness.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Ceramic composites found in nature, such as bone, nacre, and sponge spicule, often provide an effective resolution to a well‐known conflict between materials' strength and toughness. This arises, on ...the one hand, from their high ceramic content that ensures high strength of the material. On the other hand, various pathways are provided for stress dissipation, and thus toughness, due to their intricate hierarchical architectures. Such pathways include crack bridging, crack deflection, and delamination in the case of layered structures. On the basis of these inspiring ideas, we attempted here to create simultaneously strong and tough laminated alumina composite with high ceramic content. Composites were prepared from high‐grade commercial alumina with spin‐coated interlayers of ductile polymers (PMMA and PVA). The specimens' ultimate properties (strength, fracture toughness, and work of fracture) were measured by a four‐point bending method. In some cases, fracture toughness of the composites was increased by up to an order of magnitude, reminiscent of the natural layered composites. It is proposed that this increase may be attributed to an interlocking mechanism, often encountered in biological composites. The significance of sample architecture and the role of the interfacial and bulk properties of the interlayer material are discussed.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Objective To visualize and describe collaborative electronic health record (EHR) usage for hospitalized patients with heart failure.
Materials and methods We identified records of patients with heart ...failure and all associated healthcare provider record usage through queries of the Northwestern Medicine Enterprise Data Warehouse. We constructed a network by equating access and updates of a patient’s EHR to a provider-patient interaction. We then considered shared patient record access as the basis for a second network that we termed the provider collaboration network. We calculated network statistics, the modularity of provider interactions, and provider cliques.
Results We identified 548 patient records accessed by 5113 healthcare providers in 2012. The provider collaboration network had 1504 nodes and 83 998 edges. We identified 7 major provider collaboration modules. Average clique size was 87.9 providers. We used a graph database to demonstrate an ad hoc query of our provider-patient network.
Discussion Our analysis suggests a large number of healthcare providers across a wide variety of professions access records of patients with heart failure during their hospital stay. This shared record access tends to take place not only in a pairwise manner but also among large groups of providers.
Conclusion EHRs encode valuable interactions, implicitly or explicitly, between patients and providers. Network analysis provided strong evidence of multidisciplinary record access of patients with heart failure across teams of 100+ providers. Further investigation may lead to clearer understanding of how record access information can be used to strategically guide care coordination for patients hospitalized for heart failure.
Currently, normothermic ex vivo heart perfusion (NEVHP) is limited to 6-12 hours. NEVHP for 24 hours or more would allow organ treatment, assessment of organ function, and near-perfect recipient ...matching. We present a model of NEVHP using continuous hemofiltration (HFn) with sustained myocardial viability up to 24 hours. Twenty hearts from 6-10 kg piglets were procured and maintained on our NEVHP circuit. HFn hearts (n = 10) underwent NEVHP with HFn, whereas controls (n = 10) used NEVHP alone. All HFn vs. four controls were viable at 24 h (p = 0.004). At end perfusion, HFn hearts had higher left ventricular systolic pressure (51.5 ± 6.8 mm Hg, 38.3 ± 5.2 mm Hg, p = 0.05), lower coronary resistance (0.83 ± 0.11 mm Hg/mL/min, 1.18 ± 0.21mmHg/mL/min, p < 0.05), and lower serum lactate levels (2.9 ± 0.4 mmol/L, 4.1 ± 0.6 mmol/L, p < 0.0001) when compared to control hearts. HFn hearts also had less extensive myocardial damage and significantly less edema than control hearts with lower weight gain and wet-dry ratios. Using our circuit, NEVHP for 24 hours is possible with HFn and allows for preservation of myocardial function, improved tissue viability, decreased tissue edema, and less myocardial injury.
Antimicrobial peptides are a new class of antibiotics that are promising for pharmaceutical applications because they have retained efficacy throughout evolution. One class of antimicrobial peptides ...are the defensins, which have been found in different species. Here we describe a new fungal defensin, eurocin. Eurocin acts against a range of Gram-positive human pathogens but not against Gram-negative bacteria. Eurocin consists of 42 amino acids, forming a cysteine-stabilized α/β-fold. The thermal denaturation data point shows the disulfide bridges being responsible for the stability of the fold. Eurocin does not form pores in cell membranes at physiologically relevant concentrations; it does, however, lead to limited leakage of a fluorophore from small unilamellar vesicles. Eurocin interacts with detergent micelles, and it inhibits the synthesis of cell walls by binding equimolarly to the cell wall precursor lipid II.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To investigate an abbreviated, contrast-agent free diffusion-weighted (DW) breast magnetic resonance imaging (MRI) protocol that provides a single image for the radiologist to read in order to ...non-invasively examine Breast Imaging-Reporting and Data System (BI-RADS) 4 lesions detected using breast cancer screening X-ray mammography.
This retrospective evaluation within a institutional review board-approved, prospective study included 115 women (mean 57 years, range 50–69 years) with BI-RADS 4 findings on X-ray mammography and indication for biopsy over a period of 15 months. Full diagnostic breast MRI (FDP) was performed prior to biopsy (1.5 T). Maximum intensity breast diffusion (MIBD) images were generated from DW images (b = 1,500 mm/s2, 3 mm section thickness) of the breast. MIBD and T2-weighted (T2W) images were read by two radiologists and compared to the diagnostic accuracy of an expert reading of the FDP with histopathology as the reference standard. The acquisition time of MIBD and T2W MRI was about 7 minutes.
MIBD MRI provided a diagnostic accuracy of 87.93% (95% confidence interval CI: 80.58–93.24%) for R1 and 89.66% (95% CI: 82.63–94.54%) for R2. Expert reading of the FDP revealed a similar accuracy of 86.2% (95% CI: 78.67–91.43%). The positive predictive value (PPV) could be increased from 36.2% (95% CI: 28.02–45.28; X-ray mammography alone) to a mean PPV of 80.89% (R1 79.17%, R2 82.16%) using MIBD MRI. Mean reading time was 30 seconds (25%/75 percentile 24.5–41.25).
MIBD MRI might be of supplemental value if added to the work-up of BI-RADS 4 X-ray mammography screening findings. MIBD MRI might help reduce the false-positive rate prior to biopsy for reference lesions at only limited expense of measurement and reading time.
•MIBDI-MRI can help to non-invasively characterize BI-RADS 4 X-ray mammography lesions.•MIBDI-MRI only needs limited measurement and reading time.•MIBDI-MRI increased the positive predictive value (PPV) from 36.2% to 80.89%.•Radiologist mean reading time for MIBDI-MRI was about 30 seconds per patient.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Plasma lipoprotein(a) (Lpa) level is an independent risk factor of cardiovascular disease that is under strong genetic control. We conducted a genome-wide association study of plasma Lp(a) in 386 ...members of a founder population that adheres to a communal lifestyle, proscribes cigarette smoking, and prepares and eats meals communally. We identified associations with 77 single nucleotide polymorphisms (SNPs) spanning 12.5 Mb on chromosome 6q26-q27 that met criteria for genome-wide significance (P ≤ 1.3 × 10−7) and were within or flanking nine genes, including LPA. We show that variation in at least six genes in addition to LPA are significantly associated with Lp(a) levels independent of each other and of the kringle IV repeat polymorphism in the LPA gene. One novel SNP in intron 37 of the LPA gene was also associated with Lp(a) levels and carotid artery disease number in unrelated Caucasians (P = 7.3 × 10−12 and 0.024, respectively), also independent of kringle IV number. This study suggests a complex genetic architecture of Lp(a) levels that may involve multiple loci on chromosome 6q26-q27.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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