Ischemicstroke is a leading cause of death and disability in the United States, but recent advances in treatments i.e., endovascular thrombectomy and tissue plasminogen activator (t-PA) that target ...the stroke-causing blood clot, while improving overall stroke mortality rates, have had much less of an impact on overall stroke morbidity. This may in part be attributed to the lack of therapeutics targeting reperfusion-induced injury after the blood clot has been removed, which, if left unchecked, can expand injury from its core into the surrounding at risk tissue (penumbra). This occurs in two phases of increased permeability of the blood-brain barrier, a physical barrier that under physiologic conditions regulates brain influx and efflux of substances and consists of tight junction forming endothelial cells (and transporter proteins), astrocytes, pericytes, extracellular matrix, and their integrin cellular receptors. During, embryonic development, maturity, and following stroke reperfusion, cerebral vasculature undergoes significant changes including changes in expression of integrins and degradation of surrounding extracellular matrix. Integrins, heterodimers with α and β subunits, and their extracellular matrix ligands, a collection of proteoglycans, glycoproteins, and collagens, have been modestly studied in the context of stroke compared with other diseases (e.g., cancer). In this review, we describe the effect that various integrins and extracellular matrix components have in embryonic brain development, and how this changes in both maturity and in the poststroke environment. Particular focus will be on how these changes in integrins and the extracellular matrix affect blood-brain barrier components and their potential as diagnostic and therapeutic targets for ischemic stroke.
Elevated serum urate levels are recognized as leading to gouty arthritis, tophi formation, and uric acid kidney stones. While serum urate elevations have long been associated with renal disease, they ...are not usually considered to have a causal role in kidney dysfunction. However, recent epidemiologic studies have identified serum urate elevations as an independent risk factor for chronic kidney disease. Hyperuricemia has also been found to be an independent risk factor for cardiovascular disease and hypertension. An animal model of mild hyperuricemia has shed new light on a potential mechanism of microvascular changes leading to endothelial dysfunction, a precursor to both coronary artery disease and hypertension. Additional animal studies and recent epidemiologic findings have provided further evidence that soluble urate is a risk factor for nonarticular disease.
Debris flows can spontaneously develop regular large-amplitude surge waves that are interspersed by periods in which the channel fill is completely stationary. These are important because each ...individual surge is much more destructive than a steady uniform flow with the same mass flux. In this paper small-scale experiments that exhibit similar behaviour are described. The flow consists of carborundum particles that flow down a rough inclined chute covered with a static erodible layer of the same grains. For inflow conditions close to the minimum depth required for steady uniform flows to exist, small disturbances are unstable, creating waves that rapidly coarsen and grow in size. As the waves become sufficiently large, the troughs between the wave crests drop below a critical thickness and come to rest. A series of steadily travelling waves develop which erode the static layer of particles in front of them and deposit grains behind them, to form a layer that is again stationary. This is, in turn, re-eroded and deposited by the next wave. We term these waves granular erosion–deposition waves. Although erosion and deposition problems are notoriously difficult, a simple model is developed which uses a depth-averaged version of the
${\it\mu}(I)$
-rheology and Pouliquen and Forterre’s extended friction law. The viscous dissipation combines with dynamic, intermediate and static friction regimes to generate finite-length waves with static and mobile regions. The existence of stationary layers fundamentally distinguishes erosion–deposition waves from granular roll waves, which form in slightly deeper flows and are always completely mobilized. Numerical simulations show that the system of equations is able to model both erosion–deposition waves and granular roll waves. Moreover, the computed wave amplitude, wavespeed and coarsening dynamics are in good quantitative agreement with experiments.
The ability to form a dormant spore is essential for the survival of the anaerobic pathogen, Clostridioides difficile, outside of the mammalian gastrointestinal tract. The initiation of sporulation ...is governed by the master regulator of sporulation, Spo0A, which is activated by phosphorylation. Multiple sporulation factors control Spo0A phosphorylation; however, this regulatory pathway is not well defined in C. difficile. We discovered that RgaS and RgaR, a conserved orphan histidine kinase and orphan response regulator, function together as a cognate two-component regulatory system to directly activate transcription of several genes. One of these targets, agrB1D1, encodes gene products that synthesize and export a small quorum-sensing peptide, AgrD1, which positively influences expression of early sporulation genes. Another target, a small regulatory RNA now known as SpoZ, impacts later stages of sporulation through a small hypothetical protein and an additional, unknown regulatory mechanism(s). Unlike Agr systems in many organisms, AgrD1 does not activate the RgaS-RgaR two-component system, and thus, is not responsible for autoregulating its own production. Altogether, we demonstrate that C. difficile utilizes a conserved two-component system that is uncoupled from quorum-sensing to promote sporulation through two distinct regulatory pathways.
