Directed, Elliptic, and Higher Order Flow Harmonics of Protons, Deuterons, and Tritons in Au+Au Collisions at sqrt[s_{NN}]=2.4 GeV.

Flow coefficients v_{n} of the orders n=1-6 are measured with the High-Acceptance DiElectron Spectrometer (HADES) at GSI for protons, deuterons, and tritons as a function of centrality, transverse momentum, and rapidity in Au+Au collisions at sqrt[s_{NN}]=2.4 GeV. Combining the information from the flow coefficients of all orders allows us to construct for the first time, at collision energies of a few GeV, a multidifferential picture of the angular emission pattern of these particles. It reflects the complicated interplay between the effect of the central fireball pressure on the emission of particles and their subsequent interaction with spectator matter. The high precision information on higher order flow coefficients is a major step forward in constraining the equation of state of dense baryonic matter.

Strong Absorption of Hadrons with Hidden and Open Strangeness in Nuclear Matter.

We present the first observation of K^{-} and ϕ absorption within nuclear matter by means of π^{-}-induced reactions on C and W targets at an incident beam momentum of 1.7 GeV/c studied with HADES at SIS18/GSI. The double ratio (K^{-}/K^{+})_{W}/(K^{-}/K^{+})_{C} is found to be 0.319±0.009(stat)_{-0.012}^{+0.014}(syst) indicating a larger absorption of K^{-} in heavier targets as compared to lighter ones. The measured ϕ/K^{-} ratios in π^{-}+C and π^{-}+W reactions within the HADES acceptance are found to be equal to 0.55±0.04(stat)_{-0.07}^{+0.06}(syst) and to 0.63±0.06(stat)_{-0.11}^{+0.11}(syst), respectively. The similar ratios measured in the two different reactions demonstrate for the first time experimentally that the dynamics of the ϕ meson in nuclear medium is strongly coupled to the K^{-} dynamics. The large difference in the ϕ production off C and W nuclei is discussed in terms of a strong ϕN in-medium coupling. These results are relevant for the description of heavy-ion collisions and the structure of neutron stars.

Anti-FcγRIIB (CD32) Antibodies Differentially Modulate Murine FVIII-Specific Recall Response in vitro.

Fc gamma receptors (FcγRs) for IgG regulate adaptive immune responses by modulating activating and inhibitory signalling pathways within immune cells. Data from a haemophilia A mouse model demonstrate that genetic deletion or blockade of the inhibitory FcγR (CD32) suppresses the formation of antibody-secreting cells (ASCs) in vitro. Mechanisms preventing the FVIII-specific recall response, however, remain unclear. Here, the potential role of CD32 inhibition was studied by differentially modulating receptor activity with selected anti-CD32 monoclonal antibodies (mAbs). Splenocytes from immunized FVIII-/- mice were restimulated with FVIII in the absence or presence of different anti-CD32 mAbs over 6 days. At day 6, cytokine release was quantified from cell culture supernatant and the formation of FVIII-specific ASCs assessed. Binding of FVIII-containing immune complexes (F8-ICs) to bone marrow-derived dendritic cells (BMdDCs) was also investigated. The antagonistic CD32 mAb AT128 suppressed the formation of FVIII-specific ASCs and reduced secretion of IFN-γ and IL-10. In contrast, the agonistic mAbs AT130-2 and AT130-5, and their F(ab')2 fragments, allowed the formation of FVIII-specific ASCs, even though the full IgG of AT130-2 reduced binding of F8-ICs to CD32. Data suggest that an inhibitory signal is transmitted when F8-ICs bind to CD32 and that this signal is required during memory B cell (MBC) activation to support formation of FVIII-specific ASCs. If the inhibitory signal is lacking due to CD32 deletion or blockade with antagonistic anti-CD32 mAbs, FVIII-specific T cell stimulation and ASC formation are suppressed, whereas agonistic stimulation of CD32 restores T cell stimulation and ASC formation.

