Widening the prostacyclin paradigm: tissue fibroblasts are a critical site of production and anti-thrombotic protection

BACKGROUND: Prostacyclin is a fundamental signaling pathway traditionally associated with the cardiovascular system and protection against thrombosis but which also has regulatory functions in fibrosis, proliferation, and immunity. Prevailing dogma states that prostacyclin is principally derived from vascular endothelium, although it is known that other cells can also synthesize it. However, the role of nonendothelial sources in prostacyclin production has not been systematically evaluated resulting in an underappreciation of their importance relative to better characterized endothelial sources. METHODS: To address this, we have used novel endothelial cell–specific and fibroblast-specific COX (cyclo-oxygenase) and prostacyclin synthase knockout mice and cells freshly isolated from mouse and human lung tissue. We have assessed prostacyclin release by immunoassay and thrombosis in vivo using an FeCl3-induced carotid artery injury model. RESULTS: We found that in arteries, endothelial cells are the main source of prostacyclin but that in the lung, and other tissues, prostacyclin production occurs largely independently of endothelial and vascular smooth muscle cells. Instead, in mouse and human lung, prostacyclin production was strongly associated with fibroblasts. By comparison, microvascular endothelial cells from the lung showed weak prostacyclin synthetic capacity compared with those isolated from large arteries. Prostacyclin derived from fibroblasts and other nonendothelial sources was seen to contribute to antithrombotic protection. CONCLUSIONS: These observations define a new paradigm in prostacyclin biology in which fibroblast/nonendothelial-derived prostacyclin works in parallel with endothelium-derived prostanoids to control thrombotic risk and potentially a broad range of other biology. Although generation of prostacyclin by fibroblasts has been shown previously, the scale and systemic activity was not tested and unappreciated. As such, this represents a basic change in our understanding and may provide new insight into how diseases of the lung result in cardiovascular risk

Astragaloside II promotes intestinal epithelial repair by enhancing L-arginine uptake and activating the mTOR pathway

Astragaloside II (AS II) extracted from Astragalus membranaceus has been reported to promote tissue wound repair. However, the effect of AS II on inflammatory bowel disease is unknown. We investigated the effects and mechanism of AS II on intestinal wound healing in both in vitro and in vivo models. Human intestinal Caco-2 cells were treated with multiple concentrations of AS II to assess cell proliferation, scratch wound closure, L-arginine uptake, cationic amino acid transporter activity, and activation of the mTOR signaling pathway. These effects were also measured in a mouse model of colitis. AS II promoted wound closure and increased cell proliferation, L-arginine uptake, CAT1 and CAT2 protein levels, total protein synthesis, and phosphorylation of mTOR, S6K, and 4E-BP1 in Caco-2 cells. These effects were suppressed by lysine or rapamycin treatment, suggesting that the enhanced arginine uptake mediates AS II-induced wound healing. Similar results were also observed in vivo. Our findings indicate that AS II can contribute to epithelial barrier repair following intestinal injury, and may offer a therapeutic avenue in treating irritable bowel disease

Endothelial cyclooxygenase-1 paradoxically drives local vasoconstriction and atherogenesis despite underpinning prostacyclin generation

Endothelial cyclooxygenase-1–derived prostanoids, including prostacyclin, have clear cardioprotective roles associated with their anti-thrombotic potential but have also been suggested to have paradoxical pathological activities within arteries. To date it has not been possible to test the importance of this because no models have been available that separate vascular cyclooxygenase-1 products from those generated elsewhere. Here, we have used unique endothelial-specific cyclooxygenase-1 knockout mice to show that endothelial cyclooxygenase-1 produces both protective and pathological products. Functionally, however, the overall effect of these was to drive pathological responses in the context of both vasoconstriction in vitro and the development of atherosclerosis and vascular inflammation in vivo. These data provide the first demonstration of a pathological role for the vascular cyclooxygenase-1 pathway, highlighting its potential as a therapeutic target. They also emphasize that, across biology, the role of prostanoids is not always predictable due to unique balances of context, products, and receptors

Occurrence of Fusarium head blight and mycotoxins as well as morphological identification of Fusarium species in winter wheat in Kosovo

