Recommendations to Improve Tick-Borne Encephalitis Surveillance and Vaccine Uptake in Europe.

There has been an increase in reported TBE cases in Europe since 2015, reaching a peak in some countries in 2020, highlighting the need for better management of TBE risk in Europe. TBE surveillance is currently limited, in part, due to varying diagnostic guidelines, access to testing, and awareness of TBE. Consequently, TBE prevalence is underestimated and vaccination recommendations inadequate. TBE vaccine uptake is unsatisfactory in many TBE-endemic European countries. This review summarizes the findings of a scientific workshop of experts to improve TBE surveillance and vaccine uptake in Europe. Strategies to improve TBE surveillance and vaccine uptake should focus on: aligning diagnostic criteria and testing across Europe; expanding current vaccine recommendations and reducing their complexity; and increasing public education of the potential risks posed by TBEV infection.

Genetic deletion of Nox4 enhances cancerogen-induced formation of solid tumors.

Reactive oxygen species (ROS) can cause cellular damage and promote cancer development. Besides such harmful consequences of overproduction of ROS, all cells utilize ROS for signaling purposes and stabilization of cell homeostasis. In particular, the latter is supported by the NADPH oxidase 4 (Nox4) that constitutively produces low amounts of H2O2 By that mechanism, Nox4 forces differentiation of cells and prevents inflammation. We hypothesize a constitutive low level of H2O2 maintains basal activity of cellular surveillance systems and is unlikely to be cancerogenic. Utilizing two different murine models of cancerogen-induced solid tumors, we found that deletion of Nox4 promotes tumor formation and lowers recognition of DNA damage. Nox4 supports phosphorylation of H2AX (γH2AX), a prerequisite of DNA damage recognition, by retaining a sufficiently low abundance of the phosphatase PP2A in the nucleus. The underlying mechanism is continuous oxidation of AKT by Nox4. Interaction of oxidized AKT and PP2A captures the phosphatase in the cytosol. Absence of Nox4 facilitates nuclear PP2A translocation and dephosphorylation of γH2AX. Simultaneously AKT is left phosphorylated. Thus, in the absence of Nox4, DNA damage is not recognized and the increased activity of AKT supports proliferation. The combination of both events results in genomic instability and promotes tumor formation. By identifying Nox4 as a protective source of ROS in cancerogen-induced cancer, we provide a piece of knowledge for understanding the role of moderate production of ROS in preventing the initiation of malignancies.

Locally Condensed Water as a Solution for In Situ Wet Corrosion Electron Microscopy.

In microstructural corrosion studies, knowledge on the initiation of corrosion on an nm-scale is lacking. In situ transmission electron microscope (TEM) studies can elucidate where/how the corrosion starts, provided that the proper corrosive conditions are present during the investigation. In wet corrosion studies with liquid cell nanoreactors (NRs), the liquid along the electron beam direction leads to strong scattering and therefore image blurring. Thus, a quick liquid removal or thickness control of the liquid layer is preferred. This can be done by the use of a Peltier element embedded in an NR. As a prelude to such in situ work, we demonstrate the local wetting of a TEM sample, by creating a temperature decrease of 10 ± 2°C on the membrane of an NR with planar Sb/BiSb thermoelectric materials for the Peltier element. TEM samples were prepared and loaded in an NR using a dual-beam focused ion beam scanning electron microscope. A mixture of water vapor and carrier gas was passed through a chamber, which holds the micro-electromechanical system Peltier device and resulted in quick formation of a water layer/droplets on the sample. The TEM analysis after repeated corrosion of the same sample (ex situ studies) shows the onset and progression of O2 and H2S corrosion of the AA2024-T3 alloy and cold-rolled HCT980X steel lamellae.

Induction of Glucocorticoid-induced Leucine Zipper (GILZ) Contributes to Anti-inflammatory Effects of the Natural Product Curcumin in Macrophages.