Subthreshold Ξ

Results on the production of the double strange cascade hyperon Ξ^{-} are reported for collisions of p(3.5 GeV)+Nb, studied with the High Acceptance Di-Electron Spectrometer (HADES) at SIS18 at GSI Helmholtzzentrum for Heavy-Ion Research, Darmstadt. For the first time, subthreshold Ξ^{-} production is observed in proton-nucleus interactions. Assuming a Ξ^{-} phase-space distribution similar to that of Λ hyperons, the production probability amounts to P_{Ξ^{-}}=[2.0±0.4(stat)±0.3(norm)±0.6(syst)]×10^{-4} resulting in a Ξ^{-}/(Λ+Σ^{0}) ratio of P_{Ξ^{-}}/P_{Λ+Σ^{0}}=[1.2±0.3(stat)±0.4(syst)]×10^{-2}. Available model predictions are significantly lower than the measured Ξ^{-} yield.

Analysis of 161Tb by radiochemical separation and liquid scintillation counting.

The determination of 161Tb activity is problematic due to its very low fission yield, short half-life, and the complication of its gamma spectrum. At AWE, radiochemically purified 161Tb solution was measured on a PerkinElmer 1220 QuantulusTM Liquid Scintillation Spectrometer. Since there was no 161Tb certified standard solution available commercially, the counting efficiency was determined by the CIEMAT/NIST Efficiency Tracing method. The method was validated during a recent inter-laboratory comparison exercise involving the analysis of a uranium sample irradiated with thermal neutrons. The measured 161Tb result was in excellent agreement with the result using gamma spectrometry and the result obtained by Pacific Northwest National Laboratory.

Hepatic failure after injury - a common pathogenesis with sclerosing cholangitis?

OBJECTIVE: Hepatic failure after trauma occurs in about 5 - 10 % of multiple injured patients. Mortality rate remains high and liver dysfunction might deteriorate to complete liver failure and contribute to multi organ failure (MOF). Pathogenesis is multifactorial and distinct mechanisms are unknown. METHODS: To get further knowledge about pathogenesis of posttraumatic liver failure we investigated clinical course, inflammatory mediators, ERCP and histologic findings in 7 patients [6 male, 1 female, mean age 45.7 +/- 12.1 years, mean ISS 38.4 +/- 10.8 pts. (range 25-58 pts.)] that evolved hepatic failure after major trauma. Mortality rate was 14 %. RESULTS: All patients presented with a prolonged shock period after trauma and severe respiratory failure requiring differentiated ventilatory support and prone positioning. Onset of significant bilirubinemia (> 2.0 mg/dl) was day 3 to 16 days (median 11 days) after trauma. Past medical history did not reveal any underlying liver disease in all patients. Pro-and anti-inflammatory parameters like WBC, Procalcitonin, IL-4, IL-10, IL-11, IL-12, and IL-18 remained close to healthy control values. CRP was elevated but did not correlate with Bilirubin. Transaminases (ALT, AST) remained close to normal values but increased during the further course, whereas alkaline phosphatase (aP) and gamma-glutamyl transpeptidase (gGT) were already significantly elevated even before Bilirubin (gammaGT: 394 +/- 317 U/l; controls: < 56 U/l; aP 557 +/- 311 U/l; controls: < 127 U/l). Although no cholestasis was proven in ultrasound and CT investigations, all patients underwent ERCP and liver biopsy. Here, all patients presented uniform signs of multiple strictures of the intrahepatic bile ducts and sclerosing cholangitis. CONCLUSIONS: Our data provide evidence that sclerosing cholangitis contributes to liver failure after trauma. The pathomorphologic picture can not distinguish between shock liver and sclerosing cholangitis. Ischemia during posttraumatic shock might be an early trigger of hepatic failure, supported by further contributing factors such as catecholamines, parenteral nutrition, and bacterial translocation. As specific therapy for sclerosing cholangitis does not exist yet, prevention of triggers is central to avoid progressive hepatic failure in those patients. Further prospective studies have to prove whether sclerosing cholangitis is commonly involved in the pathogenesis of liver failure after trauma and shock. If so, one might speculate that early therapy with ursodeoxycholic acid might be effective thus reducing incidence and/or severity of hepatic failure in the future.

