Der internistische Check-up

Zusammenfassung: Viele präventive Maßnahmen bei gesunden Erwachsenen werden in zunehmendem Maße durch Evidenz gestützt oder verworfen. Dabei sind v.a. die Beratung bezüglich Tabakabstinenz, indizierte Impfungen und das Screening in Bezug auf Übergewicht, hohen Blutdruck, Hyperlipidämie, Zervixkarzinom, kolorektales Karzinom und Mammakarzinom bewiesenermaßen wichtig und sinnvoll. Nicht empfohlen wird ein Screening für Bronchial-, Pankreas- und Ovarialkarzinom. Ein Screening für Diabetes mellitus beim jüngeren Erwachsenen, Schilddrüsenerkrankungen und Prostatakarzinom wird nicht routinemäßig empfohlen, sollte aber je nach persönlichem Risikoprofil im Sinne eines sog. "Case findings" erwogen werden. Aus ärztlicher Sicht ist es auch wichtig, auf mögliche nicht deklarierte Beweggründe für eine Check-up-Untersuchung einzugehen, um so mögliche "Hidden Agendas" der Konsultationen aufzudecke

Cryogenic micro-calorimeters for mass spectrometric identification of neutral molecules and molecular fragments

We have systematically investigated the energy resolution of a magnetic micro-calorimeter (MMC) for atomic and molecular projectiles at impact energies ranging from $E\approx13$ to 150 keV. For atoms we obtained absolute energy resolutions down to $\Delta E \approx 120$ eV and relative energy resolutions down to $\Delta E/E\approx10^{-3}$. We also studied in detail the MMC energy-response function to molecular projectiles of up to mass 56 u. We have demonstrated the capability of identifying neutral fragmentation products of these molecules by calorimetric mass spectrometry. We have modeled the MMC energy-response function for molecular projectiles and conclude that backscattering is the dominant source of the energy spread at the impact energies investigated. We have successfully demonstrated the use of a detector absorber coating to suppress such spreads. We briefly outline the use of MMC detectors in experiments on gas-phase collision reactions with neutral products. Our findings are of general interest for mass spectrometric techniques, particularly for those desiring to make neutral-particle mass measurements

Foresight Review on Design for Safety

This review explores how a culture of design for safety can enhance the safety of the world around us. Design for safety goes beyond legislation, regulations and standards. These all play an important role for established products and services but their limited scope often leads to missed opportunities to enhance safety by taking a broader perspective. Design is applied to both mature industries (which have many years of experience and a good understanding of risks and how to reduce them) and emerging industries (that use new technologies requiring new ways of controlling risk which may not yet be known or understood). An example of an emerging risk is the internet that is enabling rapid innovation of new products which generate data. This data is widely shared across the internet and the risks associated with this are as yet not fully understood by the public. A design for safety culture takes a holistic approach to understanding the influences that affect safety. Such influences are varied and take into account the broader environment within which design operates, including complex interactions, behaviour and culture. It goes beyond traditional design methods and focuses on the goal of a safer design. Implementing design for safety requires an understanding of the challenges and the methods to address them. It needs multidisciplinary teams that bring together people with the relevant skills to understand the challenges and a collaborative approach of ‘designing with’ rather than the more traditional approach of ‘designing for’. This can be achieved through an international diverse community that works together to identify and share best practices

Characterization of the 163^{163}Ho Electron Capture Spectrum: A Step Towards the Electron Neutrino Mass Determination

The isotope $^{163}$Ho is in many ways the best candidate to perform experiments to investigate the value of the electron neutrino mass. It undergoes an electron capture process to $^{163}$Dy with an energy available to the decay, Q$_{EC}$, of about 2.8 keV. According to the present knowledge, this is the lowest Q$_{EC}$ value for such transitions. Here we discuss a newly obtained spectrum of $^{163}$Ho, taken by cryogenic metallic magnetic calorimeters with $^{163}$Ho implanted in the absorbers and operated in anticoincident mode for background reduction. For the first time, the atomic deexcitation of the $^{163}$Dy daughter atom following the capture of electrons from the 5s shell in $^{163}$Ho, the OI line, was observed with a calorimetric measurement. The peak energy is determined to be 48 eV. In addition, a precise determination of the energy available for the decay Q$_{EC}$=(2.858±0.010$_{stat}$±0.05$_{syst}$)  keV was obtained by analyzing the intensities of the lines in the spectrum. This value is in good agreement with the measurement of the mass difference between $^{163}$Ho and $^{163}$Dy obtained by Penning-trap mass spectrometry, demonstrating the reliability of the calorimetric technique

Role of the progesterone receptor for paclitaxel resistance in primary breast cancer

