Implications of the sustainable development paradigm for Switzerland

The sustainable development paradigm raises issues of global, intra- and intergenerational social equity as well as respect for nature, and economic welfare. Switzerland is confronted by these issues within its own country, and has a moral responsibility vis-a-vis the rest of the world. Syndromes of global change are affecting many eco-regions, not only in developing and transition countries, but to a lesser extent also the affluent countries. Switzerland as a nation has an impact on syndromes through its far-reaching economic activities, which are non-sustainable. At the global level, more modest consumption patterns, a considerably slowed demographic change, a nonconsumptive but sustainable use of natural resources, and conflict transformation are the main prerequisites for improving sustainability. Switzerland's current contribution to sustainability is much less than what it could be, hence the need for additional action along general principles in,accordance with Swiss traditions and innovative potentials. A number of concrete actions could be taken immediately. These are: labelling the socially and ecologically sustainable production of goods and services, and their negotiation at WTO level; enhancing international cooperation and research; strengthening education and research for sustainability, and emphasizing energy and material flux efficiency at home and abroad.

Indocyanine Green Fluorescence Imaging in the Surgical Management of an Iatrogenic Lymphatic Fistula: Description of a Surgical Technique

We present a case of laparoscopic surgical management of an iatrogenic lymphorrhea using indocyanine green (ICG). A case of a patient who developed recurrent symptomatic lymphorrhea after laparoscopic radical hysterectomy and bilateral pelvic lymphadenectomy for an early stage cervical cancer is presented. Intraoperative bipedal interdigital subcutaneous injection of ICG exactly localized the disrupted lymphatic duct on fluorescence imaging performed with a near-infrared laparoscopic fluorescent optic device, thus allowing a successful surgical repair.

PCSK9 Plasma Concentrations Are Independent of GFR and Do Not Predict Cardiovascular Events in Patients with Decreased GFR.

BACKGROUND Impaired renal function causes dyslipidemia that contributes to elevated cardiovascular risk in patients with chronic kidney disease (CKD). The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a regulator of the LDL receptor and plasma cholesterol concentrations. Its relationship to kidney function and cardiovascular events in patients with reduced glomerular filtration rate (GFR) has not been explored. METHODS Lipid parameters including PCSK9 were measured in two independent cohorts. CARE FOR HOMe (Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Forth Homburg evaluation) enrolled 443 patients with reduced GFR (between 90 and 15 ml/min/1.73 m2) referred for nephrological care that were prospectively followed for the occurrence of a composite cardiovascular endpoint. As a replication cohort, PCSK9 was quantitated in 1450 patients with GFR between 90 and 15 ml/min/1.73 m2 enrolled in the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) that were prospectively followed for cardiovascular deaths. RESULTS PCSK9 concentrations did not correlate with baseline GFR (CARE FOR HOMe: r = -0.034; p = 0.479; LURIC: r = -0.017; p = 0.512). 91 patients in CARE FOR HOMe and 335 patients in LURIC reached an endpoint during a median follow-up of 3.0 [1.8-4.1] years and 10.0 [7.3-10.6] years, respectively. Kaplan-Meier analyses showed that PCSK9 concentrations did not predict cardiovascular events in either cohort [CARE FOR HOMe (p = 0.622); LURIC (p = 0.729)]. Sensitivity analyses according to statin intake yielded similar results. CONCLUSION In two well characterized independent cohort studies, PCSK9 plasma levels did not correlate with kidney function. Furthermore, PCSK9 plasma concentrations were not associated with cardiovascular events in patients with reduced renal function.

Fibroblast Growth Factor 23 Is an Independent and Specific Predictor of Mortality in Patients With Heart Failure and Reduced Ejection Fraction

BACKGROUND Strategies to improve risk prediction are of major importance in patients with heart failure (HF). Fibroblast growth factor 23 (FGF-23) is an endocrine regulator of phosphate and vitamin D homeostasis associated with an increased cardiovascular risk. We aimed to assess the prognostic effect of FGF-23 on mortality in HF patients with a particular focus on differences between patients with HF with preserved ejection fraction and patients with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS FGF-23 levels were measured in 980 patients with HF enrolled in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study including 511 patients with HFrEF and 469 patients with HF with preserved ejection fraction and a median follow-up time of 8.6 years. FGF-23 was additionally measured in a second cohort comprising 320 patients with advanced HFrEF. FGF-23 was independently associated with mortality with an adjusted hazard ratio per 1-SD increase of 1.30 (95% confidence interval, 1.14-1.48; P<0.001) in patients with HFrEF, whereas no such association was found in patients with HF with preserved ejection fraction (for interaction, P=0.043). External validation confirmed the significant association with mortality with an adjusted hazard ratio per 1 SD of 1.23 (95% confidence interval, 1.02-1.60; P=0.027). FGF-23 demonstrated an increased discriminatory power for mortality in addition to N-terminal pro-B-type natriuretic peptide (C-statistic: 0.59 versus 0.63) and an improvement in net reclassification index (39.6%; P<0.001). CONCLUSIONS FGF-23 is independently associated with an increased risk of mortality in patients with HFrEF but not in those with HF with preserved ejection fraction, suggesting a different pathophysiologic role for both entities.