Estimation of the mortality risk of surgical intensive care patients based on routine laboratory parameters.

BACKGROUND: In established risk score models the collection and documentation of clinical data is time-consuming, causes labor-related costs, and is dependent on the examiner. MATERIAL AND METHODS: Based on low-cost laboratory parameters that are routinely measured at admission to the intensive care unit, a new score was developed (n = 271, study sample) and validated in an independent group of patients (n = 283, validation sample). Parameters were selected by a stepwise logistic regression analysis. This new score was compared to established risk models (APACHE II, SAPS II). RESULTS: Mean age was 61.3 +/- 1.2 years (study sample) and 63.1 +/- 1.1 years (validation sample), respectively. In-hospital mortality was 24.7% (67/271, study sample) and 23.3% (66/283, validation sample). The following parameters were used to build the new score called Dense Laboratory Whole Blood Applied Risk Estimation (DELAWARE): alanine aminotransferase, C-reactive protein, cholesterol, creatine kinase MB, leukocytes, potassium, thrombocytes, triglycerides, and age. The areas under the curves were 0.853/0.813 (study sample/validation sample). In the study sample DELAWARE correlated with APACHE II (r = 0.586) and SAPS II (r = 0.614; p < 0.001), respectively. CONCLUSIONS: A general admission risk score for surgical intensive care patients solely based on quality controlled low-cost routine laboratory parameters is feasible.

Anticonvulsive action of (+/-)-kavain estimated from its properties on stimulated synaptosomes and Na+ channel receptor sites.

Kava pyrones are constituents of the intoxicating pepper (Piper methysticum Forst), which has been shown to be anticonvulsive. The question of how the excitability of neurons is affected was investigated by determining the interaction of (+/-)-kavain with epitopes (site 1, site 2) of voltage-dependent Na+ channels and the action of (+/-)-kavain on 4-aminopyridine-stimulated synaptosomes as model of repetitive firing neurons. [3H]Saxitoxin and [3H]batrachotoxin were used for radioligand-binding assays performed with synaptosomal membranes. Gultamate released from 4-aminopyridine-stimulated cerebrocortical synaptosomes and the cytosolic concentrations of Na+ and Ca2+ ([Na+]i, [Ca+]i) were detected fluorometrically by using an enzyme-linked assay, sodium-binding benzofuranisophthalate (SBFI) and Fura-2, respectively. (+/-)-Kavain failed to compete with [3H]saxitoxin up to 400 mumol/l but dose-dependently suppressed binding of [3H]batrachotoxin with an IC50 value of 88 mumol/l (Ki = 72 mumol/l) although displacement of [3H]batrachotoxin was restricted to 33% of control at 400 mumol/l (+/-)-kavain. In stimulated synaptosomes, 5 mmol/l 4-aminopyridine provoked an increase in [Na+]i and [Ca2+]i by 9 mmol/l Na+ and 235 nmol/l Ca2+. Comparable to the reduction in [3H]batrachotoxin binding, 400 mumol/l (+/-)-kavain suppressed the increase in [Na+]i and [Ca2+]i to 38 and 29% of control, respectively. Consistent with the increase in [Na+]i and [Ca2+]i, 5 mmol/l 4-aminopyridine provoked glutamate release (rate: 38 pmol/s*mg protein) which was dose-dependently diminished to 60% of control by 400 mumol/l (+/-)-kavain. KCl depolarization (40 mmol/l) provoked an increase in [Ca2+]i and glutamate release almost identical to the responses elicited by 4-aminopyridine but 400 mumol/l (+/-)-kavain suppressed only the rate of glutamate release by 9% of control. The data suggest an interaction of (+/-)-kavain with voltage-dependent Na+ and Ca2+ channels, thereby suppressing the 4-aminopyridine-induced increase in [Na+]i, [Ca2+]i and the release of endogenous glutamate.

