Comparison of contrast-enhanced multi-station MR angiography and digital subtraction angiography of the lower extremity arterial disease

PURPOSE: To compare diagnostic accuracy of multi-station, high-spatial resolution contrast-enhanced MR angiography (CE-MRA) of the lower extremities with digital subtraction angiography (DSA) as the reference standard in patients with symptomatic peripheral arterial occlusive disease. MATERIALS AND METHODS: Of 485 consecutive patients undergoing a run-off CE-MRA, 152 patients (86 male, 66 female; mean age, 71.6 years) with suspected peripheral arterial occlusive disease were included into our Institutional Review Board approved study. All patients underwent MRA and DSA of the lower extremities within 30 days. MRA was performed at 1.5 Tesla with a single bolus of 0.1 mmol/kg body weight of gadobutrol administered at a rate of 2.0 mL/s at three stations. Two readers evaluated the MRA images independently for stenosis grade and image quality. Sensitivity and specificity were derived. RESULTS: Sensitivity and specificity ranged from 73% to 93% and 64% to 89% and were highest in the thigh area. Both readers showed comparable results. Evaluation of good and better quality MRAs resulted in a considerable improvement in diagnostic accuracy. CONCLUSION: Contrast-enhanced MRA demonstrates good sensitivity and specificity in the investigation of the vasculature of the lower extremities. While a minor investigator experience dependence remains, it is standardizable and shows good inter-observer agreement. Our results confirm that the administration of Gadobutrol at a standard dose of 0.1 mmol/kg for contrast-enhanced runoff MRA is able to detect hemodynamically relevant stenoses. Use of contrast-enhanced MRA as an alternative to intra-arterial DSA in the evaluation and therapeutic planning of patients with suspected peripheral arterial occlusive disease is well justified. J. Magn. Reson. Imaging 2013;37:1427-1435. © 2012 Wiley Periodicals, Inc.

The 1945-1949 droughts in Switzerland

This paper studies the representation of a drought period that affected Central Europe from 1945 to 1949 in the “Twentieth Century Reanalysis” (20CR). We analysed temperature and precipitation fields in 20CR and compared them to other data products. From the monthly precipitation rate at a 20CR grid point in the Swiss Plateau, the Standardised Precipitation Index over six months (SPI6) was calculated and compared with the corresponding index calculated from station data. For additional analyses, 20CR soil moisture, run off, and evaporation data were used. 20CR well reproduces the temperature and precipitation anomalies over Central Europe during this period, although during 1947, the precipitation anomaly is shifted to the east as compared to observations. With respect to the SPI6 index, the agreement between 20CR and station data is good except again for 1947 (conversely, drought was overestimated in 20CR for 1945 and 1949). Low SPI values in 20CR are accompanied by negative soil moisture anomalies and a negative water balance. Thus, apart from the shift in the spatial drought pattern in 1947, the drought is depicted in a realistic way in 20CR.

Recruitment dynamics of the grove-dominant tree Microberlinia bisulcata in African rain forest: extending the light response versus adult longevity trade-off concept

In groves of ectomycorrhizal caesalpiniaceous species in the Atlantic coastal forest of Central Africa the dominant tree Microberlinia bisulcata, which is shade-intolerant as a seedling but highly light-responding as a sapling, shows very limited regeneration. M. bisulcata saplings were mapped in an 82.5-ha plot at Korup and found to be located significantly far (>40 m) away from adults, a result confirmed by direct testing in a second 56-ha plot. Sapling growth over 6 years, the distribution of newly emerging seedlings around adults, recruitment of saplings in a large opening and the outward extent of seedlings at the grove edge were also investigated. Two processes appear to have been operating: (1) a very strong and consistent restriction of the very numerous seedlings establishing after masting close to adults, and (2) a strong but highly spatially variable promotion of distant survivors by increased light from the deaths of large trees of species other than M. bisulcata (which itself has very low mortality rate). This leads to an apparent escape-from-adults effect. To maintain saplings in the shade between multiple short periods of release ectomycorrhizal connections to other co-occurring caesalp species may enable a rachet-type mechanism. The recorded sapling dynamics currently contribute an essential part of the long-term cycling of the groves. M. bisulcata is an interesting example of an important group of tropical trees, particularly in Africa, which are both highly light-demanding when young yet capable also of forming very large forest emergents. To more comprehensively explain tropical tree responses, the case is made for adding a new dimension to the trade-off concept of early tree light-response versus adult longevity.

