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Diagnosing immediate drug hypersensitivity reactions (IDHRs) can pose a significant challenge and there is an urgent need for safe and reliable tests. Evidence has emerged that the basophil activation test (BAT), an in vitro assay that mirrors the in vivo response, can be a complementary test for many drugs. In this position paper, members of Task Force (TF) "Basophil activation test in the evaluation of Drug Hypersensitivity Reactions" from the European Academy of Allergy and Clinical Immunology (EAACI) present the data from a survey about the use and utility of BAT in IDHRs in Europe. The survey results indicate that there is a great interest for using BAT especially for diagnosing IDHRs. However, there are still main needs, mainly in the standardization of the protocols. Subsequently consensus‐based recommendations were formulated for: (i) Technical aspects of BAT in IDHRs including type of sample, management of drugs, flow cytometry protocols, interpretation of the results; and (ii) Drug‐specific aspects that should be taken into account when performing BAT in relation to betalactams, neuromuscular blocking agents, fluoroquinolones, chlorhexidine, opioids, radio contrast media, chemotherapeutics, biological agents, nonsteroidal anti‐inflammatory drugs, COVID vaccine, and excipients. Moreover, aspects in the evaluation of pediatric population have also been considered. All this indicates that BAT offers the clinician and laboratory a complementary tool for a safe diagnostic for IDHRs, although its place in the diagnostic algorithm depends on the drug class and patient population (phenotype, geography, and age). The standardization of BAT is important for generalizing this method beyond the individual laboratory. [ABSTRACT FROM AUTHOR]

The article discusses the basophil activation test (BAT) as a diagnostic tool for managing patients with IgE-mediated allergies. The authors emphasize the need for standardization and external quality assurance (EQA) of laboratory protocols and results interpretation. A task force was created to develop a consensus protocol for BAT-EQA, and round robin tests were conducted to train participating laboratories. The article presents a proposed standard operating protocol for BAT and highlights the importance of EQA for routine implementation of the assay. The authors conclude that the consensus protocol provides acceptable inter- and intralaboratory variability and can be implemented across Europe. [Extracted from the article]

Beneath the tilted fault blocks of the Galicia rifted margin, a bright reflection, termed S, has been interpreted as the master detachment fault controlling the extension of the margin. However, on time-migrated sections, S appears to be locally offset by the steep faults of the upper section. We investigate the true geometry of S and its relation to the overlying faults through iterative prestack depth migration. We conclude that it is not significantly offset by the faults, which instead appear to stop abruptly at S. Thus, we interpret S as the master detachment and consider its role during extension.

Diffusion of atoms or molecules (generally: particles) is driven by differences and gradients of the chemical potential of the particles in their accessible space. If the difference of the chemical potential is due to differences of concentrations alone, one arrives at the diffusion equations of Fick. The diffusion coefficients are described in known models by vibrations of atoms in condensed matter which cause the exchange of preferentially neutral particles with neighbouring particles, impurities, interstitial places and vacancies near or on surfaces, grain boundaries, dislocation lines and in the homogeneous bulk. The rates of electronic transitions, however, increase also in melts and solids of chemically bonded particles with increasing temperature. Such transitions cause large fluctuating deviations of the local energy, the charge distribution and the local chemical and electrical potentials. The fluctuating deviations interact with the core ions and drive particles to interchange. This mechanism that supplements the known mechanisms of diffusion has not yet found adequate attention in the literature until now. Foundations, experimental results, evidence and consequences for diffusion are discussed. [ABSTRACT FROM AUTHOR]

