Prostaglandin D
2
(PGD
2
) released by degranulating mast cells is believed to play a key role in orchestrating mechanisms of inflammation in allergies and asthma. The biological effects of PGD
2
are ...mediated by D-prostanoid (DP1), CRTH2 (DP2), and thromboxane prostanoid (TP) receptors. The CRTH2 receptor is involved in induction of migration and activation of T helper type 2 (Th
2
) lymphocytes, eosinophils, and basophils; up-regulation of adhesion molecules; and promotion of pro-inflammatory Th
2
-type cytokines (interleukin IL-4, 5, 13), whereas the DP receptor is associated with relaxation of smooth muscles, vasodilation, inhibition of cell migration, and apoptosis of eosinophils. A number of CRTH2/PGD
2
receptor antagonists have been investigated in asthma and allergic diseases. The CRTH2 antagonist (OC000459) or dual CRTH2 and TP receptor antagonist (ramatroban) were effective in reducing eosinophilia, nasal mucosal swelling, and clinical symptoms of allergic rhinitis, with the latter drug registered for clinical use in this indication. OC000459 and setipiprant reduced the late but not early phase of response in an allergen challenge in atopic asthmatics. In persistent asthma, some molecules induced limited improvement in lung function, quality of life, and asthma symptoms (OC000459, BI671800), but in other trials with AMG 853 and AZ1981 these findings were not confirmed. The clear discrepancy between animal studies and clinical efficacy of CRTH2 antagonism in allergic rhinitis, and lack of efficacy in a general cohort of asthmatics, highlight the issue of patient phenotyping. There is no doubt that the PGD
2
/CATH2/DP1 pathway plays a key role in allergic inflammation and further studies with selective or combined antagonisms in well defined cohorts of patients are needed.
The article presents the results of the influence of laser heating on the properties of replaceable cutting inserts with various anti-wear coatings. Based on the existing own and external ...publications, it was found that in order to improve the cutting properties (durability in the cutting process of steel), it is extremely important to increase the adhesion strength of hard coatings to the cutting inserts. For this purpose, laser heating with different values of the laser beam power density was used. First, the measurements of the adhesion, and then the wear and durability of the cutting blades in the process of longitudinal turning of the commonly used nitriding steel were carried out. In order to confirm the adhesion measurements carried out on the basis of the vibration signal evaluation, observations were additionally made using a scanning microscope and using 2D and 3D images on a profilometer. As a result of the research, it was found, among other things, a significant correlation between the values of adhesion of coatings to cemented carbide substrates and the durability of the blades in the steel turning process. A significant effect of laser heating on the above-mentioned properties of replaceable cutting inserts was observed. The most favorable value of the applied power density was determined, for which the blades have the best cutting properties. The research indicate that significant increase in adhesion and tool life can be achieved for the laser beam power density of up to 8280 W/cm2. In the most favorable case, an increase in tool life of about 48% was obtained for the indexable cutting insert with a TiCN coating when turning 41CrAlMo7-10 steel.
Patients with moderate-to-severe asthma may now be treated using a variety of monoclonal antibodies that target key inflammatory cytokines involved in disease pathogenesis. Existing clinical data on ...anti-IgE, anti-IL-5 and other immunological pathways indicate these therapies to offer reduced exacerbation rates, improved lung function, greater asthma control and better quality of life. However, as several patients still do not achieve satisfactory clinical response with the antibodies available, many more biologics, aiming different immunological pathways, are under evaluation. This review summarizes recent data on existing and potential monoclonal antibodies in asthma. Recent advances have resulted in the registration of a new antibody targeting TSLP (tezepelumab), with others being under development. Some of the researched monoclonal antibodies (e.g. anti-IL-13 tralokinumab and lebrikizumab or anti-IL-17A secukinumab) have shown optimistic results in preliminary research; however, these have been discontinued in asthma clinical research. In addition, as available monoclonal antibody treatments have shown little benefit among patients with T
-low asthma, research continues in this area, with several antibodies in development. This article summarizes the available pre-clinical and clinical data on new and emerging drugs for treating severe asthma, discusses discontinued treatments and outlines future directions in this area.