Applying erosion damage mapping to asses and quantify off-site effects of soil erosion in Switzerland

In order to fill existing knowledge gaps in the temporal and spatial distribution of soil erosion, its sources and causes, as well as in relation to its off-site impacts, erosion damage mapping of all visible erosion features was carried out at three study sites in Switzerland. The data illustrate that about one-quarter of the cultivated land was affected by water erosion. Observed mean annual soil loss rates are considered rather low (0.7–2.3 t/ha/y) compared to other European countries. However, substantial losses of >70 t/ha were recorded on individual plots. This paper focuses on the spatial aspects of soil erosion, by observing and comparing the study areas in a 1-year period from October 2005 to October 2006. The analyses illustrate that the sites differ considerably in average soil loss rates, but show similar patterns of off-site effects. In about one-third of the damaged plots an external source of surface runoff upslope contributed to the damage (run-on). Similarly, more than 50 per cent of the soil eroded on arable land deposited downslope on adjacent plots, roads, public/private infrastructure, etc., and 20 per cent of it reached open water bodies. Large amounts of eroded soil which deposit off-site, often related to slope depressions, are considered muddy floods and were frequently observed in Switzerland. Mapping, in conclusion, helps to sheds light on some of the important challenges of today, in particular: to comprehensively assess socioeconomic and ecological off-site effects of soil erosion, to attribute off-site impacts to on-site causes, and to raise awareness of all stakeholders involved, in order to improve ongoing discussions on policy formulation and implementation at the national and international levels.

Arteriolar vasoconstrictive response: comparing the effects of arginine vasopressin and norepinephrine

INTRODUCTION: This study was designed to examine differences in the arteriolar vasoconstrictive response between arginine vasopressin (AVP) and norepinephrine (NE) on the microcirculatory level in the hamster window chamber model in unanesthetized, normotonic hamsters using intravital microscopy. It is known from patients with advanced vasodilatory shock that AVP exerts strong additional vasoconstriction when incremental dosage increases of NE have no further effect on mean arterial blood pressure (MAP). METHODS: In a prospective controlled experimental study, eleven awake, male golden Syrian hamsters were instrumented with a viewing window inserted into the dorsal skinfold. NE (2 microg/kg/minute) and AVP (0.0001 IU/kg/minute, equivalent to 4 IU/h in a 70 kg patient) were continuously infused to achieve a similar increase in MAP. According to their position within the arteriolar network, arterioles were grouped into five types: A0 (branch off small artery) to A4 (branch off A3 arteriole). RESULTS: Reduction of arteriolar diameter (NE, -31 +/- 12% versus AVP, -49 +/- 7%; p = 0.002), cross sectional area (NE, -49 +/- 17% versus AVP, -73 +/- 7%; p = 0.002), and arteriolar blood flow (NE, -62 +/- 13% versus AVP, -80 +/- 6%; p = 0.004) in A0 arterioles was significantly more pronounced in AVP animals. There was no difference in red blood cell velocities in A0 arterioles between groups. The reduction of diameter, cross sectional area, red blood cell velocity, and arteriolar blood flow in A1 to A4 arterioles was comparable in AVP and NE animals. CONCLUSION: Within the microvascular network, AVP exerted significantly stronger vasoconstriction on large A0 arterioles than NE under physiological conditions. This observation may partly explain why AVP is such a potent vasopressor hormone and can increase systemic vascular resistance even in advanced vasodilatory shock unresponsive to increases in standard catecholamine therapy.

