The European Academy for Cognitive Behavioural Therapy for Insomnia : An initiative of the European Insomnia Network to promote implementation and dissemination of treatment

Insomnia, the most prevalent sleep disorder worldwide, confers marked risks for both physical and mental health. Furthermore, insomnia is associated with considerable direct and indirect healthcare costs. Recent guidelines in the US and Europe unequivocally conclude that cognitive behavioural therapy for insomnia (CBT‐I) should be the first‐line treatment for the disorder. Current treatment approaches are in stark contrast to these clear recommendations, not least across Europe, where, if any treatment at all is delivered, hypnotic medication still is the dominant therapeutic modality. To address this situation, a Task Force of the European Sleep Research Society and the European Insomnia Network met in May 2018. The Task Force proposed establishing a European CBT‐I Academy that would enable a Europe‐wide system of standardized CBT‐I training and training centre accreditation. This article summarizes the deliberations of the Task Force concerning definition and ingredients of CBT‐I, preconditions for health professionals to teach CBT‐I, the way in which CBT‐I should be taught, who should be taught CBT‐I and to whom CBT‐I should be administered. Furthermore, diverse aspects of CBT‐I care and delivery were discussed and incorporated into a stepped‐care model for insomnia.Peer reviewe

Prevention of Birch Pollen-Related Food Allergy by Mucosal Treatment with Multi-Allergen-Chimers in Mice

Among birch pollen allergic patients up to 70% develop allergic reactions to Bet v 1-homologue food allergens such as Api g 1 (celery) or Dau c 1 (carrot), termed as birch pollen-related food allergy. In most cases, specific immunotherapy with birch pollen extracts does not reduce allergic symptoms to the homologue food allergens. We therefore genetically engineered a multi-allergen chimer and tested if mucosal treatment with this construct could represent a novel approach for prevention of birch pollen-related food allergy.BALB/c mice were poly-sensitized with a mixture of Bet v 1, Api g 1 and Dau c 1 followed by a sublingual challenge with carrot, celery and birch pollen extracts. For prevention of allergy sensitization an allergen chimer composed of immunodominant T cell epitopes of Api g 1 and Dau c 1 linked to the whole Bet v 1 allergen, was intranasally applied prior to sensitization.Intranasal pretreatment with the allergen chimer led to significantly decreased antigen-specific IgE-dependent β-hexosaminidase release, but enhanced allergen-specific IgG2a and IgA antibodies. Accordingly, IL-4 levels in spleen cell cultures and IL-5 levels in restimulated spleen and cervical lymph node cell cultures were markedly reduced, while IFN-γ levels were increased. Immunomodulation was associated with increased IL-10, TGF-β and Foxp3 mRNA levels in NALT and Foxp3 in oral mucosal tissues. Treatment with anti-TGF-β, anti-IL10R or anti-CD25 antibodies abrogated the suppression of allergic responses induced by the chimer.Our results indicate that mucosal application of the allergen chimer led to decreased Th2 immune responses against Bet v 1 and its homologue food allergens Api g 1 and Dau c 1 by regulatory and Th1-biased immune responses. These data suggest that mucosal treatment with a multi-allergen vaccine could be a promising treatment strategy to prevent birch pollen-related food allergy

Secretogranin II; a Protein Increased in the Myocardium and Circulation in Heart Failure with Cardioprotective Properties

Background: Several beneficial effects have been demonstrated for secretogranin II (SgII) in non-cardiac tissue. As cardiac production of chromogranin A and B, two related proteins, is increased in heart failure (HF), we hypothesized that SgII could play a role in cardiovascular pathophysiology. Methodology/Principal Findings: SgII production was characterized in a post-myocardial infarction heart failure (HF) mouse model, functional properties explored in experimental models, and circulating levels measured in mice and patients with stable HF of moderate severity. SgII mRNA levels were 10.5 fold upregulated in the left ventricle (LV) of animals with myocardial infarction and HF (p<0.001 vs. sham-operated animals). SgII protein levels were also increased in the LV, but not in other organs investigated. SgII was produced in several cell types in the myocardium and cardiomyocyte synthesis of SgII was potently induced by transforming growth factor-beta and norepinephrine stimulation in vitro. Processing of SgII to shorter peptides was enhanced in the failing myocardium due to increased levels of the proteases PC1/3 and PC2 and circulating SgII levels were increased in mice with HF. Examining a pathophysiological role of SgII in the initial phase of post-infarction HF, the SgII fragment secretoneurin reduced myocardial ischemia-reperfusion injury and cardiomyocyte apoptosis by 30% and rapidly increased cardiomyocyte Erk1/2 and Stat3 phosphorylation. SgII levels were also higher in patients with stable, chronic HF compared to age-and gender-matched control subjects: median 0.16 (Q1-3 0.14-0.18) vs. 0.12 (0.10-0.14) nmol/L, p<0.001. Conclusions: We demonstrate increased myocardial SgII production and processing in the LV in animals with myocardial infarction and HF, which could be beneficial as the SgII fragment secretoneurin protects from ischemia-reperfusion injury and cardiomyocyte apoptosis. Circulating SgII levels are also increased in patients with chronic, stable HF and may represent a new cardiac biomarker