Milestones in the development of thermodynamics are the discovery of the absolute temperature scale and the recognition that differential "heat" is a form of energy given as the product of absolute temperature and differential entropy. Following a new path, the last statement results from a careful analysis of the heat transfer applying the first theorem without reference to the usual cycles in thermodynamics. This confirms also characteristic properties of entropy. In particular, the total entropy can never decrease in a process. In thermal equilibrium, the differential thermal energy is proportional to the differential entropy with the constant of proportionality being the temperature of the heat and entropy. Hence, thermal energy and entropy are transferred simultaneously into the same storage facilities, some of which are mentioned. However, the issue which one is the superior quantity is obsolete. The entropy is maximum for a given amount of exchanged thermal energy and, vice versa, for a given amount of exchanged entropy the concomitant energy is minimum. We calculate the thermal energy and entropy of phonons (as bosons) in oscillators and of electrons (as fermions) in their states of solids and melts as examples from statistical thermodynamics. The thermal energy or heat is the sum of the energies of all bosons and fermions in their elementary states or quantum states according to Bose Einstein and Fermi Dirac statistics in thermal equilibrium minus the total energy in the limit T→0 K. The entropy can be written as mixing entropy of all of these quantum states weighted with their occupancies, in agreement with an earlier publication. Thus, entropy is a logarithmic metrics of the number of all possible variants to distribute the respective total energy over all elementary states in thermal equilibrium. [ABSTRACT FROM AUTHOR]

Abstract: The viscosity of fluids and melts is an important characteristic to steer processes and reactions of materials, to use lubricants and to fabricate diverse products of glass. To steer such fabrication processes reliably and free of failures one necessarily needs to understand and use the true data of the viscosity. The forces applied to measure the viscosity act also to accelerate parts of the samples and particularly to deform them elastically. To evaluate the viscosity one must necessarily consider such ‘side reactions’. Cylindrical samples under longitudinal deformation are demonstrated to deform rather elastically than by viscous flow upon application of the load, e. g. Neglecting this effect the ’viscosity’ apparently decreasing with increasing load may be misinterpreted as non‐Newtonian viscosity. In fact, it represents the change from viscous to elastic behaviour with decreasing time interval of the application of force. Furthermore, production of entropy during deformation for measurement has to be taken into account adequately. The sample warms up during heavy deformation. If the viscosity depends strongly on the temperature, one must take into account that temperature and viscosity change with the intensity of the load. Then the so called ’shear thinning’ is rather ’sheer heating’. This is demonstrated quantitatively with data of the viscosity as a function of the load, which have recently been published using capillary rheometers. [ABSTRACT FROM AUTHOR]

In this review, we report on relevant current topics in allergen immunotherapy ( AIT) which were broadly discussed during the first Aarhus Immunotherapy Symposium (Aarhus, Denmark) in December 2015 by leading clinicians, scientists and industry representatives in the field. The aim of this symposium was to highlight AIT-related aspects of public health, clinical efficacy evaluation, mechanisms, development of new biomarkers and an overview of novel therapeutic approaches. Allergy is a public health issue of high socioeconomic relevance, and development of evidence-based action plans to address allergy as a public health issue ought to be on national and regional agendas. The underlying mechanisms are in the focus of current research that lays the ground for innovative therapies. Standardization and harmonization of clinical endpoints in AIT trials as well as current knowledge about potential biomarkers have substantiated proof of effectiveness of this disease-modifying therapeutic option. Novel treatments such as peptide immunotherapy, intralymphatic immunotherapy and use of recombinant allergens herald a new age in which AIT may address treatment of allergy as a public health issue by reaching a large fraction of patients. [ABSTRACT FROM AUTHOR]

The availability of allergen molecules ('components') from several protein families has advanced our understanding of immunoglobulin E (IgE)-mediated responses and enabled 'component-resolved diagnosis' ( CRD). The European Academy of Allergy and Clinical Immunology ( EAACI) Molecular Allergology User's Guide ( MAUG) provides comprehensive information on important allergens and describes the diagnostic options using CRD. Part A of the EAACI MAUG introduces allergen molecules, families, composition of extracts, databases, and diagnostic IgE, skin, and basophil tests. Singleplex and multiplex IgE assays with components improve both sensitivity for low-abundance allergens and analytical specificity; IgE to individual allergens can yield information on clinical risks and distinguish cross-reactivity from true primary sensitization. Part B discusses the clinical and molecular aspects of IgE-mediated allergies to foods (including nuts, seeds, legumes, fruits, vegetables, cereal grains, milk, egg, meat, fish, and shellfish), inhalants (pollen, mold spores, mites, and animal dander), and Hymenoptera venom. Diagnostic algorithms and short case histories provide useful information for the clinical workup of allergic individuals targeted for CRD. Part C covers protein families containing ubiquitous, highly cross-reactive panallergens from plant (lipid transfer proteins, polcalcins, PR-10, profilins) and animal sources (lipocalins, parvalbumins, serum albumins, tropomyosins) and explains their diagnostic and clinical utility. Part D lists 100 important allergen molecules. In conclusion, IgE-mediated reactions and allergic diseases, including allergic rhinoconjunctivitis, asthma, food reactions, and insect sting reactions, are discussed from a novel molecular perspective. The EAACI MAUG documents the rapid progression of molecular allergology from basic research to its integration into clinical practice, a quantum leap in the management of allergic patients. [ABSTRACT FROM AUTHOR]

