Double-blind, placebo-controlled evaluation of grass pollen specific immunotherapy with oral drops administered sublingually or supralingually

SummaryForty-one patients suffering from grass pollen allergy underwent specific immunotherapy with standardized allergen extract consisting of six grass pollens (H-Al per os) administered either sublingually or supralingually for one year. In order to investigate clinical and immunological changes induced by the administration of allergens via the oral mucosa, the double-blind, placebo-controlled, randomized design of the trial with 30 other patients enrolled in placebo groups was applied.Specific immunotherapy with oral drops administered sublingually or supralingually was performed in the same way, keeping the drops under or on the tongue, respectively, for 1–2min before swallowing them; at the end of the trial the cumulative dose of the allergen was almost 20 times higher than that of the subcutaneous therapy with corresponding allergen preparation. Data about symptoms scores and drugs intake during grass pollen season, as well as skin reactivity, levels of specific IgG and IgE antibodies, before the study and after the study's completion, were obtained.It was found that both routes of administration are effective according to subjective clinical parameters and drug consumption, with a highly significant reduction of symptoms and drug intake favoring sublingual administration where a reduction of more than 60% was achieved. Only sublingual active group showed a significant increase in Dactylis glomerata-specific IgG serum levels. Adverse effects were limited to a small number of generally mild local and/or systemic reactions.The results suggest that the administration of allergens via the oral mucosa is safe and clinically effective, favoring the sublingual rather than supralingual route

Overcoming High Energy Backgrounds at Pulsed Spallation Sources

Instrument backgrounds at neutron scattering facilities directly affect the quality and the efficiency of the scientific measurements that users perform. Part of the background at pulsed spallation neutron sources is caused by, and time-correlated with, the emission of high energy particles when the proton beam strikes the spallation target. This prompt pulse ultimately produces a signal, which can be highly problematic for a subset of instruments and measurements due to the time-correlated properties, and different to that from reactor sources. Measurements of this background have been made at both SNS (ORNL, Oak Ridge, TN, USA) and SINQ (PSI, Villigen, Switzerland). The background levels were generally found to be low compared to natural background. However, very low intensities of high-energy particles have been found to be detrimental to instrument performance in some conditions. Given that instrument performance is typically characterised by S/N, improvements in backgrounds can both improve instrument performance whilst at the same time delivering significant cost savings. A systematic holistic approach is suggested in this contribution to increase the effectiveness of this. Instrument performance should subsequently benefit.Comment: 12 pages, 8 figures. Proceedings of ICANS XXI (International Collaboration on Advanced Neutron Sources), Mito, Japan. 201

Liposomal encapsulation enhances and prolongs the anti-inflammatory effects of water-soluble dexamethasone phosphate in experimental adjuvant arthritis

Introduction The objective of this study was to evaluate the efficacy of intravenous (i.v.) injection of liposomally encapsulated dexamethasone phosphate (DxM-P) in comparison to free DxM-P in rats with established adjuvant arthritis (AA). This study focused on polyethylene glycol (PEG)-free liposomes, to minimize known allergic reactions caused by neutral PEG-modified (PEG-ylated) liposomes. Methods Efficacy was assessed clinically and histologically using standard scores. Non-specific and specific immune parameters were monitored. Activation of peritoneal macrophages was analyzed via cytokine profiling. Pharmacokinetics/biodistribution of DxM in plasma, synovial membrane, spleen and liver were assessed via mass spectrometry. Results Liposomal DxM-P (3 × 1 mg/kg body weight; administered intravenously (i.v.) on Days 14, 15 and 16 of AA) suppressed established AA, including histological signs, erythrocyte sedimentation rate, white blood cell count, circulating anti-mycobacterial IgG, and production of interleukin-1beta (IL-1β) and IL-6 by peritoneal macrophages. The suppression was strong and long-lasting. The clinical effects of liposomal DxM-P were dose-dependent for dosages between 0.01 and 1.0 mg/kg. Single administration of 1 mg/kg liposomal DxM-P and 3 × 1 mg/kg of free DxM-P showed comparable effects consisting of a partial and transient suppression. Moreover, the effects of medium-dose liposomal DxM-P (3 × 0.1 mg/kg) were equal (in the short term) or superior (in the long term) to those of high-dose free DxM-P (3 × 1 mg/kg), suggesting a potential dose reduction by a factor between 3 and 10 by liposomal encapsulation. For at least 48 hours after the last injection, the liposomal drug achieved significantly higher levels in plasma, synovial membrane, spleen and liver than the free drug. Conclusions This new PEG-free formulation of macrophage-targeting liposomal DxM-P considerably reduces the dose and/or frequency required to treat AA, with a potential to enhance or prolong therapeutic efficacy and limit side-effects also in the therapy of rheumatoid arthritis. Depot and/or recirculation effects in plasma, inflamed joint, liver, and spleen may contribute to this superiority of liposomally encapsulated DxM-P