Wheat (Triticum aestivum L.) is an important cereal crop in Kosovo and a major component of population food. Fusarium head blight (FHB) of wheat is an economically very significant disease. FHB leads to various losses in quality like reduced germination of seeds, reduced baking quality and reduced nutritional quality through mycotoxin contamination. In 2010 and 2011 the incidence and identity of the Fusarium spp. infecting wheat in Kosovo as well as mycotoxin contamination was investigated. The results of two years research work show that the incidence of FHB on winter wheat in 2010 was low (<6%). In the year 2011 the disease incidence was clearly higher (up to 31%). Based on morphological characters, F. graminearum was the most frequently Fusarium sp. identified on wheat kernels in the year 2010 (100%) and 2011 (98%). Less frequently isolated species included F. cerealis (<1%) and F. avenaceum (<1%). Wheat flour samples were analyzed by liquid chromatography coupled to mass spectrometry and found to be contaminated with a variety of mycotoxins, most importantly deoxynivalenol and zearalenone. This is the first report on the incidence as well as on the identification of Fusarium species isolated from naturally infected winter wheat in Kosovo

Comparison of quantitative Holocene temperature reconstructions using multiple proxies from a northern boreal lake

Four biotic proxies (plant macrofossils, pollen, chironomids and diatoms) are employed to quantitatively reconstruct variations in mean July air temperatures (T-jul) at Lake Loitsana (northern Finland) during the Holocene. The aim is to evaluate the robustness and biases in these temperature reconstructions and to compare the timing of highest T-jul in the individual reconstructions. The reconstructed T-jul values are evaluated in relation to local-scale/site-specific processes associated with the Holocene lake development at Loitsana as these factors have been shown to significantly influence the fossil assemblages found in the Lake Loitsana sediments. While pollen-based temperatures follow the classical trend of gradually increasing early-Holocene T-jul with a mid-Holocene maximum, the aquatic/wetland assemblages reconstruct higher-than-present T-jul already during the early Holocene, that is, at the peak of summer insolation. The relatively low early-Holocene July temperatures recorded by the pollen are the result of site-specific factors possibly combined with a delayed response of the terrestrial ecosystem compared with the aquatic ecosystem. Our study shows that all reconstructions are influenced at least to some extent by local factors. This finding stresses the need to evaluate quantitatively reconstructed climate values against local lake development and highlights the benefit of using multi-proxy data in Holocene climate reconstructions.Peer reviewe

ElectromyoFigureic Evaluation of Functional Adaptation of Patients with New Complete Dentures

Objective. The objective of this study was to evaluate the level of adaptation of patients to newly fitted complete dentures in their dominant and nondominant sides, by means of ElectromyoFigureic signals. Materials and Methods. Eighty-eight patients with complete dentures were evaluated in the study. Masticatory muscle (masseter and temporal) bioelectric activity of the patients with complete dentures was recorded at maximum intercuspal relation. Parametric statistical data were analyzed with one-way repeated measures ANOVA test. Results. Measurement time was significantly different for both dominant (DS) and nondominant (NDS) sides: FΣs-DS = 21.51, p=0.0001; FΣs-NDS = 13.25, p=0.0001. Gender was also significantly different: FΣs-DS-gender = 41.53, p=0.001; FΣs-NDS-gender = 85.76, p=0.0001. The average surface area values showed significant difference in females. Prior experience with dentures showed no significant difference for both sides of mastication: FΣs-DS-experiences = 1.83, p=0.1772; F Σs-NDS-experiences = 3.30, p=0.0697. Conclusion. The planimetric indicators of bioelectric activity of masseter and temporalis muscles at maximum physiological loading conditions are significant discriminators of the level of functional adaptation of patients with new complete dentures

A persistent neutrophil-associated immune signature characterizes post-COVID-19 pulmonary sequelae.

Interstitial lung disease and associated fibrosis occur in a proportion of individuals who have recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through unknown mechanisms. We studied individuals with severe coronavirus disease 2019 (COVID-19) after recovery from acute illness. Individuals with evidence of interstitial lung changes at 3 to 6 months after recovery had an up-regulated neutrophil-associated immune signature including increased chemokines, proteases, and markers of neutrophil extracellular traps that were detectable in the blood. Similar pathways were enriched in the upper airway with a concomitant increase in antiviral type I interferon signaling. Interaction analysis of the peripheral phosphoproteome identified enriched kinases critical for neutrophil inflammatory pathways. Evaluation of these individuals at 12 months after recovery indicated that a subset of the individuals had not yet achieved full normalization of radiological and functional changes. These data provide insight into mechanisms driving development of pulmonary sequelae during and after COVID-19 and provide a rational basis for development of targeted approaches to prevent long-term complications

Everyday legitimacy and international administration: global governance and local legitimacy in Kosovo