GILZ (glucocorticoid-induced leucine zipper) is inducible by glucocorticoids and plays a key role in their mode of action. GILZ attenuates inflammation mainly by inhibition of NF-κB and mitogen-activated protein kinase activation but does not seem to be involved in the severe side effects observed after glucocorticoid treatment. Therefore, GILZ might be a promising target for new therapeutic approaches. The present work focuses on the natural product curcumin, which has previously been reported to inhibit NF-κB. GILZ was inducible by curcumin in macrophage cell lines, primary human monocyte-derived macrophages, and murine bone marrow-derived macrophages. The up-regulation of GILZ was neither associated with glucocorticoid receptor activation nor with transcriptional induction or mRNA or protein stabilization but was a result of enhanced translation. Because the GILZ 3'-UTR contains AU-rich elements (AREs), we analyzed the role of the mRNA-binding protein HuR, which has been shown to promote the translation of ARE-containing mRNAs. Our results suggest that curcumin treatment induces HuR expression. An RNA immunoprecipitation assay confirmed that HuR can bind GILZ mRNA. In accordance, HuR overexpression led to increased GILZ protein levels but had no effect on GILZ mRNA expression. Our data employing siRNA in LPS-activated RAW264.7 macrophages show that curcumin facilitates its anti-inflammatory action by induction of GILZ in macrophages. Experiments with LPS-activated bone marrow-derived macrophages from wild-type and GILZ knock-out mice demonstrated that curcumin inhibits the activity of inflammatory regulators, such as NF-κB or ERK, and subsequent TNF-α production via GILZ. In summary, our data indicate that HuR-dependent GILZ induction contributes to the anti-inflammatory properties of curcumin.

sST2 translation is regulated by FGF2 via an hnRNP A1-mediated IRES-dependent mechanism.

Translation is an energy-intensive process and tightly regulated. Generally, translation is initiated in a cap-dependent manner. Under stress conditions, typically found within the tumor microenvironment in association with e.g. nutrient deprivation or hypoxia, cap-dependent translation decreases, and alternative modes of translation initiation become more important. Specifically, internal ribosome entry sites (IRES) facilitate translation of specific mRNAs under otherwise translation-inhibitory conditions. This mechanism is controlled by IRES trans-acting factors (ITAF), i.e. by RNA-binding proteins, which interact with and determine the activity of selected IRESs. We aimed at characterizing the translational regulation of the IL-33 decoy receptor sST2, which was enhanced by fibroblast growth factor 2 (FGF2). We identified and verified an IRES within the 5'UTR of sST2. Furthermore, we found that MEK/ERK signaling contributes to FGF2-induced, sST2-IRES activation and translation. Determination of the sST2-5'UTR structure by in-line probing followed by deletion analyses identified 23 nucleotides within the sST2-5'UTR to be required for optimal IRES activity. Finally, we show that the RNA-binding protein heterogeneous ribonucleoprotein A1 (hnRNP A1) binds to the sST2-5'UTR, acts as an ITAF, and thus controls the activity of the sST2-IRES and consequently sST2 translation. Specifically, FGF2 enhances nuclear-cytoplasmic translocation of hnRNP A1, which requires intact MEK/ERK activity. In summary, we provide evidence that the sST2-5'UTR contains an IRES element, which is activated by a MEK/ERK-dependent increase in cytoplasmic localization of hnRNP A1 in response to FGF2, enhancing the translation of sST2.

Morphological and Chemical Evolution of Gradually Deposited Diamond-Like Carbon Films on Polyethylene Terephthalate: From Subplantation Processes to Structural Reorganization by Intrinsic Stress Release Phenomena.

Diamond-like carbon (DLC) films on polyethylene terephthalate (PET) are nowadays intensively studied composites due to their excellent gas barrier properties and biocompatibility. Despite their applicative features being highly explored, the interface properties and structural film evolution of DLC coatings on PET during deposition processes are still sparsely investigated. In this study two different types of DLC films were gradually deposited on PET by radio frequency plasma-enhanced chemical vapor deposition (RF-PECVD) using acetylene plasma. The surface morphology of the deposited samples has been analyzed by atomic force microscopy (AFM). Their chemical composition was investigated by diffusive reflectance infrared Fourier transform (DRIFT) and Raman spectroscopy analysis and the surface wettability by contact angle measurements. Subplantation processes and interface effects are revealed through the morphological and chemical analysis of both types. During plasma deposition processes the increasing carbon load causes the rise of intrinsic film stress. It is proven that stress release phenomena cause the transition between polymer-like to a more cross-linked DLC network by folding dehydrogenated chains into closed 6-fold rings. These findings significantly lead to an enhanced understanding in DLC film growth mechanism by RF-PECVD processes.