The SQ tree SLIT-tablet is highly effective and well tolerated: Results from a randomized, double-blind, placebo-controlled phase III trial

Background: The SQ tree sublingual immunotherapy (SLIT)tablet (ALK-Abello, Horsholm, Denmark) is developed for treatment of tree pollen-induced allergic rhinoconjunctivitis (ARC).Objective: The aim of this pivotal phase III trial was to demonstrate the efficacy and safety of the SQ tree SLIT-tablet.Methods: This was a randomized, double-blind, placebo-controlled trial with 634 subjects (12-65 years) with moderate-to-severe ARC despite use of symptom-relieving medication. Eligible subjects were randomized 1:1 to active or placebo treatment. The primary end point was the average daily ARC total combined score (TCS) during the birch pollen season (BPS) analyzed for subjects with diary data during the BPS. Secondary end points included average daily symptom scores (DSS) during the BPS, average TCS and DSS during the tree pollen season (TPS), and average daily medication scores (DMS) in the BPS and TPS.Results: The primary and key secondary end points demonstrated statistically significant and clinically relevant effects of the SQ tree SLIT-tablet compared with placebo. For the BPS, absolute (relative) differences from placebo were 3.02 (40%) for TCS, 1.32 (37%) for DSS, and 1.58 (49%) for DMS (all P < .0001). For the TPS, absolute (relative) differences from placebo were 2.27 (37%) for TCS, 0.99 (33%) for DSS, and 1.20 (47%) for DMS (all P < .0001). Treatment was well tolerated. The most frequently reported treatment-related adverse events were mild or moderate local reactions related to sublingual administration.Conclusion: The trial demonstrated the efficacy and safety of the SQ tree SLIT-tablet compared with placebo during the BPS and TPS in adolescents and adults with birch pollen-induced ARC (EudraCT 2015-004821-15)

Co- and post-translational translocation through the protein-conducting channel:analogous mechanisms at work?

Many proteins are translocated across, or integrated into, membranes. Both functions are fulfilled by the 'translocon/translocase', which contains a membrane-embedded proteinconducting channel (PCC) and associated soluble factors that drive translocation and insertion reactions using nucleotide triphosphates as fuel. This perspective focuses on reinterpreting existing experimental data in light of a recently proposed PCC model comprising a front-to-front dimer of SecY or Sec61 heterotrimeric complexes. In this new framework, we propose (i) a revised model for SRP-SR-mediated docking of the ribosome-nascent polypeptide to the PCC; (ii) that the dynamic interplay between protein substrate, soluble factors and PCC controls the opening and closing of a transmembrane channel across, and/or a lateral gate into, the membrane; and (iii) that co-and post-translational translocation, involving the ribosome and SecA, respectively, not only converge at the PCC but also use analogous mechanisms for coordinating protein translocation

Next-Generation Allergic Rhinitis and Its Impact on Asthma (ARIA) Guidelines for Allergic Rhinitis Based on Grading of Recommendations Assessment, Development and Evaluation (GRADE) and Real-World Evidence

The selection of pharmacotherapy for patients with allergic rhinitis aims to control the disease and depends on many factors. Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines have considerably improved the treatment of allergic rhinitis. However, there is an increasing trend toward use of real-world evidence to inform clinical practice, especially because randomized controlled trials are often limited with regard to the applicability of results. The Contre les Maladies Chroniques pour un Vieillissement Actif (MACVIA) algorithm has proposed an allergic rhinitis treatment by a consensus group. This simple algorithm can be used to step up or step down allergic rhinitis treatment. Next-generation guidelines for the pharmacologic treatment of allergic rhinitis were developed by using existing GRADE-based guidelines for the disease, real-world evidence provided by mobile technology, and additive studies (allergen chamber studies) to refine the MACVIA algorithm.info:eu-repo/semantics/publishedVersio

Next-Generation Allergic Rhinitis and Its Impact on Asthma (ARIA) Guidelines for Allergic Rhinitis Based on Grading of Recommendations Assessment, Development and Evaluation (GRADE) and Real-World Evidence