Aconitum sp. alkaloids: the modulation of voltage-dependent Na+ channels, toxicity and antinociceptive properties.

Alkaloids from Aconitum sp., used as analgesics in traditional Chinese medicine, were investigated to elucidate their antinociceptive and toxic properties considering: (1) binding to Na+ channel epitope site 2, (2) alterations in synaptosomal Na+ and Ca2+ concentration ([Na+]i, [Ca2+]i), (3) arrhythmogenic action of isolated atria, (4) antinociceptive and (5) acute toxic action in mice. The study revealed a high affinity group (Ki 1 microM) and a low affinity group (Ki 10 microM) of alkaloids binding to site 2. The compounds of the high affinity group induce an increase in synaptosomal [Na+]i and [Ca2+]i (EC50 3 microM), are antinociceptive (ED50, 25 microg/kg), provoke tachyarrhythmia and are highly toxic (LD50 70 microg/kg), whereas low affinity alkaloids reduce [Ca2+]i, induce bradycardia and are less antinociceptive (ED50 20 mg/kg) and less toxic (LD50 30 mg/kg). These results suggest that the alkaloids can be grouped in Na+ channel activating and blocking compounds, but none of the alkaloids seem to be suitable as analgesics because of the low LD50/ED50 values.

Mode of antinociceptive and toxic action of alkaloids of Aconitum spec..

Extracts of the plant Aconitum spec. are used in traditional Chinese medicine predominantly as anti-inflammatory and analgesic agents, the latter allegedly equally potent as morphine but without any habit-forming potential. As the only pharmacologically active compounds, the C19 diterpenoid alkaloid aconitine, and some of its derivatives, have been proven to be antinociceptive in different analgesic assays, but the mode of action is unknown. To elucidate the mode of action, ten aconitine-like derivatives were investigated with respect to their affinity for voltage-dependent Na+ channels, the action on synaptosomal Na+ and Ca2+ homoeostasis and their antinociceptive, arrhythmogenic and acute toxic properties. Since aconitine is known to bind to site II of Na+ channels, we determined the affinity of the aconitine-like derivatives in vitro to synaptosomal membranes by the [3H]-batrachotoxinin-binding assay and their properties on intrasynaptosomal concentrations of free Na+ and Ca2+ ([Na+]i and [Ca2+]i), both the latter determined fluorometrically with SBFI and Fura-2 respectively. Furthermore, the alkaloids' arrhythmogenic potential was investigated in guinea-pig isolated atria and the antinociceptive action on formalin-induced hyperalgesia and the acute toxic action estimated in mice. The results show that the alkaloids could be divided into at least three groups. The first is characterized by a high affinity to the site II of Na+ channels (Ki about 1.2 microM), the ability to enhance [Na+]i and [Ca2+]i (EC50 about 3 microM), a strong arrhythmogenic action that starts at about 30 nM, an antinociceptive effect (ED50 about 0.06 mg/kg) and high acute toxicity (LD50 values about 0.15 mg/kg). To this group belong aconitine, 3-acetylaconitine and hypaconitine. The second group, with lappaconitine as the only member, has an affinity to Na+ channels an order of magnitude lower (Ki = 11.5 microM), less acute toxicity (LD50 about 5 mg/kg), and a two orders of magnitude lower antinociceptive action (ED50 about 2.8 mg/kg) and lower cardiotoxicity (bradycardia observed at 3 microM). Additionally, lappaconitine suppresses the increase in [Ca2+]i of aconitine-stimulated synaptosomes and increases the excitation threshold of left atria, indicating an inhibition of Na+ channels. The other derivatives, i.e. delcorine, desoxydelcorine, karakoline, lappaconidine, lappaconine and lycoctonine, belong to the third group, which has hardly any effects. They have a low affinity to Na+ channels with Ki values in the millimolar range, show no effect on synaptosomal [Na+]i and [Ca2+]i, no arrhythmogenic potential up to 100 microM, no antinociceptive activity and low toxicity with LD50 values greater than 50 mg/kg. For the investigated alkaloids we suggest two different antinociceptive-like modes of action. Aconitine, hypaconitine and 3-acetylaconitine may induce a block of neuronal conduction by a permanent cell depolarisation, whereas lappaconitine might act like local anaesthetics. However, because of the low LD50/ED30 quotients of 2-6, the antinociceptive-like action of the Aconitum alkaloids seems to reflect severe intoxication rather than a specific antinociceptive action. The structure/activity relationship shows that alkaloids that activate or block Na+ channels have a benzoyl ester side chain in the C-14 or C-4 positions respectively, whereas the other compounds lack this group.