THE AUSTRIAN VACCINATION PARADOX: TICK-BORNE ENCEPHALITIS VACCINATION VERSUS INFLUENZA VACCINATION.

This paper describes a paradoxical situation in Austria. The vaccination rate against tick-borne encephalitis (TBE) in the general population is 82%, which is the highest worldwide, whereas the vaccination rate against influenza is about 8% and is among the lowest worldwide. A high awareness of TBE among the Austrian population achieved by an annual social marketing programme and the wide use of effective and well-tolerated vaccines have led to a successful containment of that disease. The vaccination coverage increased from 6% in 1980 to 82% in 2013 and exceeds 90% in some high-risk areas. This has led to a steady decline in the number of TBE cases from several hundred cases to 50 to 100 cases per year. The situation in regard to influenza vaccination is the opposite. Although Austria has issued one of the most extensive recommendations for influenza vaccination worldwide, the vaccination rate of the general population is extremely low. The possible reasons for the failure in the implementation of recommendations are ignorance, lack of social marketing and the predominance of a distinct discordance within the health system in general, and the Austrian medical fraternity in particular.

Characterization of pomiferin triacetate as a novel mTOR and translation inhibitor.

Deregulation of the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR)-70kDa ribosomal protein S6 kinase 1 (p70(S6K)) pathway is commonly observed in many tumors. This pathway controls proliferation, survival, and translation, and its overactivation is associated with poor prognosis for tumor-associated survival. Current efforts focus on the development of novel inhibitors of this pathway. In a cell-based high-throughput screening assay of 15,272 pure natural compounds, we identified pomiferin triacetate as a potent stabilizer of the tumor suppressor programmed cell death 4 (Pdcd4). Mechanistically, pomiferin triacetate appeared as a general inhibitor of the PI3K-Akt-mTOR-p70(S6K) cascade. Interference with this pathway occurred downstream of Akt but upstream of p70(S6K). Specifically, mTOR kinase emerged as the molecular target of pomiferin triacetate, with similar activities against mTOR complexes 1 and 2. In an in vitro mTOR kinase assay pomiferin triacetate dose-dependently inhibited mTOR with an IC50 of 6.2 µM. Molecular docking studies supported the interaction of the inhibitor with the catalytic site of mTOR. Importantly, pomiferin triacetate appeared to be highly selective for mTOR compared to a panel of 17 lipid and 50 protein kinases tested. As a consequence of the mTOR inhibition, pomiferin triacetate efficiently attenuated translation. In summary, pomiferin triacetate emerged as a novel and highly specific mTOR inhibitor with strong translation inhibitory effects. Thus, it might be an interesting lead structure for the development of mTOR- and translation-targeted anti-tumor therapies.

Inflammatory conditions induce IRES-dependent translation of cyp24a1.

Rapid alterations in protein expression are commonly regulated by adjusting translation. In addition to cap-dependent translation, which is e.g. induced by pro-proliferative signaling via the mammalian target of rapamycin (mTOR)-kinase, alternative modes of translation, such as internal ribosome entry site (IRES)-dependent translation, are often enhanced under stress conditions, even if cap-dependent translation is attenuated. Common stress stimuli comprise nutrient deprivation, hypoxia, but also inflammatory signals supplied by infiltrating immune cells. Yet, the impact of inflammatory microenvironments on translation in tumor cells still remains largely elusive. In the present study, we aimed at identifying translationally deregulated targets in tumor cells under inflammatory conditions. Using polysome profiling and microarray analysis, we identified cyp24a1 (1,25-dihydroxyvitamin D3 24-hydroxylase) to be translationally upregulated in breast tumor cells co-cultured with conditioned medium of activated monocyte-derived macrophages (CM). Using bicistronic reporter assays, we identified and validated an IRES within the 5' untranslated region (5'UTR) of cyp24a1, which enhances translation of cyp24a1 upon CM treatment. Furthermore, IRES-dependent translation of cyp24a1 by CM was sensitive to phosphatidyl-inositol-3-kinase (PI3K) inhibition, while constitutive activation of Akt sufficed to induce its IRES activity. Our data provide evidence that cyp24a1 expression is translationally regulated via an IRES element, which is responsive to an inflammatory environment. Considering the negative feedback impact of cyp24a1 on the vitamin D responses, the identification of a novel, translational mechanism of cyp24a1 regulation might open new possibilities to overcome the current limitations of vitamin D as tumor therapeutic option.