The selection of pharmacotherapy for patients with allergic rhinitis aims to control the disease and depends on many factors. Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines have considerably improved the treatment of allergic rhinitis. However, there is an increasing trend toward use of real-world evidence to inform clinical practice, especially because randomized controlled trials are often limited with regard to the applicability of results. The Contre les Maladies Chroniques pour un Vieillissement Actif (MACVIA) algorithm has proposed an allergic rhinitis treatment by a consensus group. This simple algorithm can be used to step up or step down allergic rhinitis treatment. Next-generation guidelines for the pharmacologic treatment of allergic rhinitis were developed by using existing GRADE-based guidelines for the disease, real-world evidence provided by mobile technology, and additive studies (allergen chamber studies) to refine the MACVIA algorithm.info:eu-repo/semantics/publishedVersio

Differentiation of COVID-19 signs and symptoms from allergic rhinitis and common cold: An ARIA-EAACI-GA2LEN consensus

Background: Although there are many asymptomatic patients, one of the problems of COVID-19 is early recognition of the disease. COVID-19 symptoms are polymorphic and may include upper respiratory symptoms. However, COVID-19 symptoms may be mistaken with the common cold or allergic rhinitis. An ARIA-EAACI study group attempted to differentiate upper respiratory symptoms between the three diseases. Methods: A modified Delphi process was used. The ARIA members who were seeing COVID-19 patients were asked to fill in a questionnaire on the upper airway symptoms of COVID-19, common cold and allergic rhinitis. Results: Among the 192 ARIA members who were invited to respond to the questionnaire, 89 responded and 87 questionnaires were analysed. The consensus was then reported. A two-way ANOVA revealed significant differences in the symptom intensity between the three diseases (p&nbsp;&lt;.001). Conclusions: This modified Delphi approach enabled the differentiation of upper respiratory symptoms between COVID-19, the common cold and allergic rhinitis. An electronic algorithm will be devised using the questionnaire

Inter-Species Complementation of the Translocon Beta Subunit Requires Only Its Transmembrane Domain

In eukaryotes, proteins enter the secretory pathway through the translocon pore of the endoplasmic reticulum. This protein translocation channel is composed of three major subunits, called Sec61α, β and γ in mammals. Unlike the other subunits, the β subunit is dispensable for translocation and cell viability in all organisms studied. Intriguingly, the knockout of the Sec61β encoding genes results in different phenotypes in different species. Nevertheless, the β subunit shows a high level of sequence homology across species, suggesting the conservation of a biological function that remains ill-defined. To address its cellular roles, we characterized the homolog of Sec61β in the fission yeast Schizosaccharomyces pombe (Sbh1p). Here, we show that the knockout of sbh1+ results in severe cold sensitivity, increased sensitivity to cell-wall stress, and reduced protein secretion at 23°C. Sec61β homologs from Saccharomyces cerevisiae and human complement the knockout of sbh1+ in S. pombe. As in S. cerevisiae, the transmembrane domain (TMD) of S. pombe Sec61β is sufficient to complement the phenotypes resulting from the knockout of the entire encoding gene. Remarkably, the TMD of Sec61β from S. cerevisiae and human also complement the gene knockouts in both yeasts. Together, these observations indicate that the TMD of Sec61β exerts a cellular function that is conserved across species

BUILDING BRIDGES FOR INNOVATION IN AGEING : SYNERGIES BETWEEN ACTION GROUPS OF THE EIP ON AHA

The Strategic Implementation Plan of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) proposed six Action Groups. After almost three years of activity, many achievements have been obtained through commitments or collaborative work of the Action Groups. However, they have often worked in silos and, consequently, synergies between Action Groups have been proposed to strengthen the triple win of the EIP on AHA. The paper presents the methodology and current status of the Task Force on EIP on AHA synergies. Synergies are in line with the Action Groups' new Renovated Action Plan (2016-2018) to ensure that their future objectives are coherent and fully connected. The outcomes and impact of synergies are using the Monitoring and Assessment Framework for the EIP on AHA (MAFEIP). Eight proposals for synergies have been approved by the Task Force: Five cross-cutting synergies which can be used for all current and future synergies as they consider overarching domains (appropriate polypharmacy, citizen empowerment, teaching and coaching on AHA, deployment of synergies to EU regions, Responsible Research and Innovation), and three cross-cutting synergies focussing on current Action Group activities (falls, frailty, integrated care and chronic respiratory diseases).Peer reviewe