Development of the Abbott AxSYM Free PSA assay: performance characteristics and preliminary clinical evaluation.

The AxSYM Free PSA assay was demonstrated to have good analytical sensitivity and reproducibility. The F/T ratio determinations for 385 men tested during the Prostate Awareness Week who had biopsies due to an elevated total PSA value and/or a suspicious DRE demonstrated that the percentage of free PSA was lower in patients found to have prostate cancer than those that were biopsy negative for the overall group and for all patient categories examined. The optimal strategy for combining PSA values, F/T ratios, DRE and other clinical and diagnostic parameters to improve the early detection of prostate cancer requires additional clinical studies.

Potential impact of releases from a new molybdenum-99 production facility on regional measurements of airborne xenon isotopes.

The monitoring of the radioactive xenon isotopes (131m)Xe, (133)Xe, (133m)Xe, and (135)Xe is important for the detection of nuclear explosions. While backgrounds of the xenon isotopes are short-lived, they are constantly replenished from activities dominated by the fission-based production of (99)Mo used for medical procedures. At present, one of the most critical locations on earth for the monitoring of nuclear explosions is the Korean peninsula where the Democratic People's Republic of Korea (DPRK) has announced that it conducted three nuclear tests between 2006 and 2013. This paper explores the backgrounds that would be caused by the medium to large scale production of (99)Mo in the region of the Korean peninsula.

Analysis of data from sensitive U.S. monitoring stations for the Fukushima Dai-ichi nuclear reactor accident.

The March 11, 2011 9.0 magnitude undersea megathrust earthquake off the coast of Japan and subsequent tsunami waves triggered a major nuclear event at the Fukushima Dai-ichi nuclear power station. At the time of the event, units 1, 2, and 3 were operating and units 4, 5, and 6 were in a shutdown condition for maintenance. Loss of cooling capacity to the plants along with structural damage caused by the earthquake and tsunami resulted in a breach of the nuclear fuel integrity and release of radioactive fission products to the environment. Fission products started to arrive in the United States via atmospheric transport on March 15, 2011 and peaked by March 23, 2011. Atmospheric activity concentrations of (131)I reached levels of 3.0×10(-2) Bqm(-3) in Melbourne, FL. The noble gas (133)Xe reached atmospheric activity concentrations in Ashland, KS of 17 Bqm(-3). While these levels are not health concerns, they were well above the detection capability of the radionuclide monitoring systems within the International Monitoring System of the Comprehensive Nuclear-Test-Ban Treaty.

Deep subthreshold Xi;{-} production in Ar + KCl reactions at 1.76A GeV.

We report first results on a deep subthreshold production of the doubly strange hyperon Xi;{-} in a heavy-ion reaction. At a beam energy of 1.76A GeV the reaction Ar + KCl was studied with the High Acceptance Di-Electron Spectrometer at SIS18/GSI. A high-statistics and high-purity Lambda sample was collected, allowing for the investigation of the decay channel Xi;{-} --> Lambdapi;{-}. The deduced Xi;{-}/(Lambda + Sigma;{0}) production ratio of (5.6 +/- 1.2_{-1.7};{+1.8}) x 10;{-3} is significantly larger than available model predictions.