International administrations are a very specific form of statebuilding. This paper examines the limits illustrated by the experience in Kosovo. Here, the international administration faced the same requirements of any legitimate, Liberal government, but without the checks and balances normally associated with Liberal governance. Thus, the international administration was granted full authority and the power thereby associated, but without the legitimacy upon which the Liberal social contract rests. The state-building agenda put forth came to be seen as more exogenous, reinforcing the delegitimization process. This paper will specifically address the influence of the Weberian approach to legitimacy on the statebuilding literature, as well as its limits. It will then propose other possible avenues for statebuilding, more in line with a wider understanding of legitimacy and intervention

Polymorphic variants of SCN1A and EPHX1 influence plasma carbamazepine concentration, metabolism and pharmacoresistance in a population of Kosovar Albanian epileptic patients

Aim The present study aimed to evaluate the effects of gene variants in key genes influencing pharmacokinetic and pharmacodynamic of carbamazepine (CBZ) on the response in patients with epilepsy. Materials & Methods Five SNPs in two candidate genes influencing CBZ transport and metabolism, namely ABCB1 or EPHX1, and CBZ response SCN1A (sodium channel) were genotyped in 145 epileptic patients treated with CBZ as monotherapy and 100 age and sex matched healthy controls. Plasma concentrations of CBZ, carbamazepine-10,11-epoxide (CBZE) and carbamazepine-10,11-trans dihydrodiol (CBZD) were determined by HPLC-UV-DAD and adjusted for CBZ dosage/kg of body weight. Results The presence of the SCN1A IVS5-91G>A variant allele is associated with increased epilepsy susceptibility. Furthermore, carriers of the SCN1A IVS5-91G>A variant or of EPHX1 c.337T>C variant presented significantly lower levels of plasma CBZ compared to carriers of the common alleles (0.71±0.28 vs 1.11±0.69 μg/mL per mg/Kg for SCN1A IVS5-91 AA vs GG and 0.76±0.16 vs 0.94±0.49 μg/mL per mg/Kg for EPHX1 c.337 CC vs TT; PG showed a reduced microsomal epoxide hydrolase activity as reflected by a significantly decreased ratio of CBZD to CBZ (0.13±0.08 to 0.26±0.17, pT SNP and SCN1A 3148A>G variants were not associated with significant changes in CBZ pharmacokinetic. Patients resistant to CBZ treatment showed increased dosage of CBZ (657±285 vs 489±231 mg/day; P<0.001) but also increased plasma levels of CBZ (9.84±4.37 vs 7.41±3.43 μg/mL; P<0.001) compared to patients responsive to CBZ treatment. CBZ resistance was not related to any of the SNPs investigated. Conclusions The SCN1A IVS5-91G>A SNP is associated with susceptibility to epilepsy. SNPs in EPHX1 gene are influencing CBZ metabolism and disposition. CBZ plasma levels are not an indicator of resistance to the therapy

Increased 30-Day Mortality in Very Old ICU Patients with COVID-19 Compared to Patients with Respiratory Failure without COVID-19

Purpose: The number of patients ≥ 80 years admitted into critical care is increasing. Coronavirus disease 2019 (COVID-19) added another challenge for clinical decisions for both admission and limitation of life-sustaining treatments (LLST). We aimed to compare the characteristics and mortality of very old critically ill patients with or without COVID-19 with a focus on LLST. Methods: Patients 80 years or older with acute respiratory failure were recruited from the VIP2 and COVIP studies. Baseline patient characteristics, interventions in intensive care unit (ICU) and outcomes (30-day survival) were recorded. COVID patients were matched to non-COVID patients based on the following factors: age (± 2 years), Sequential Organ Failure Assessment (SOFA) score (± 2 points), clinical frailty scale (± 1 point), gender and region on a 1:2 ratio. Specific ICU procedures and LLST were compared between the cohorts by means of cumulative incidence curves taking into account the competing risk of discharge and death. Results: 693 COVID patients were compared to 1393 non-COVID patients. COVID patients were younger, less frail, less severely ill with lower SOFA score, but were treated more often with invasive mechanical ventilation (MV) and had a lower 30-day survival. 404 COVID patients could be matched to 666 non-COVID patients. For COVID patients, withholding and withdrawing of LST were more frequent than for non-COVID and the 30-day survival was almost half compared to non-COVID patients. Conclusion: Very old COVID patients have a different trajectory than non-COVID patients. Whether this finding is due to a decision policy with more active treatment limitation or to an inherent higher risk of death due to COVID-19 is unclear.info:eu-repo/semantics/publishedVersio