Optimized on-line enantioselective capillary electrophoretic method for kinetic and inhibition studies of drug metabolism mediated by cytochrome P450 enzymes.

Pharmacokinetic and pharmacodynamic properties of a chiral drug can significantly differ between application of the racemate and single enantiomers. During drug development, the characteristics of candidate compounds have to be assessed prior to clinical testing. Since biotransformation significantly influences drug actions in an organism, metabolism studies represent a crucial part of such tests. Hence, an optimized and economical capillary electrophoretic method for on-line studies of the enantioselective drug metabolism mediated by cytochrome P450 enzymes was developed. It comprises a diffusion-based procedure, which enables mixing of the enzyme with virtually any compound inside the nanoliter-scale capillary reactor and without the need of additional optimization of mixing conditions. For CYP3A4, ketamine as probe substrate and highly sulfated γ-cyclodextrin as chiral selector, improved separation conditions for ketamine and norketamine enantiomers compared to a previously published electrophoretically mediated microanalysis method were elucidated. The new approach was thoroughly validated for the CYP3A4-mediated N-demethylation pathway of ketamine and applied to the determination of its kinetic parameters and the inhibition characteristics in presence of ketoconazole and dexmedetomidine. The determined parameters were found to be comparable to literature data obtained with different techniques. The presented method constitutes a miniaturized and cost-effective tool, which should be suitable for the assessment of the stereoselective aspects of kinetic and inhibition studies of cytochrome P450-mediated metabolic steps within early stages of the development of a new drug.

Chemical Composition of Micrometer-Sized Filaments in an Aragonite Host by a Miniature Laser Ablation/Ionization Mass Spectrometer

Detection of extraterrestrial life is an ongoing goal in space exploration, and there is a need for advanced instruments and methods for the detection of signatures of life based on chemical and isotopic composition. Here, we present the first investigation of chemical composition of putative microfossils in natural samples using a miniature laser ablation/ionization time-of-flight mass spectrometer (LMS). The studies were conducted with high lateral (similar to 15 mu m) and vertical (similar to 20-200 nm) resolution. The primary aim of the study was to investigate the instrument performance on micrometer-sized samples both in terms of isotope abundance and element composition. The following objectives had to be achieved: (1) Consider the detection and calculation of single stable isotope ratios in natural rock samples with techniques compatible with their employment of space instrumentation for biomarker detection in future planetary missions. (2) Achieve a highly accurate chemical compositional map of rock samples with embedded structures at the micrometer scale in which the rock matrix is easily distinguished from the micrometer structures. Our results indicate that chemical mapping of strongly heterogeneous rock samples can be obtained with a high accuracy, whereas the requirements for isotope ratios need to be improved to reach sufficiently large signal-to-noise ratio (SNR). Key Words: Biogenicity-Biomarkers-Biosignatures-Filaments-Fossilization. Astrobiology 15, 669-682.

A Study of Radon in Air and Water in Maine Schools

The transfer coefficient of radon from water to air was investigated in schools. Kitchens, bathrooms and locker rooms were studied for seven schools in Maine. Simulations were done in water-use rooms where radon in air detectors were in place. Quantities measured were radon in water (270-24500 F) and air (0-80 q), volume of water used, emissivities (0.01-0.99) and ventilation rates (0.012-0.066A). Variation throughout the room of the radon concentration was found. Values calculated for the transfer coefficient for kitchens and baths were ranged from 9.6 x to 2.0 x The transfer coefficient was calculated using these parameters and was also measured using concentrations of radon in water and air. This provides a means by which radon in air can be estimated using the transfer coefficient and the concentration in the water in other schools and it can be used to estimate the dose caused by radon released from water use. This project was partially funded by the United States Environmental Protection Agency (grant #X828l2 101-0) and by the State of Maine (grant #10A500178). These are the first measurements of this type to be done in schools in the United States.