Background The safety and efficacy of specific immunotherapy for mold allergy are not known in children and adolescents. Objective We evaluated the efficacy and safety of specific immunotherapy with ...a standardized allergen extract in a randomized, double-blind, placebo-controlled, 3-year prospective study of patients who were allergic to only Alternaria alternata. Methods Fifty children and adolescents (25 girls; 5-18 years of age) with A alternata –induced seasonal allergic rhinoconjunctivitis and/or bronchial asthma were randomly assigned to groups given treatment (Novo-Helisen Depot, A alternata 100%) or placebo. The primary end point was the combined symptom medication score. Secondary end points included safety, quality of life, and sensitivity to allergen-specific nasal challenge. Results Forty-five children completed the 3-year study. Although there was no significant change in year 1, the combined symptom medication score decreased in years 2 and 3 of the study (by 38.7% and 63.5%, respectively; P < .001 for each). The reduction in symptoms was associated with a significant improvement in quality of life ( P < .05) and decrease in sensitivity after allergen-specific nasal challenge. Side effects were observed in 7 patients; the most common (edema at the site of injection) occurred after 11 injections. Conclusions Allergen-specific immunotherapy with standardized A alternata extract reduces symptoms of asthma and rhinoconjunctivitis in children and adolescents without serious side effects.
This study proposes a novel use of laser heating to increase the adhesion between coatings fabricated by low-temperature PVD and replaceable cemented carbide cutting inserts, thus extending the life ...of these cutting tools in the machining of difficult-to-machine materials. Our previous studies conducted on CVD coatings showed that these coatings had higher adhesion due to a much higher process temperature. However, taking into account the fact that PVD coatings have better technological properties (e.g., lower structure porosity, higher hardness, and better tribological properties) than CVD coatings, it is fully justified to investigate ways of improving the PVD coating adhesion to the substrate. In this study, replaceable cutting inserts with different hard coatings of titanium nitride were used. Laser heating was conducted with different power densities. The adhesion strength of the tested coatings was determined via vibration spectrum analysis. In addition, 2D surface imaging, scanning electron microscopy, and X-ray fluorescence spectrometry were employed to examine the coatings after laser heating. A significant increase in the adhesion of single-layer (TiN) and double-layer (TiCN + TiN) coatings to the cemented carbide substrate, together with increased tool life, was observed after heating the samples with 40% of the maximum laser power. The application of a multilayer coating containing thermal shock-sensitive (TiAlSi) N did not increase the tool life. This paper attempts to interpret the obtained results.
Serum chitinases may be novel biomarkers of airway inflammation and remodeling, but less is known about factors regulating their levels.
To examine serum chitotriosidase activity and YKL-40 levels in ...patients with asthma and chronic obstructive pulmonary disease (COPD) and evaluate clinically relevant factors that may affect chitinase levels, including genetic variability, corticosteroid treatment, disease exacerbations, and allergen exposure.
Serum chitotriosidase (CHIT1) activity and YKL-40 (CHI3L1) levels, as well as the CHIT1 rs3831317 and CHI3L1 rs4950928 genotypes, were examined in subsets of patients with mild to moderate asthma (n = 76), severe asthma (n = 93), and COPD (n = 64) taking part in the European multicenter BIOAIR (Longitudinal Assessment of Clinical Course and Biomarkers in Severe Chronic Airway Disease) study. Blood was obtained at baseline, before and after a 2-week oral steroid intervention, up to six times during a 1-year period, and during exacerbations. Baseline chitinase levels were also measured in 72 healthy control subjects. The effect of allergen inhalation on blood and sputum YKL-40 levels was measured in two separate groups of patients with mild atopic asthma; one group underwent repeated low-dose allergen challenge (n = 15), and the other underwent high-dose allergen challenge (n = 16).
Serum chitotriosidase and YKL-40 were significantly elevated in patients with asthma and those with COPD compared with healthy control subjects. Genotype and age strongly affected both YKL-40 and chitotriosidase activity, but associations with disease remained following adjustment for these factors. Correlations were observed with lung function but not with other biomarkers, including exhaled nitric oxide, blood eosinophils, periostin, and IgE. Generally, acute exacerbations, allergen-induced airway obstruction, and corticosteroid treatment did not affect circulating chitinase levels.
YKL-40 and chitotriosidase are increased in asthma and more so in COPD. The data in the present study support these substances as being relatively steroid-insensitive, non-T-helper cell type 2-type biomarkers distinctly related to chronic inflammatory disease processes.