Oxidative stress precedes peak systemic inflammatory response in pediatric patients undergoing cardiopulmonary bypass operation

Oxidative stress seems to contribute to cardiopulmonary bypass (CPB)-related postoperative complications. Pediatric patients are particularly prone to these complications. With this in mind, we measured oxidative stress markers in blood plasma of 20 children undergoing elective heart surgery before, during, and up to 48 h after cessation of CPB, along with inflammatory parameters and full analysis of iron status. Ascorbate levels were decreased by approximately 50% (P < 0.001) at the time of aorta cross-clamp removal (or pump switch-off in 4 patients with partial CPB), and associated with corresponding increases in dehydroascorbate (P < 0.001, r = -0.80) and malondialdehyde (P < 0.01, r = -0.59). In contrast to the immediate oxidative response, peak levels of IL-6 and IL-8 were not observed until 3-12 h after CPB cessation. The early loss of ascorbate correlated with duration of CPB (P < 0.002, r = 0.72), plasma hemoglobin after cross-clamp removal (P < 0.001, r = 0.70), and IL-6 and IL-8 levels at 24 and 48 h after CPB (P < 0.01), but not with postoperative lactate levels, strongly suggesting that hemolysis, and not inflammation or ischemia, was the main cause of early oxidative stress. The correlation of ventilation time with early changes in ascorbate (P < 0.02, r = 0.55), plasma hemoglobin (P < 0.01, r = 0.60), and malondialdehyde (P < 0.02, r = 0.54) suggests that hemolysis-induced oxidative stress may be an underlying cause of CPB-associated pulmonary dysfunction. Optimization of surgical procedures or therapeutic intervention that minimize hemolysis (e.g., off-pump surgery) or the resultant oxidative stress (e.g., antioxidant treatment) should be considered as possible strategies to lower the rate of postoperative complications in pediatric CPB.

Carotenoid-based plumage colors and immune function: Is there a trade-off for rare carotenoids?

Theory suggests that carotenoid-based signals are used in animal communication because they contain specific information about parasite resistance or immunocompetence. This implies that honesty of carotenoid-based signals is maintained by a trade-off between pigmentation and immune function for carotenoids, assuming that the carotenoids used for coloration are also immunoenhancing. We tested this hypothesis by altering the diets of nestling great tits (Paris major) with supplementary beadlets containing the carotenoids that are naturally ingested with food or beadlets containing the carotenoids that are incorporated into the feathers; a control group received beadlets containing no carotenoids. We simultaneously immune challenged half of the nestlings of each supplementation group, using a two-factorial design. Activatior of the immune system led to reduced color expression. However, only nestlings fed with the naturally ingested carotenoids and not with the carotenoids deposited in the feathers showed an increased cellular immune response. This shows that the carotenoids used for ornamentation do not promote the immune function, which conflicts with the trade-off hypothesis. Our results indicate that honesty of carotenoid-based signals is maintained by an individual's physiological limitation to absorb and/or transport carotenoids and by access to carotenoids, indicating that preferences for carotenoid-based traits in sexual selection or parent-offspring interactions select for competitive individuals, rather than specifically for immune function.

[Study protocol of the VISEP study. Response of the SepNet study group]

In the commentary by Zander et al. the authors appear concerned about the methods and results of our, at that time, unpublished sepsis trial evaluating hydroxyethyl starch (HES) and insulin therapy. Unfortunately, the authors' concerns are based on false assumptions about the design, conduct and modes of action of the compounds under investigation. For instance, in our study the HES solution was not used for maintenance of daily fluid requirements, so that the assumption of the authors that this colloid was used "exclusively" is wrong. Moreover, the manufacturer of Hemohes, the HES product we used, gives no cut-off value for creatinine, thus the assumption that this cut-off value was "doubled" in our study is also incorrect. Other claims by the authors such as that lactated solutions cause elevated lactate levels, iatrogenic hyperglycemia and increase O(2) consumption are unfounded. There is no randomized controlled trial supporting such a claim - this claim is neither consistent with our study data nor with any credible published sepsis guidelines or with routine practice worldwide. We fully support open scientific debate. Our study methods and results have now been published after a strict peer-reviewing process and this data is now open to critical and constructive reviewing. However, in our opinion this premature action based on wrong assumptions and containing comments by representatives of pharmaceutical companies does not contribute to a serious, unbiased scientific discourse.