Na 1 Nachlass Max Horkheimer, 692 - "The Economic and Social Consequences of Preparedness Economics" (p. IX 167.1-7)

"The Economic and Social Consequences of Preparedness Economics" (1937-1939):; 1. "First Draft of a Memorandum on a Research Project on The Economic Consequences of Preparedness Economics, planned by the International Instittute of Social Research" (13.12.1938). Typoskript mit handschriftlichen Ergänzungen, 2 Blatt; 2. Albert Lauterbach: "Project submitted to the Social Science Research Council: Sociological and Economic Aspects of Preparedness Economics". Typoskript, 3 Blatt; 3. Günther Reimann: "The Economics of Chemical Production". Typoskript, 4 Blatt; 4. Franz Neumann: "Bemerkungen zum Exposé Dr. Heiders 'Die Rolle der Bürokratie im totalitären Staat'" (22.2.1937). Typoskript, 1 Blatt; 5. Joseph Soudek: "Soziale und wirtschaftliche Aspekte der Wehrwirtschaft". Typoskript mit handschriftlichen Korrekturen und Ergänzungen von Friedrich Pollock (16.1.1939), 5 Blatt; 6. "Recovery and Boom Politics", Gliederungsentwurf, 3 Blatt; 7. "Interventionism and Business Cycles", Gliederungsentwurf, 7 Blatt;

EFFECTS OF THE ACTA2 R258C MUTATION ON VASCULAR SMOOTH MUSCLE CELL PHENOTYPE AND PROPERTIES

Thoracic Aortic Aneurysms and Dissections (TAAD) are the fifteenth leading cause of death in the United States. About 15% of TAAD patients have family history of the disease. The most commonly mutated gene in these families is ACTA2, encoding smooth muscle-specific α-actin. ACTA2 missense mutations predispose individuals both to TAAD and to vascular occlusive disease of small, muscular arteries. Mice carrying an Acta2 R258C mutant transgene with a wildtype Acta2 promoter were generated and bred with Acta2-/- mice to decrease the wildtype: mutant Acta2 ratio. Acta2+/+ R258C TGmice have decreased aortic contractility without aortic disease. Acta2+/- R258C TG mice, however, have significant aortic dilatations by 12 weeks of age and a hyperproliferative response to injury. We characterized smooth muscle cells (SMCs) from bothmouse models under the hypothesis that mutant α-actin has a dominant negative effect, leading to impaired contractile filament formation/stability, improper focal adhesion maturation and increased proliferation. Explanted aortic SMCs from Acta2+/+ R258C TG mice are differentiated - they form intact filaments, express higher levels of contractile markers compared to wildtype SMCs and have predominantly nuclear Myocardin-Related Transcription Factor A (MRTF-A) localization. However, ultracentrifugation assays showed large unpolymerized actin fractions, suggesting that the filaments are brittle. In contrast, Acta2+/- R258C TG SMCs are less well-differentiated, with pools of unpolymerized actin, more cytoplasmic MRTF-A and decreased contractile protein expression compared to wildtype cells. Ultracentrifugation assays after treating Acta2+/- R258C TGSMCs with phalloidin showed actin filament fractions, indicating that mutant α-actin can polymerize into filaments. Both Acta2+/+ R258C TGand Acta2+/- R258C TGSMCs have larger and more peripheral focal adhesions compared to wildtype SMCs. Rac1 was more activated in Acta2+/+ R258C TGSMCs; both Rac1 and RhoA were less activated in Acta2+/- R258C TG SMCs, and FAK was more activated in both transgenic SMC lines compared to wildtype. Proliferation in both cell lines was significantly increased compared to wildtype cells and could be partially attenuated by inhibition of FAK or PDGFRβ. These data support a dominant negative effect of the Acta2 R258C mutation on the SMC phenotype, with increasing phenotypic severity when wildtype: mutant α-actin levels are decreased.

Differential Activity of the KRAS Oncogene by Method of Activation: Implications for Signaling and Therapeutic Intervention