Highlights • First known systematic review reporting the impact of pharmacist immunizers on vaccination rates. • Limited number of randomized controlled trials and high quality studies. • Pharmacist ...involvement in immunization services increased vaccine coverage rates.
Febuxostat is a new non-purine xanthine oxidase inhibitor that is more potent than allopurinol 300 mg daily. In two Phase III trials, significantly more febuxostat-treated gout patients met the ...primary endpoint serum urate (sUA) <6 mg/dl (<360 μmol/l) at the last three visits (48 and 53% with 80 mg; 65 and 62% with 120 mg), compared with those receiving allopurinol 300 mg (22 and 21%; P < 0.001 in both studies). Febuxostat was more effective than allopurinol in the subset with impaired renal function; no dose adjustment is required in mild-to-moderate renal impairment. Long-term extension studies confirmed the efficacy and tolerability of febuxostat. In patients who achieved the sUA target of 6 mg/dl (360 μmol/l), the incidence of gout flares fell steadily and tophi resolved in many patients. The incidence of adverse events such as dizziness, diarrhoea, headache and nausea with febuxostat was similar to allopurinol. The incidence of cardiovascular side-effects (Antiplatelet Trialists Collaboration events) was numerically higher with febuxostat than with allopurinol, but this was not statistically significant. Co-administration of febuxostat with AZA or 6-mercaptopurine is not recommended. Prophylaxis (colchicine and/or NSAIDs) against acute attacks should be used for at least the first 6 months, since early mobilization flares were observed in the clinical trials. In conclusion, febuxostat is more effective than allopurinol 300 mg daily in reducing sUA levels <6 mg/dl (360 μmol/l), the target recommended by EULAR, and offers a new option for the long-term treatment of gout.
Existing criteria for the classification of gout have suboptimal sensitivity and/or specificity, and were developed at a time when advanced imaging was not available. The current effort was ...undertaken to develop new classification criteria for gout.
An international group of investigators, supported by the American College of Rheumatology and the European League Against Rheumatism, conducted a systematic review of the literature on advanced imaging of gout, a diagnostic study in which the presence of monosodium urate monohydrate (MSU) crystals in synovial fluid or tophus was the gold standard, a ranking exercise of paper patient cases, and a multi-criterion decision analysis exercise. These data formed the basis for developing the classification criteria, which were tested in an independent data set.
The entry criterion for the new classification criteria requires the occurrence of at least one episode of peripheral joint or bursal swelling, pain, or tenderness. The presence of MSU crystals in a symptomatic joint/bursa (ie, synovial fluid) or in a tophus is a sufficient criterion for classification of the subject as having gout, and does not require further scoring. The domains of the new classification criteria include clinical (pattern of joint/bursa involvement, characteristics and time course of symptomatic episodes), laboratory (serum urate, MSU-negative synovial fluid aspirate), and imaging (double-contour sign on ultrasound or urate on dual-energy CT, radiographic gout-related erosion). The sensitivity and specificity of the criteria are high (92% and 89%, respectively).
The new classification criteria, developed using a data-driven and decision-analytic approach, have excellent performance characteristics and incorporate current state-of-the-art evidence regarding gout.
This paper presents an analysis of climate policy instruments for the decarbonisation of the global electricity sector in a non-equilibrium economic and technology diffusion perspective. Energy ...markets are driven by innovation, path-dependent technology choices and diffusion. However, conventional optimisation models lack detail on these aspects and have limited ability to address the effectiveness of policy interventions because they do not represent decision-making. As a result, known effects of technology lock-ins are liable to be underestimated. In contrast, our approach places investor decision-making at the core of the analysis and investigates how it drives the diffusion of low-carbon technology in a highly disaggregated, hybrid, global macroeconometric model, FTT:Power-E3MG. Ten scenarios to 2050 of the electricity sector in 21 regions exploring combinations of electricity policy instruments are analysed, including their climate impacts. We show that in a diffusion and path-dependent perspective, the impact of combinations of policies does not correspond to the sum of impacts of individual instruments: synergies exist between policy tools. We argue that the carbon price required to break the current fossil technology lock-in can be much lower when combined with other policies, and that a 90% decarbonisation of the electricity sector by 2050 is affordable without early scrapping.
•Policy scenarios for decarbonising of the global electricity sector by 90%.•Strong synergies exist between different energy policy instruments.•Carbon pricing not a sufficient policy instrument for large emissions reductions.•Improved agent behaviour assumptions for energy modelling beyond cost-optimisation.
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