Mucosal tolerance induction for treatment of type I allergy

In den letzten Jahrzehnten wurde ein ständiger Anstieg der Prävalenz von Type I-Allergien beobachtet, so dass mittlerweile mehr als 25% der Bevölkerung in westlichen Ländern an Allergien leiden. Häufig werden Allergiker mit zunehmendem Alter gegen mehrere Allergene co-sensibiliisert, wobei diese Patienten schwierig zu behandeln werden. Goldstandard der Allergiebehandlung ist die Allergen-spezifische Immuntherapie. Jedoch birgt diese Therapieform auch einige Nachteile, wie zum Beispiel regelmäßige Injektionen über einen Zeitraum von 2-3 Jahre, Gefahr von anaphylaktischen Nebenwirkungen sowie eine geringe Erfolgsquote bei der Behandlung von Mehrfachallergien. Um die Compliance der Patienten zu erhöhen, aber auch um die Effizienz der Therapie zu verbessern, ist in den letzten Jahren an folgenden Ansätzen gearbeitet worden: Verwendung von rekombinanten Allergenen, die dem Sensibilisierungsprofil der Patienten entsprechen, Applikation effektiver Adjuvantien, und der Wechsel zu einer mukosalen (z.B. oral, nasal) Route der Applikation zur Umgehung der häufigen Injektionen. Entsprechend wurden im Zuge dieser Doktorarbeit neue Behandlungsansätze entwickelt und neue Mausmodele für Einfach- und Mehrfachsensibilisierung etabliert, um Effektivität und Wirkungsmechanismen dieser neuen Ansätze in vivo und in vitro testen zu können. (i) Eine vielversprechende Strategie zur Behandlung von Allergien sind rekombinant hergestellte Allergene. Die rekombinante Produktion garantiert eine genaue strukturelle wie auch immunologische Definition des Allergens. Die Identifizierung von Allergenen, wie auch die Herstellung als rekombinantes Protein sind die Grundsteine bei der Entwicklung von neuen Formen von Immunotherapeutika wie hypoallergene Varianten von Allergenen, Fusionsmoleküle oder Multiallergenkonstrukte. Wir beschreiben die Charakterisierung und rekombinante Herstellung eines neuen Allergens der Dörrobstmotte, das Thioredoxin Plo i 2. In in vivo Studien in Mäusen konnten wir das allerogene Potential dieses Allergens, im Vergleich mit einem anderen Mottenallergen (Plo i 1), untersuchen. Mittels Immunoblot-Experimenten mit humanen Sera wurde die IgE-Reaktivität des Thioredoxins Plo i 2 analysiert, und so Plo i 2 als neue relevante Allergiequelle für mehrfachsensibilisierte Haus- und Meeresfrüchteallergiker, definiert. (ii) Pollen-allergische Patienten sind häufig co-sensibilisiert gegen homologe Lebensmittelallergene; dies wird als sogenannte Pollen-assoziierte-Lebensmittelallergie bezeichnet und manifestiert sich klinisch als „orales Allergiesyndrom“ (OAS). Mehr als 70% der Birkenpollenallergiker leiden unter einer Pollen-assoziierten-Lebensmittelallergie, somit zählt diese Form der Birkenpollen-assoziierten-Lebensmittelallergie zu einer der häufigsten Varianten der Mehrfachallergien. Da das OAS im Rahmen der Behandlung gegen Birkenpollenallergie meist nur ungenügend beeinflusst werden kann, haben wir ein Multiallergenkonstrukt entwickelt, das eine gleichzeitige Behandlung der Birkenpollen- und Nahrungsmittelallergien ermöglichen soll. Dieses Multiallergenkonstrukt wurde gentechnologische hergestellt,, bestehend aus dem gesamten Hauptbirkenpollenallergen Bet v 1 verlinkt mit den immundominanten T-Zell-Epitopen der Birkenpollen-assoziierten- Lebensmittelallergene Dau c 1 (Hauptallergen der Karotte) und Api g 1 (Hauptallergen des Selleries). Um das immunmodulatorische Potential dieses Konstrukts auszutesten, wurde ein Mausmodel für Mehrfachsensibilisierung mit oralem Allergiesyndrom etabliert. Wir konnten zeigen, dass nach intranasaler Applikation dieses Konstrukts die allergische Immunantwort in Richtung Th1 Antwort moduliert wurde und eine Suppression der allergischen Immunantworten durch Induktion von regulatorischen Immunmechansimen erreicht werden konnte. (iii) Um die Effektivität von Toleranzinduktion mittels rekombinanter Allergene oder Allergenkonstrukte zu erhöhen, können mukosale Adjuvantien als sogenannte „mukosale Transportsysteme“ verwende werden. Eines der mukosalen Adjuvantien mit tolerogenem Potenzial ist Choleratoxin (CT) bzw. die B-Untereinheit von Choleratoxin (CTB). In der vorliegenden Arbeit beschreiben wir die gentechnologische Konstruktion eines Fusionsmoleküls von CTB und Bet v 1. Dieses Fusionsmolekül wurde intranasal in einem Mausmodel für Birkenpollenallergie appliziert um dessen immunmodulatorische Kapazität zu untersuchen. Die Allergie-reduzierende Wirkung des neuen Konstrukts beruhte auf der gleichzeitigen Modulierung der Th2 Immunantwort Richtung Th1 und der Induktion von lokalen, protektiven IgA Antikörpern. Zusammenfassend, wir haben drei verschiedene Strategien (rekombinante Allergene, Multiallergenkonstrukte für mukosale Applikation und Verwendung neuer mukosaler