The interrelation of thermodynamics and statistical properties of quantum systems can be demonstrated with comparatively little mathematical effort using two state systems (or two state particles). Basic results are summarized for this model system. The entropy can be interpreted as the entropy of mixing particles in their low and high energy state. Thus, an apparent single component system can be considered as a two component system with variable particle numbers. This result has recently been generalized for elementary bosonic and fermionic systems or particles with many different excited states. In this case, one has to take into account as many components as different internal states of the particles are available. The numbers of particles of each component, however, are not constant but depend on the temperature at thermal equilibrium according to statistical principles. In the literature, the concept of negative internal temperatures was previously introduced to characterize and describe special inverted occupation probabilities out of thermal equilibrium. This interpretation of inverted occupation numbers is revisited explicitly for nuclear spin systems. The interpretation of inverted occupancy by negative temperature is based on ignoring athermal contributions to the internal energy due to the inversion procedure. Accordingly, negative temperatures are not justified in the case of systems out of thermal equilibrium but seem to be misleading and confusing. Instead, the different states of the particles represent distinctive components possessing different chemical potentials, magnetic moments or other properties. The present paper intends to remove the confusion about negative temperatures. It shows how processes out of thermal equilibrium are described and understood without difficulties by balancing the different kinds of particles together with their energy and production of entropy within the framework of thermodynamics. [ABSTRACT FROM AUTHOR]

Entropy as a function of temperature at constant volume, S(T), can be determined by integrating the molar specific entropy capacity CV/T (CV: molar specific heat capacity at constant volume). As a second approach, S(T) at constant volume can be determined by differentiating the free energy with respect to the temperature, T. Recently, it has been shown for a system obeying Boltzmann statistics that these mathematical approaches are equivalent to applying the formula of the mixing entropy, if the ground and excited states of the same sub-systems or elementary systems are considered as mixing objects or quantum components. This result considerably extends the applicability of the formula of the mixing entropy, which is derived in textbooks just for mixing real indifferent components. In the present paper, it is shown that the formula of the mixing entropy can also be applied to calculate the entropy of Bose and Fermi systems. Thus, all entropy can be calculated and interpreted as mixing entropy of real components or quantum components. In reverse, the transitions between the ground and the excited states of any system can be explained as mixing processes. This interpretation is applied to the melting transition of chemically bonded solids and in particular to the glass transition whereby upon cooling the mixing entropy of the melt is (at least partly) frozen in the configuration. These results suggest a new interpretation of the glass transition and a new definition of structural glass. [ABSTRACT FROM AUTHOR]