Blood pressure awareness in Austria: lessons from a 30 years horizon.

BACKGROUND: Blood pressure (BP) awareness is a main focus of public health efforts. In Austria, an increase of knowledge and perception regarding hypertension was seen after a nationwide educational campaign in 1978, but subsequent surveys documented only short-term impact. We report results of the latest survey in 2009 in comparison to 1978 and 1998. METHODS: Balanced for Austrian demographic characteristics 1,005 men and women older than 15 years of age were randomly selected for face-to-face interviews about BP awareness, risk factors, and hazards of hypertension and treatment options including life-style interventions. RESULTS: Overall, 15% identified themselves as hypertensive, which is similar to results from 1978 (14%) but significantly higher than 1998 (12%; P < 0.01). The proportion of hypertensives not undertaking any measure (i.e., pharmacotherapy or life-style changes) significantly decreased since 1998 (5% vs. 10%; P < 0.0001). Thirty-three percent recalled to have measured their BP within the last 3 months, which is comparable to 1998 (34%) but lower than in 1978 (49%) after the nationwide educational BP campaign (P < 0.0001). Alarmingly, an unchanged proportion of 8% reported no BP measurement ever (1978 and 1998: 8%, respectively). Sixty-one percent believed they would be able to clearly identify symptoms of hypertension, while only 19% knew that hypertension might not be noticeable. Heart attack and stroke were considered the most common sequelae of hypertension. CONCLUSION: Despite a high understanding of the risks of hypertension among the Austrian population, a widespread misconception regarding BP symptoms and infrequent personal checks are worrisome and might also be valid in other Western countries.

Effect of daily intake of yoghurt and bread enriched with biologically active substances on blood lipids and vitamin A in adolescents and young adults.

OBJECTIVE: The aim was to investigate whether the daily intake of special nutrients, enriched with supplements from natural origins, has any effect on blood parameters. DESIGN AND SUBJECTS: In this double-blind placebo-controlled clinical trial, 80 healthy subjects (mean age 26.3 years) were statistically assigned to two groups. Group I had to eat two special yoghurt and bread products a day. The other probands represented the control group (II). SETTING: Plasma concentrations of blood parameters were measured at the beginning and at the end of the study, and dietary intake was calculated. RESULTS: In group I, total cholesterol decreased. This was due to a significant drop of low-density lipoprotein-cholesterol from 106.0 to 99.0 mg/dl. A significant reduction of the apolipoprotein B and an increase of vitamin A in group I were also observed. CONCLUSION: Regular intake of specially fortified food influences parameters, especially lipids and lipoproteins.

Trends in mortality and mean age at death from lung cancer in Austria (1975-2007).

OBJECTIVE: To investigate trends in mortality and mean age at death from lung cancer (MADLC) compared to mean age at death from all causes (MAD) over the period 1975 - 2007 in Austria. Results are assessed with respect to secular trends in smoking habits. METHODS: MAD and MADLC were computed by year and gender as the expected value of a fitted Weibull distribution. Age-period-cohort effects on lung cancer death rates were estimated by hierarchical Poisson models. RESULTS: In females MADLC was on average about 2 years higher than in males and tended to decrease since the mid 1980s, while after the mid 1990s MADLC in males increased such that the difference between men and women shrank to about half a year in 2007. Females dying from lung cancer lost about 6 years of life during the late 1970s but more than 10 years after 2000, while males lost 2 years in the 1970s and 5 years after 2000. Males demonstrated a decreasing risk with increasing year of birth, with the exception of cohorts born during or immediately after the World Wars that showed peak relative risks (RR). Females did not show pronounced birth cohort effect except for a peak RR for cohorts born during and after World War II. CONCLUSIONS: MADLC provides additional information about secular trends in addition to incidence data. The declining trend of MADLC in females and in males up to the mid 1990s points to a change of smoking habits with an earlier onset of smoking in both genders. The subsequent increase in males during the last decade may be attributed to an increasing proportion of quitters because smoking cessation delays onset of lung cancer.