Adjuvantien) zur Verbesserung der Prävention (und möglicherweise auch Therapie) von Typ I-Allergie entwickelt, deren Nutzen durch eine erfolgreiche Suppression der allergischen Immunantwort in Einfach- und Mehrfachsensibilisierungsmodele demonstriert wurde. Derartige experimentelle Studien sollen dazu beitragen, bestehende Behandlungsansätze zu verbessern, sowie auch neue Behandlungsstrategien für allergische Erkrankungen zu entwickeln.The prevalence of type I allergy is constantly increasing in industrialized countries: more than 25% of the population suffer from allergic disorders. With increasing age allergic individuals become co-sensitized to additional allergens, and become difficult to treat due to the multi-sensitization. Allergen-specific immunotherapy is state of the art treatment of allergic diseases. However, due to a low compliance of patients to frequent injections, and the reduced efficacy in multi-sensitized individuals, a change to a less invasive route of application via the mucosa offers a promising approach. The aim of this thesis was to develop new treatment strategies for primary and secondary prevention of type I allergy, focusing on strategies being applied via the mucosal surfaces. Therefore, three novel approaches were developed and tested that might lead to improvement of the current treatment strategies: (i) Use of recombinant allergens, (ii) development of multi-allergen constructs for mucosal tolerance induction, and (iii) use of mucosal adjuvants systems for improved mucosal treatment strategies. Furthermore, murine models of mono- and poly-sensitization were established, to investigate the immunological mechanisms of mucosal tolerance induction as well. Ad i) Recombinant forms of allergens are promising tools for treatment of allergy, because of their defined structural and immunological properties as well as the standardized production procedures. Furthermore, identification and production of allergens as recombinant proteins are the essential steps to develop advanced forms of immunotherapeutica such as hypoallergenic variants, fusion molecules, or multi-allergen constructs. A novel allergen of Indianmeal moth, the thioredoxin Plo i 2 was identified and recombinantly produced. The allergenic potential of Plo i 2 was investigated by in vivo studies in mice, in comparison to the moth allergen Plo i 1. IgE-reactivity tested by blotting experiments with human sera, defined thioredoxin Plo i 2 as new relevant source in multi-sensitized indoor and seafood allergic patients. Ad ii) In pollen allergic patients co-sensitization to homologue food allergens often occurs, termed as pollen-related food allergy and clinically manifested as “oral allergy syndrome” (OAS). With about 70% of birch pollen allergic patients, birch pollen-related food allergy is the most common form of this multi-sensitivity. For a new experimental approach to treat birch pollen-related food allergy, a multi-allergen construct composed of the whole major birch pollen allergen Bet v 1 linked to the immunodominant T cell epitopes of the Bet v 1-related food allergens Dau c 1 (major allergen of carrot) and Api g 1 (major allergen of celery), were genetically engineered. In order to investigate immunomodulatory potential of this chimer, a murine model of poly-sensitization and OAS was established. Intranasal application of the chimer modulated allergic immune responses towards Th1 immune responses via regulatory mechanisms. Ad iii) In order to enhance the effectiveness of mucosal tolerance induction with recombinant allergens or allergen constructs, mucosal adjuvants were used as mucosal delivery systems. The strong tolerogenic nontoxic B subunit of cholera toxin (CTB) served as mucosal adjuvant which was genetically conjugated to the birch pollen allergen Bet v 1. For improvement of mucosal tolerance induction the CTB-Bet v 1 fusion molecule was intranasally applied in a murine model of birch pollen allergy. The immunomodulatory properties of the fusion molecule were demonstrated by a modulation of Th2 immune responses towards Th1, accompanied by induction of protective IgA antibodies. In summary, we have presented three different strategies - (i) production of recombinant allergens or allergen constructs, (ii) use of mucosal route of application, (iii) use of mucosal adjuvants - to improve prevention of type I allergy. The benefit of mucosal application of recombinant allergens conjugated to adjuvants as fusion protein or to other allergens as multi-allergen construct was demonstrated by successful suppression of allergic immune responses in mono- and poly-sensitized models. Such experimental studies will contribute to the improvement of new treatment approaches with increased effectiveness against the constantly increasing number of allergic diseases