Response of the Lateglacial fauna to climatic change

This study deals with faunal finds from the Swiss Paleolithic, especially from the Late Glacial. Faunal assemblages from archeological sites as well as off-site finds dated by scientific means are included. In the middle of the Oldest Dryas the large glacial species – mammoth, rhinoceros, cave bear, musk ox – become extinct. During the Early Bølling the last arctic species disappear, and are succeeded by animals like red deer and elk, preferring a moderate climate. From the middle of the Allerød, species typical of a denser forest (roe deer and wild boar) are very frequent.

Characterization of the potential role for RNA-binding protein FUS/TLS in DNA damage response: A quantitative proteomic approach

FUS/TLS (fused in sarcoma/translocated in liposarcoma) is a ubiquitously expressed RNA-binding protein of the hnRNP family, that has been discovered as fused to transcription factors, through chromosomal translocations, in several human sarcomas and found in protein aggregates in neurons of patients with an inherited form of Amyotrophic Lateral Sclerosis (ALS) [1]. To date, FUS/TLS has been implicated in a variety of cellular processes such as gene expression control, transcriptional regulation, pre-mRNA splicing and miRNA processing [2]. In addition, some evidences link FUS/TLS to genome stability control and DNA damage response. In fact, mice lacking FUS/TLS are hypersensitive to ionizing radiation (IR) and show high levels of chromosome instability and in response to double-strand breaks, FUS/TLS gets phosphorylated by the protein kinase ATM [3,4,5]. Furthermore, the inducible depletion of FUS/TLS in a neuroblastoma cell line (SH-SY5Y FUS/TLS TET-off iKD) subjected to genotoxic stress (IR) resulted in an increased phosphorylation of γH2AX respect to control cells, suggesting an higher activation of the DNA damage response. The study aims to investigate the specific role of FUS/TLS in DNA damage response through the characterization of the proteomic profile of SH-SY5Y FUS/TLS iKD cells subjected to DNA damage stress, by mass spectrometry-based quantitative proteomics (e.g. SILAC). Preliminary results of mass spectrometric identification of FUS/TLS interacting proteins in HEK293 cells, expressing a recombinant flag-tagged FUS/TLS protein, highlighted the interactions with several proteins involved in DNA damage response, such as DNA-PK, XRCC-5/-6, and ERCC-6, raising the possibilities that FUS/TLS is involved in this pathway, even thou its exact role still need to be addressed.

Electron and photon energy calibration with the ATLAS detector using LHC Run 1 data

This paper presents the electron and photon energy calibration achieved with the ATLAS detector using about 25 fb−1 of LHC proton–proton collision data taken at centre-of-mass energies of √s = 7 and 8 TeV. The reconstruction of electron and photon energies is optimised using multivariate algorithms. The response of the calorimeter layers is equalised in data and simulation, and the longitudinal profile of the electromagnetic showers is exploited to estimate the passive material in front of the calorimeter and reoptimise the detector simulation. After all corrections, the Z resonance is used to set the absolute energy scale. For electrons from Z decays, the achieved calibration is typically accurate to 0.05% in most of the detector acceptance, rising to 0.2% in regions with large amounts of passive material. The remaining inaccuracy is less than 0.2–1% for electrons with a transverse energy of 10 GeV, and is on average 0.3% for photons. The detector resolution is determined with a relative inaccuracy of less than 10% for electrons and photons up to 60 GeV transverse energy, rising to 40% for transverse energies above 500 GeV.