Synthesis, characterization, in vitro antitumoral investigations and interaction with plasmid pBR322 DNA of R2eddp-platinum(IV) complexes (R = Et, n-Pr).

The studies on synthetic, spectroscopic and biological properties of platinum(IV) complexes, [PtCl(4)(R(2)eddp)] (R = Et, 1; n-Pr, 2), containing kappa(2)N,N' bidentate ligands, esters of ethylenediamine-N,N'-di-3-propionic acid (HOOCCH(2)CH(2)NHCH(2)CH(2)NHCH(2)CH(2)COOH, H(2)eddp), are reported. Complexes have been characterized by infrared, (1)H and (13)C NMR spectroscopy and elemental analysis and it was concluded that the coordination of the ligands occurs via nitrogen donor atoms of the ester ligands (R(2)eddp). Cytotoxicity studies were performed for ligand precursors and corresponding platinum(IV) complexes. Although the n-Pr(2)eddp.2HCl itself showed no activity (IC(50) values > 125 microM) in selected cell lines, the activity of complex 2, via apoptotic mode of cell death, has increased significantly for a broad range of cancer cell lines tested in vitro (IC(50) = 8.6-49 microM). As it was found that complexes 1 and 2 are able to interact with pBR322 plasmid DNA, platinum(IV) complexes of this type may act as drugs and pro-drugs.

[Economic concepts for measuring the costs of illness of osteoporosis: an international comparison]. / Okonomische Konzepte zur Erfassung der Krankheitskosten von Osteoporose: Osterreich im internationalen Vergleich.

Worldwide osteoporosis is underestimated and despite availability of effective and cost effective treatments, these are often not implemented. Apart from a demographically driven increase in disease cases, failure to implement or tardy implementation of preventive measures as well as poor treatment compliance leads to a deterioration of the health economic outcomes. This in turn causes considerable costs to the health care system and to society, through ineffective intake of medication, diminished quality of life and inability to work as well as substantial costs of rehabilitation of patients. Health economic analyses and methods are increasingly used by decision makers to set priorities and evaluate alternative treatment measures about their cost-effectiveness. In order to be able to capture the costs of illness incurred by osteoporosis, different diseases specific models and methods have been developed, such as the reference model of the IOF, an osteoporosis-specific Markov model or internationally comparable intervention thresholds. Health economists estimate that osteoporosis-related costs will double by 2050 in both Europe and the individual countries. For Europe this means an increase from 40 billion Euro in 2000 to almost 80 billion Euro in 2050. In Austria, an aggregation of the different costs of osteoporosis is not possible, due to a lack of comparability and availability of data. The international ICUROS study and the Austrian Osteoporosis Report 2007 are the first steps towards counteracting this situation.

Epidemiology of allergies in Austria. Results of the first Austrian allergy report.

The first Austrian Allergy Report is a compilation of all available epidemiological data relating to allergies in Austria. According to this report the cumulative prevalence of allergies in the Viennese population is 27.6% for men and 32.2% for women and the period prevalence in the year before questioning 19.6% and 22.4% respectively. 20.8% of men and 23.1% of women reported about allergies at health examinations. However, an allergy sensitivity to at least one inhalation allergen, verifiable by means of a prick test, is detectable in 50.8% of the general population and in 39.3% of those free from ailments. Analysis of the hospital discharge statistics of all Austrian hospitals shows that around 12,000 people per year were admitted on grounds of an allergy. In accordance with international studies some population sub groups are more often affected than others. Women suffer from allergies somewhat more frequently than men, although the sex difference is reversed among children. Allergies occur in all age groups, with most studies showing that people in their twenties are most frequently affected. People with higher levels of education, in more highly qualified jobs and living in urban areas are more commonly affected by allergies than people from lower socio-economic levels and rural communities. The internationally identified increase in trend can also be identified in Austria with a 2fold, 3.6fold, and 4.6fold increase in the prevalence of hay fever, asthma and atopic eczema respectively, determined from the military health examinations of all recruits for national service between 1986 and 2003/04, although a clear decline in allergy prevalence was registered between 2003/04 and 2005. Health reports like the first Austrian Allergy Report provide the basis for international comparison of basic data. These data also enable the evaluation of the impact of different diseases on the health system as well as the development of public health strategies.