The function of cultured mast cells may depend on genetic or environmental influence on the stem cell donor. This study investigates whether asthma or atopy in the donor influenced the growth and sensitivity of mast cells cultured from patients with asthma and healthy controls under identical conditions. Mast cells were cultured from peripheral blood from twelve patients with an objectively confirmed asthma diagnosis and eight healthy subjects. During the last 2 weeks of culture, mast cells were incubated with IL-4 and 80 kU/l recombinant human Ig E containing two clones (7% + 7%) specific for mite allergen Der p2. The sensitivity of Ig E-mediated activation of mast cells was investigated as Fcε RI-mediated upregulation of CD63. Ten subjects were atopic, defined as a positive skin prick test (>3 mm) to at least one of ten common allergens. After activation with recombinant Der p2, the maximum CD63 median fluorescence intensity was 20 456 ± 1640 ( SE) for patients with asthma and 22 275 ± 1971 ( SE) for controls (ns). The fraction of CD63 positive cells was 54.4% in patients with asthma and 48.4% in controls (ns). The allergen concentration inducing 50% of the maximal CD63 response was similar in patients with asthma [−0.4795 log ng/ml ± 0.092 ( SE)] and controls (−0.6351 log ng/ml ± 0.083, ns) and in atopic and non-atopic subjects. When cultured, sensitized and activated under identical conditions, mast cells from allergic asthmatics and healthy controls respond similar. Activation of cultured mast cells appears to depend on culture conditions ( IL-4, Ig E) rather than on donor status as atopy and asthma. [ABSTRACT FROM AUTHOR]

The Legendre transformation has found widespread application in thermodynamics, Hamilton-Lagrange-mechanics and optics. It attributes the values of the coordinates ( x, y ( x)) representing the points of a monotonic piecewise smooth functional curve y ( x) the slopes mx ( x) = dy ( x)/ dx and the intercepts y ( mx) of their tangents on the y-axis. Thus, the initial curve y ( x) is represented by the ordered set of all slopes mx ( x) = dy ( x)/ dx of its tangents together with their intercepts y ( mx) on the y-axis. It is shown that the transformed or conjugated function must basically be supplemented by a homogeneous linear function of the relevant variable. This is usually neglected in the literature. In addition, a new interpretation of the Legendre transformation is presented and discussed: For this purpose the derivative mx ( x) is considered as the proper initial function and integrated between x0 and x. This integral is complemented by the integral of x ( mx) ((the inverse function of mx ( x)) over mx between mx0 = mx ( x0) and mx ( x), if mx ( x) and x ( mx) are strictly monotonic. The sum of both integrals yields the 'area' ( xmx - x0 mx0). Legendre's transformation is obtained by reordering the respective terms. The procedure of transformation corresponds to integration by parts. Some examples and consequences of the properties considered are demonstrated and discussed using the simple model of two-state systems. The general results of the present work remove possible internal inconsistencies in thermodynamics. [ABSTRACT FROM AUTHOR]

In order to understand the thermodynamic properties of solids and melts one has to consider simultaneously their entropy and energy as a function of temperature. Therefore, the molar entropy, S, and enthalpy (energy), H, of crystals, glasses and melts of the same one-component systems have been suitably depicted including the transformation from the melt into a solid, i. e. a glass or crystal. S and H of glasses correspond to a simple continuation of these functions from the molten state to lower temperatures. Since crystallisation occurs spontaneously such a process necessarily produces entropy causing the temperature to increase. Thus, the glassy and the crystalline state are not connected by an isothermal process, which is in contrast to the assumption in the classical nucleation and crystallisation theory as well as in the arguments causing Kauzmann's paradox. For the temperature T → 0 K the enthalpy and entropy of the glass are larger by Δ H0 and Δ S0 as compared to the stable crystal. The calculations are illustrated using experimental data for quartz and silica glass from P. Richet, Y. Bottinga, L. Deniélou, J. P. Petitet and C. Téqui. [ABSTRACT FROM AUTHOR]