Paclitaxel plays an important role in the treatment of primary breast cancer. However, a substantial proportion of patients treated with paclitaxel does not appear to derive any benefit from this therapy. We performed a prospective study using tumour cells isolated from 50 primary breast carcinomas. Sensitivity of primary tumour cells to paclitaxel was determined in a clinically relevant range of concentrations (0.85–27.2 μg ml−1 paclitaxel) using an ATP assay. Chemosensitivity data were used to study a possible association with immunohistochemically determined oestrogen and progesterone receptor (ER and PR) status, as well as histopathological parameters. Progesterone receptor (PR) mRNA expression was also determined by quantitative RT–PCR. We observed a clear association of the PR status with chemosensitivity to paclitaxel. Higher levels of immunohistochemically detected PR expression correlated with decreased chemosensitivity (P=0.008). Similarly, high levels of PR mRNA expression were associated with decreased paclitaxel chemosensitivity (P=0.007). Cells from carcinomas with T-stages 3 and 4 were less sensitive compared to stages 1 and 2 (P=0.013). Multiple regression analysis identified PR receptor status and T-stage as independent predictors of paclitaxel chemosensitivity, whereas the ER, N-stage, grading and age were not influential. In conclusion, in vitro sensitivity to paclitaxel was higher for PR-negative compared with PR-positive breast carcinoma cells. Thus, PR status should be considered as a possible factor of influence when designing new trials and chemotherapy protocols

Notes of a Meeting Held in the Diplomatic Reception Room of the Department of State on Monday, March 20, 1911

The document is a carbon transcript of notes from a meeting held in the State Department respecting the necessity of more such meetings, the present organization of the Department, expenditures, and esprit de corps. Present at the meeting were: The Assistant Secretaries, the Solicitor, the Director of the Consular Service, the Chief Clerk and the Chiefs and Assistant Chiefs of the Divisions and Bureaus of the Department.https://digitalcommons.ursinus.edu/fmhw_speeches/1004/thumbnail.jp

Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment.

The currently available techniques for the safety evaluation of candidate drugs are usually cost-intensive and time-consuming and are often insufficient to predict human relevant cardiotoxicity. The purpose of this study was to develop an in vitro repeated exposure toxicity methodology allowing the identification of predictive genomics biomarkers of functional relevance for drug-induced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The hiPSC-CMs were incubated with 156 nM doxorubicin, which is a well-characterized cardiotoxicant, for 2 or 6 days followed by washout of the test compound and further incubation in compound-free culture medium until day 14 after the onset of exposure. An xCELLigence Real-Time Cell Analyser was used to monitor doxorubicin-induced cytotoxicity while also monitoring functional alterations of cardiomyocytes by counting of the beating frequency of cardiomyocytes. Unlike single exposure, repeated doxorubicin exposure resulted in long-term arrhythmic beating in hiPSC-CMs accompanied by significant cytotoxicity. Global gene expression changes were studied using microarrays and bioinformatics tools. Analysis of the transcriptomic data revealed early expression signatures of genes involved in formation of sarcomeric structures, regulation of ion homeostasis and induction of apoptosis. Eighty-four significantly deregulated genes related to cardiac functions, stress and apoptosis were validated using real-time PCR. The expression of the 84 genes was further studied by real-time PCR in hiPSC-CMs incubated with daunorubicin and mitoxantrone, further anthracycline family members that are also known to induce cardiotoxicity. A panel of 35 genes was deregulated by all three anthracycline family members and can therefore be expected to predict the cardiotoxicity of compounds acting by similar mechanisms as doxorubicin, daunorubicin or mitoxantrone. The identified gene panel can be applied in the safety assessment of novel drug candidates as well as available therapeutics to identify compounds that may cause cardiotoxicity

Genetic determinants of steatosis and fibrosis progression in paediatric non‐alcoholic fatty liver disease

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents today. In comparison with adult disease, paediatric NAFLD may show a periportal localization, which is associated with advanced fibrosis. This study aimed to assess the role of genetic risk variants for histological disease pattern and severity in childhood NAFLD. METHODS: We studied 14 single nucleotide polymorphisms (SNP) in a cohort of 70 adolescents with biopsy-proven NAFLD. Genotype was compared to an adult control cohort (n = 200) and analysed in relation to histological disease severity and liver tissue proteomics. RESULTS: Three of the 14 SNPs were significantly associated with paediatric NAFLD after FDR adjustment, rs738409 (PNPLA3, P = 2.80 × 10-06 ), rs1044498 (ENPP1, P = 0.0091) and rs780094 (GCKR, P = 0.0281). The severity of steatosis was critically associated with rs738409 (OR=3.25; 95% CI: 1.72-6.52, FDR-adjusted P = 0.0070). The strongest variants associated with severity of fibrosis were rs1260326, rs780094 (both GCKR) and rs659366 (UCP2). PNPLA3 was associated with a portal pattern of steatosis, inflammation and fibrosis. Proteome profiling revealed decreasing levels of GCKR protein with increasing carriage of the rs1260326/rs780094 minor alleles and downregulation of the retinol pathway in rs738409 G/G carriers. Computational metabolic modelling highlighted functional relevance of PNPLA3, GCKR and UCP2 for NAFLD development. CONCLUSIONS: This study provides evidence for the role of PNPLA3 as a determinant of portal NAFLD localization and severity of portal fibrosis in children and adolescents, the risk variant being associated with an impaired hepatic retinol metabolism