Tax incentives on electrical vehicles from an Austrian and European perspective

Transport is a very important topic in our society and this sector is responsible for around one quarter of global greenhouse gas emissions and it is the second biggest share after the energy industry. There is huge international and European pressure to meet specified greenhouse gas emissions. For example, the EUs aim is to reduce greenhouse gases up to 80-95% compared to 1990 until 2050. There are different ways on how to implement and support EVs. The most important measurements are financial and non-financial incentives for electrical cars. One of the financial ones are tax incentives and they are especially vital to make EVs more attractive to customers and companies. Austria has already implemented some tax incentives to promote electrical vehicles. Germany is home to a huge automobile industry has also introduced several tax incentives for EVs. In Norway, EVs are already well-established and this country offers generous incentives for electromobility. Therefore, those three countries will be compared with the help of a TCO (total costs of ownership) calculation. The aim of this comparative calculation is to reveal differences to the Austrian taxation on electric cars, in relation to Germany and Norway.submitted by Lisa HoflehnerUniversität Linz, Masterarbeit, 2018(VLID)283043

Analysis of transverse corner cracks from continuous casting process and comparison to laboratory experiments

Low alloyed steel slabs produced by continuous casting can present transverse corner cracks, which are critical due to the oxide layer formed within the crack. Understanding this type of failure and reproducibility of the phenomenon through laboratory tests is of great value for dealing with this problem. The present work analyzed samples from slab corners, where cracks were identified. The fracture surfaces were examined using a scanning electron microscope (SEM) and cut to have their microstructure analyzed with a light optical microscope (LOM). Using etching to reveal the microstructure of the samples from the slabs, it was seen that the cracks were initiated and propagated at the prior austenite grain boundaries. Furthermore, the SEM images from the corner samples were compared to those from the physical simulation of the continuous casting process from previous work, and the structure found was like the ones tested at critical temperatures. The same was noted for the microstructure analysis, where cracks were also seen to follow the grain boundaries. Therefore, it was concluded that the behavior resulted from the laboratory tests performed with in-situ melted samples with the BETA 250-5 machine were in good accordance with the reality of the continuous casting process