Despite having been identified over thirty years ago and definitively established as having a critical role in driving tumor growth and predicting for resistance to therapy, the KRAS oncogene remains a target in cancer for which there is no effective treatment. KRas is activated b y mutations at a few sites, primarily amino acid substitutions at codon 12 which promote a constitutively active state. I have found that different amino acid substitutions at codon 12 can activate different KRas downstream signaling pathways, determine clonogenic growth potential and determine patient response to molecularly targeted therapies. Computer modeling of the KRas structure shows that different amino acids substituted at the codon 12 position influences how KRas interacts with its effecters. In the absence of a direct inhibitor of mutant KRas several agents have recently entered clinical trials alone and in combination directly targeting two of the common downstream effecter pathways of KRas, namely the Mapk pathway and the Akt pathway. These inhibitors were evaluated for efficacy against different KRAS activating mutations. An isogenic panel of colorectal cells with wild type KRas replaced with KRas G12C, G12D, or G12V at the endogenous loci differed in sensitivity to Mek and Akt inhibition. In contrast, screening was performed in a broad panel of lung cell lines alone and no correlation was seen between types of activating KRAS mutation due to concurrent oncogenic lesions. To find a new method to inhibit KRAS driven tumors, siRNA screens were performed in isogenic lines with and without active KRas. The knockdown of CNKSR1 (CNK1) showed selective growth inhibition in cells with an oncogenic KRAS. The deletion of CNK1 reduces expression of mitotic cell cycle proteins and arrests cells with active KRas in the G1 phase of the cell cycle similar to the deletion of an activated KRas regardless of activating substitution. CNK1 has a PH domain responsible for localizing it to membrane lipids making KRas potentially amenable to inhibition with small molecules. The work has identified a series of small molecules capable of binding to this PH domain and inhibiting CNK1 facilitated KRas signaling.

Retreat of top cliff of Kurungnakh Island, Lena Delta, Siberia, Russia, 2010-2014, with links to shapefiles

Thawing-induced cliff top retreat in permafrost landscapes is mainly due to thermo-erosion. Ground-ice-rich permafrost landscapes are specifically vulnerable to thermo-erosion and may show high degradation rates. Within the HGF Alliance Remote Sensing and the FP7 PAGE21 permafrost programs we investigated how SAR and optical remote sensing can contribute to the monitoring of erosion rates of ice-rich cliffs in Arctic Siberia (Lena Delta, Russia). We produced two different vector products: i) Intra-annual cliff top retreat based on TerraSAR-X (TSX) satellite data (2012-2014): High-temporal resolution time series of TSX satellite data allow the inter-annual and intra-annual monitoring of the upper cliff-line retreat also under bad weather conditions and continuous cloud coverage. This published SAR product contains the retreating upper cliff lines of a 1.5 km long part of eroding ice-rich coast of Kurungnakh Island in the central Lena Delta. The upper cliff line was mapped using a thresholding approach for images acquired in the years 2012, 2013 and 2014 for the months June (2013, 2014), July (2013, 2014), August (2012, 2013, 2014) and September (2013, 2014). The cliff top retreat vector product is called 'upper_cliff_TerraSAR-X'. While the 2014 cliff lines show a clear retreat of 2 to 3 m/month, the cliff top lines for 2012 and 2013 are not chronologically ordered. However, lines from the end of the season of a year are always close to the lines from the beginning of the next summer season, indicating low cliff retreat in winter. ii) 4-year cliff top retreat based on optical satellite data (2010-2014): Long-term cliff top retreat could be assessed with two high-spatial resolution optical satellite images (GeoEye-1, 2010-08-05 and Worldview-1, 2014-08-19). The cliff top retreat vector product is called 'upper_cliff_optical'. Results: The long-term cliff top retreat derived from optical satellite data are 35 m cliff retreat within 4 years. The higher-temporal resolution SAR data equivalently show long-term rates of 18 m within 2 years and nearly now degradation activities in winter but maximum erosion rates in summer months.The Intra-seasonal cliff top retreat lines from 2014 show a rate of 2 to 3 m per month.

Nd, Pb, and Be isotopes of ferromanaganese crusts of the Atlantic Ocean

The isotopic composition of Nd in present-day deep waters of the central and northeastern Atlantic Ocean is thought to fingerprint mixing of North Atlantic Deep Water with Antarctic Bottom Water. The central Atlantic Romanche and Vema Fracture Zones are considered the most important pathways for deep water exchange between the western and eastern Atlantic basins today. We present new Nd isotope records of the deepwater evolution in the fracture zones obtained from ferromanganese crusts, which are inconsistent with simple water mass mixing alone prior to 3 Ma and require additional inputs from other sources. The new Pb isotope time series from the fracture zones are inexplicable by simple mixing of North Atlantic Deep Water and Antarctic Bottom Water for the entire past 33 Myr. The distinct and relatively invariable Nd and Pb isotope records of deep waters in the fracture zones appear instead to have been controlled to a large extent by contributions from Saharan dust and the Orinoco/Amazon Rivers. Thus the previously observed similarity of Nd and Pb isotope time series from the western and eastern North Atlantic basins is better explainable by direct supply of Labrador Seawater to the eastern basin via a northern pathway rather than by advection of North Atlantic Deep Water via the Romanche and Vema Fracture Zones.