Risk-conscious Reconstruction in Pakistan-administered Kashmir. A Case Study of the Chakhama Valley

The Chakhama Valley, a remote area in Pakistan-administered Kashmir, was badly damaged by the 7.6-magnitude earthquake that struck India and Pakistan on 8 October 2005. More than 5% of the population lost their lives, and about 90% of the existing housing was irreparably damaged or completely destroyed. In early 2006, the Aga Khan Development Network (AKDN) initiated a multisector, community-driven reconstruction program in the Chakhama Valley on the premise that the scale of the disaster required a response that would address all aspects of people's lives. One important aspect covered the promotion of disaster risk management for sustainable recovery in a safe environment. Accordingly, prevailing hazards (rockfalls, landslides, and debris flow, in addition to earthquake hazards) and existing risks were thoroughly assessed, and the information was incorporated into the main planning processes. Hazard maps, detailed site investigations, and proposals for precautionary measures assisted engineers in supporting the reconstruction of private homes in safe locations to render investments disaster resilient. The information was also used for community-based land use decisions and disaster mitigation and preparedness. The work revealed three main problems: (1) thorough assessment of hazards and incorporation of this assessment into planning processes is time consuming and often little understood by the population directly affected, but it pays off in the long run; (2) relocating people out of dangerous places is a highly sensitive issue that requires the support of clear and forceful government policies; and (3) the involvement of local communities is essential for the success of mitigation and preparedness.

Treatment with the HIV protease inhibitor Nelfinavir triggers the unfolded protein response and may overcome proteasome inhibitor resistance of multiple myeloma in combination with bortezomib: a phase I trial (SAKK 65/08).

Downregulation of the unfolded protein response mediates proteasome inhibitor resistance in Multiple Myeloma.The Human Immunodeficieny Virus protease inhibitor nelfinavir activates the unfolded protein response in vitro. We determined dose limiting toxicity and recommended dose for phase II of nelfinavir in combination with the proteasome inhibitor bortezomib. 12 patients with advanced hematological malignancies were treated with nelfinavir (2500 - 5000 mg/d p.o., d 1-14, 3+3 dose escalation) and bortezomib (1.3 mg/m2, d 1, 4, 8, 11; 21 day cycles). A run in phase with nelfinavir monotherapy allowed pharmakokinetic/pharmakodynamic assessment of nelfinavir in the presence or absence of concomittant bortezomib. Endpoints included dose limiting toxicity, activation of the unfolded protein response, proteasome activity, toxicity and response to trial treatment. Nelfinavir 2 x 2500 mg was the recommended phase II dose identified. Nelfinavir alone significantly upregulated expression of proteins related to the unfolded protein response in peripheral blood mononuclear cells and inhibited proteasome activity. Of 10 evaluable patients in the dose escalation cohort, 3 achieved a partial response, 4 stable disease for ≥ 2 cycles, while 3 had progressive disease as best response. In an exploratory extension cohort with 6 relapsed, bortezomib-refractory, lenalidomide-resistant myeloma patients treated at the recommended phase II dose, 3 reached a partial response, 2 a minor response and one progressive disease. The combination of nelfinavir with bortezomib is safe and shows promising signals for activity in advanced, bortezomib-refractory MM. Induction of the unfolded protein response by nelfinavir may overcome the biological features of proteasome inhibitor resistance. (Trial registration NCT01164709).

The Long-Run Phillips Curve: A Structural VAR Investigation

Both cointegration methods, and non-cointegrated structural VARs identified based on either long-run restrictions, or a combination of long-run and sign restrictions, are used in order to explore the long-run trade-off between inflation and the unemployment rate in the post-WWII U.S., U.K., Euro area, Canada, and Australia. Overall, neither approach produces clear evidence of a non-vertical trade-off. The extent of uncertainty surrounding the estimates is however substantial, thus implying that a researcher holding alternative priors about what a reasonable slope of the long-run trade-off might be will likely not see her views falsified