The burden of cancer in Austria

The aim of this study was to assess the overall progress against cancer in Austria by analysing changes in age-adjusted mortality rates from 1970 to 1996. For the years 1970 to 1996, age-adjusted rates for all malignant neoplasms and for selected sites were calculated for men and women, according to year, age and sex. The number of cancer deaths were obtained from the Austrian Central Statistical Office--age-adjusted mortality rates of all malignant neoplasms decreased in men between 1971 and 1996 by 13% (from 289.1 to 251.4 deaths per 100,000), and in women between 1970 and 1996 by 19.1% (from 276.6 to 223.7 deaths per 100,000). Among older people (> or = 55 years) the mortality decreased by 13% in men and by 17% in women; among younger people (< 55 years) by 12% and 30%, respectively. The decrease in total cancer mortality is promoted by three tumour sites (the leading causes of cancer deaths in 1970). In both sexes, the decrease of stomach cancer mortality had the major impact, followed by colorectal cancer in women and by lung cancer in men. The observed changes in mortality are primarily related to changing incidence and early detection, rather than improvements in treatment. Unfortunately, there is evidence that prevention is losing ground in Austria. The implementation of the well-established knowledge of cancer prevention and the strengthening of preventative research is urgently needed

Duration to Establish an Emergency Vascular Access and How to Accelerate It: A Simulation-Based Study Performed in Real-Life Neonatal Resuscitation Rooms

Objectives: To compare the duration to establish an umbilical venous catheter and an intraosseous access in real hospital delivery rooms and as a secondary aim to assess delaying factors during establishment and to provide recommendations to accelerate vascular access in neonatal resuscitation. Design: Retrospective analysis of audio-video recorded neonatal simulation training. Settings: Simulation training events in exact replications of actual delivery/resuscitation rooms of 16 hospitals with different levels of care (Austria and Germany). Equipment was prepared the same way as for real clinical events. Subjects: Medical teams of four to five persons with birth-related background (midwives, nurses, neonatologists, and anesthesiologists) in a realistic team composition. Interventions: Audio-video recorded mannequin-based simulated resuscitation of an asphyxiated newborn including the establishment of either umbilical venous catheter or intraosseous access. Measurements and Main Results: The duration of access establishment (time from decision to first flush/aspiration), preparation (decision to start of procedure), and the procedure itself (start to first flush/aspiration) was significantly longer for umbilical venous catheter than for intraosseous access (overall duration 199 vs 86 s). Delaying factors for umbilical venous catheter establishment were mainly due to the complex approach itself, the multitude of equipment required, and uncertainties about necessary hygiene standards. Challenges in intraosseous access establishment were handling of the unfamiliar material and absence of an intraosseous access kit in the resuscitation room. There was no significant difference between the required duration for access establishment between large centers and small hospitals, but a trend was observed that duration for umbilical venous catheter was longer in small hospitals than in centers. Duration for intraosseous access was similar in both hospital types. Conclusions: Vascular access establishment in neonatal resuscitation could be accelerated by infrastructural improvements and specific training of medical teams. In simulated in situ neonatal resuscitation, intraosseous access is faster to establish than umbilical venous catheter. Future studies are required to assess efficacy and safety of both approaches in real resuscitation settings

Improved methodical approach for quantitative BRET analysis of G protein coupled receptor dimerization

G Protein Coupled Receptors (GPCR) can form dimers or higher ordered oligomers, the process of which can remarkably influence the physiological and pharmacological function of these receptors. Quantitative Bioluminescence Resonance Energy Transfer (qBRET) measurements are the gold standards to prove the direct physical interaction between the protomers of presumed GPCR dimers. For the correct interpretation of these experiments, the expression of the energy donor Renilla luciferase labeled receptor has to be maintained constant, which is hard to achieve in expression systems. To analyze the effects of non-constant donor expression on qBRET curves, we performed Monte Carlo simulations. Our results show that the decrease of donor expression can lead to saturation qBRET curves even if the interaction between donor and acceptor labeled receptors is non-specific leading to false interpretation of the dimerization state. We suggest here a new approach to the analysis of qBRET data, when the BRET ratio is plotted as a function of the acceptor labeled receptor expression at various donor receptor expression levels. With this method, we were able to distinguish between dimerization and non-specific interaction when the results of classical qBRET experiments were ambiguous. The simulation results were confirmed experimentally using rapamycin inducible heterodimerization system. We used this new method to investigate the dimerization of various GPCRs, and our data have confirmed the homodimerization of V2 vasopressin and CaSR calcium sensing receptors, whereas our data argue against the heterodimerization of these receptors with other studied GPCRs, including type I and II angiotensin, β2 adrenergic and CB1 cannabinoid receptors

Circadian-Related Heteromerization of Adrenergic and Dopamine D4 Receptors Modulates Melatonin Synthesis and Release in the Pineal Gland

Dopamine and adrenergic receptor complexes form under a circadian-regulated cycle and directly modulate melatonin synthesis and release from the pineal gland

Circadian-Related Heteromerization of Adrenergic and Dopamine D4 Receptors Modulates Melatonin Synthesis and Release in the Pineal Gland

Dopamine and adrenergic receptor complexes form under a circadian-regulated cycle and directly modulate melatonin synthesis and release from the pineal gland

Helix 8 of the viral chemokine receptor ORF74 directs chemokine binding

The constitutively active G-protein-coupled receptor and viral oncogene ORF74, encoded by Kaposi sarcoma-associated herpesvirus (human herpesvirus 8), binds a broad range of chemokines, including CXCL1 (agonist), CXCL8 (neutral ligand), and CXCL10 (inverse agonist). Although chemokines interact with the extracellular N terminus and loops of the receptor, we demonstrate that helix 8 (Hx8) in the intracellular carboxyl tail (C-tail) of ORF74 directs chemokine binding. Partial deletion of the C-tail resulted in a phenotype with reduced constitutive activity but intact regulation by ligands. Complete deletion of the C-tail, including Hx8, resulted in an inactive phenotype that lacks CXCL8 binding sites and has an increased number of binding sites for CXCL10. Similar effects were obtained with the single R7.6

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe

Structure of the human κ-opioid receptor in complex with JDTic

Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and—in the case of κ-opioid receptor (κ-OR)—dysphoria and psychotomimesis. Here we report the crystal structure of the human κ-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 Å resolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human κ-OR. Modelling of other important κ-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 5′-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure–activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for κ-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human κ-OR