CD4+CD25+ regulatory T cells (Tregs) are involved in the maintenance of peripheral tolerance and ensure a balanced immune response competent of fighting pathogens and at the same time recognizing commensals as harmless. This feature is lost in Crohn's disease (CD). The forkhead/winged helix transcription factor FoxP3 is a master gene for Treg function and defects in the FoxP3 gene lead to a clinical picture similar to inflammatory bowel disease (IBD). Murine colitis can be cured by adoptive transfer of Tregs and ex vivo-generated gut-specific Tregs represent an attractive option for therapy in CD. Thus, defective Tregs could contribute to the development of CD. We cultured biopsies of colonic mucosa in the presence of high concentrations of interleukin (IL)-2 and IL-4 to overcome the anergic nature of naturally occurring CD4+CD25+ Tregs in the mucosa. We investigated the expression of FoxP3 and regulatory potential of gut-derived CD4+CD25+ T cells cultured from patients with CD and healthy individuals. The FoxP3 expression was analysed by reverse transcriptase polymerase chain reaction (RT-PCR), and the suppressive effect of FoxP3+CD4+CD25+ T cells on proliferation and cytokine production of autologous CD4+ T cells was assessed by flow cytometry. Cultured gut-derived T cells with CD4+CD25+ phenotype expressed FoxP3 and were able as the freshly isolated Tregs from peripheral blood to suppress proliferation and cytokine production of autologous CD4+ T cells. Thus, we demonstrate that FoxP3+CD4+CD25+ T cells with regulatory properties can be propagated in vitro from inflamed mucosa of CD patients, which may be of interest in adoptive immunotherapy. [ABSTRACT FROM AUTHOR]

Mast cells have long been recognized as the principal cell type that initiates the inflammatory response characteristic of acute allergic type 1 reactions. Our goal has been to further characterize maturation of progenitors to mast cells.Mast cells were cultured from human cord blood derived CD133+ progenitors. Mast cell function was tested using histamine release. During differentiation mast cells surface marker expression was monitored by flow cytometry.CD133+ progenitors expressed the early haematopoietic and myeloid lineage markers CD34, CD117, CD13 and CD33. Mature mast cells expressed CD117, CD13 and CD33, and expression of the high affinity immunoglobulin E recpetor FcℇRI increased during culture. Cytokine receptors interleukin (IL)-5R, IL-3R,granulocyte-macrophage-colony stimulating factor (GM-CSF)R and IL-18R were expressed at high levels during maturation. Chemokine receptors CXCR4 and CXCR2 were highly expressed on both newly purified CD133+ cells and mature cells.Human mast cells can be cultured from a CD34+/CD117+/CD13+/CD33+ progenitor cell population in cord blood that is tryptase and chymase negative. Developing and mature mast cells express a wide range of chemokine and cytokine receptors. We found high levels of expression of CD123, IL-5R and GM-CSF receptors, also found on eosinophils and basophils, and high levels of expression of the receptor for the inflammatory cytokine IL-18. [ABSTRACT FROM AUTHOR]

Integrinα4β 7 is the principal gut-homing receptor, and it is assumed that expression of this specific integrin directs lymphocytes to the gutin vivo. Adoptive cellular immunotherapy against inflammatory bowel disease (IBD) may depend on the expression of integrinα4β 7 to accomplish local delivery of intravenously injected regulatory T cells in inflamed gut mucosa. The present study aimed to investigate whetherin vitroexpanded human T cells from the colonic mucosa maintain integrin expression, showin vitroadhesion and retainin vivogut-homing properties during cultivation. Whole colonic biopsies from healthy subjects were cultured in the presence of interleukin-2 (IL-2) and IL-4. The integrin expression of the cultured T cells was determined by flow cytometry andin vitroadhesion was assessed in a mucosal addressin cell adhesion molecule 1 (MAdCAM-1) adhesion assay. We studied the homing pattern after autologous infusion of 3 × 108 111Indium (111In)-labelled T cells in five healthy subjects using scintigraphic imaging. The cultured CD4+CD45RO+ gut-derived T cells express higher levels of integrinα4β 7 than peripheral blood lymphocytes (PBLs) and show strong adhesion to MAdCAM-1in vitro, even after111In-labelling. Scintigraphic imaging, however, showed no gut-homingin vivo. After prolonged transit through the lungs, the T cells migrated preferentially to the spleen, liver and bone marrow. In conclusion, it is feasible to infuse autologous T cells cultured from the gut mucosa, which may be of interest in adoptive immunotherapy. Despite high expression of the gut-homing integrinα4β 7 and adhesion to MAdCAM-1in vitro, evaluation by111In-scintigraphy demonstrated no gut-homing in healthy individuals. [ABSTRACT FROM AUTHOR]