Background Prostaglandins that constrict and relax airways are synthesized in reactions catalyzed by either COX-1 or COX-2. It is not known whether selective inhibition of COX-2 makes asthmatic ...responses better or worse. Objective To determine the effects of the selective COX-2 inhibitor, etoricoxib, on allergen-induced bronchoconstriction in asthmatic subjects. Methods Sixteen subjects with mild atopic asthma underwent rising dose inhalation challenges with allergen or methacholine to determine PD20 FEV1 during a control study period or after 10 to 13 days of treatment with etoricoxib (90 mg once daily). The order of study periods was randomized with at least 2-week washout periods. Induced sputum cells and fractional exhaled nitric oxide levels were used to assess airway inflammation and blood assays for COX-1 and COX-2 activity to assess enzyme inhibition. Urinary excretion of lipids was used to assess prostaglandin biosynthesis. Results Etoricoxib did not change baseline lung function, nor airway responsiveness to allergen or to methacholine. Neither were the allergen-induced increase in sputum eosinophils and fractional exhaled nitric oxide levels affected by treatment. The biochemical effectiveness of the treatment was established both in the blood assays and by the distinct inhibitory effect of etoricoxib on urinary excretion of tetranor-prostaglandin E2 ( P < .001). Conclusions This first study of COX-2 inhibition in provoked asthma found no negative effects of etoricoxib on allergen-induced airflow obstruction and sputum eosinophils, basal lung function, or methacholine responsiveness. The study suggests that short-term use of COX-2 inhibitors is safe in subjects with asthma.
Despite the proven efficacy of biologics in the treatment of severe asthma, still a limited number of patients are included in the Polish therapeutic programme.
To identify major limitations in the ...qualification paths and predominant reasons leading to exclusion from available biologic treatments. The clinical profiles of patients referred for biologics were also examined.
Data on demographic characteristics, clinical profile, biomarkers, and medical history from one visit of patients that had been referred for qualification for biologics in 2018/2019 to the Barlicki Hospital (Poland) were collected. A comparison between eligible and ineligible patients was made.
Within 2 years, only 116 patients had been referred to the biologic therapy of whom 93 (80%) had been suitable for the biologic programme. Criteria for the omalizumab programme included major limitations such as: frequent use of oral corticosteroids in the past, and serum total-IgE 30-1000 IU/ml, and for mepolizumab were blood eosinophil count (EOScount) > 350/μl and spirometric criterion. Ineligible patients had a significantly lower EOScount and better lung function than eligible individuals despite no significant differences in the number of exacerbations or quality of life between groups. A high percentage of ineligible patients had been referred to re-verify the diagnosis of severe asthma.
Potential limitations for biologic therapy include restrictive criteria limiting the group of patients to the most severe cases and referring patients with difficult-to-treat asthma without a differential diagnosis. Low awareness and knowledge among physicians who often are not familiar with qualification criteria require extensive education.
Indication of the proper scope of application of high-speed steels (HSS) produced by conventional methods and powder metallurgy for cutting tool blades requires a thorough assessment of their ...properties in various cutting conditions. According to common knowledge, the properties of tools made of both types of steel are largely determined by the arrangement of carbide phases. It turns out, however, that the surface morphology of the cutting blades is at least as important for their operational properties. This was already indicated by the preliminary research of the authors of the article, in which it was found that the surface topography significantly affects their durability depending on the applied value of the cutting speed in dry machining conditions and in the presence of a cooling lubricant. As it turned out, contrary to the literature data, blades made of sintered HSS do not have better service properties in all cutting conditions than blades made by conventional methods (e.g., in forging and hot rolling processes). Hence, it was necessary to determine the justified range of use of both types of steel for cutting blades. Cutting blades with a similar chemical composition from conventional high-speed steel and those produced in the powder metallurgy process were tested. Wear curves were determined on the basis of the tests. On this basis, for the assumed value of the blunting index, the tool life of the cutting edges was determined during the cutting of selected structural steel, commonly used for high-strength machine parts. Tests of the cutting ability of the blades were carried out without and with the use of a cooling--lubricating liquid. In order to correctly interpret the obtained results of the wear and durability tests of the cutting edges, verification tests were carried out. A detailed analysis of the research material made it possible to determine the recommended range of applicability of conventional and sintered HSS for the tested case.
This review presents seven national asthma programmes to support the European Asthma Research and Innovation Partnership in developing strategies to reduce asthma mortality and morbidity across ...Europe. From published data it appears that in order to influence asthma care, national/regional asthma programmes are more effective than conventional treatment guidelines. An asthma programme should start with the universal commitments of stakeholders at all levels and the programme has to be endorsed by political and governmental bodies. When the national problems have been identified, the goals of the programme have to be clearly defined with measures to evaluate progress. An action plan has to be developed, including defined re-allocation of patients and existing resources, if necessary, between primary care and specialised healthcare units or hospital centres. Patients should be involved in guided self-management education and structured follow-up in relation to disease severity. The three evaluated programmes show that, thanks to rigorous efforts, it is possible to improve patients' quality of life and reduce hospitalisation, asthma mortality, sick leave and disability pensions. The direct and indirect costs, both for the individual patient and for society, can be significantly reduced. The results can form the basis for development of further programme activities in Europe.
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