Time-resolved measurement of interatomic coulombic decay in Ne2.

The lifetime of interatomic Coulombic decay (ICD) [L. S. Cederbaum et al., Phys. Rev. Lett. 79, 4778 (1997)] in Ne2 is determined via an extreme ultraviolet pump-probe experiment at the Free-Electron Laser in Hamburg. The pump pulse creates a 2s inner-shell vacancy in one of the two Ne atoms, whereupon the ionized dimer undergoes ICD resulting in a repulsive Ne+(2p(-1))-Ne+(2p(-1)) state, which is probed with a second pulse, removing a further electron. The yield of coincident Ne+-Ne2+ pairs is recorded as a function of the pump-probe delay, allowing us to deduce the ICD lifetime of the Ne2(+)(2s(-1)) state to be (150±50) fs, in agreement with quantum calculations.

[Detection of colorectal findings for cancer prevention by immunochemical stool test with different sensitivity levels]. / Detektion von kolorektalen Befunden zur Darmkrebsprävention mit immunologischem Stuhltest in verschiedenen Empfindlichkeitsstufen.

Immunochemical stool blood tests have a significantly higher sensitivity for the detection of advanced neoplasia and colorectal cancer. Based on national and international studies it has been required to include them into the national cancer screening programme in Germany also. The sensitivity (detection limit) can be set by the manufacturer in order to achieve an optimal and balanced result between sensitivity and specificity. The present study was conducted with 639 patients who have undergone both the screening colonoscopy, as well as the immunochemical stool blood test. The test "immoCARE-C" provided by the company CARE diagnostica Laborreagenzien GmbH was used in the study. The test has been evaluated with seven levels of detection limits between 500  ng/mL and 25  ng/mL. The best sensitivity for detection of advanced lesions was demonstrated by a cut-off of 50 ng/mL and 25  ng/mL. The specificity did not fall below 90  %. These positive results lead to considerations to organise a primary access to such tests in the prevention of colorectal cancer as a kind of filter before offering the screening colonoscopy.

Decreased insulin secretion and increased risk of type 2 diabetes associated with allelic variations of the WFS1 gene: the Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study.

AIMS/HYPOTHESIS: We investigated associations of allelic variations in the WFS1 gene with insulin secretion and risk of type 2 diabetes in a general population prospective study. METHODS: We studied 5,110 unrelated French men and women who participated in the prospective Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. Additional cross-sectional analyses were performed on 4,472 French individuals with type 2 diabetes and 3,065 controls. Three single nucleotide polymorphisms (SNPs) were genotyped: rs10010131, rs1801213/rs7672995 and rs734312. RESULTS: We observed statistically significant associations between the major alleles of the three variants and prevalent type 2 diabetes in the DESIR cohort at baseline. Cox analyses showed an association between the G-allele of rs10010131 and incident type 2 diabetes (HR 1.34, 95% CI 1.08-1.70, p = 0.007). Similar results were observed for the G-allele of rs1801213 and the A-allele of rs734312. The GGA haplotype was associated with an increased risk of diabetes as compared with the ACG haplotype (HR 1.26, 95% CI 1.04-1.42, p = 0.02). We also observed statistically significant associations of the three SNPs with plasma glucose, HbA(1c) levels and insulin secretion at baseline and throughout the study in individuals with type 2 diabetes or at risk of developing diabetes. However, no association was observed in those who remained normoglycaemic at the end of the follow-up. Associations between the three variants and type 2 diabetes were replicated in cross-sectional studies of type 2 diabetic patients in comparison with a non-diabetic control group. CONCLUSIONS/INTERPRETATION: The most frequent haplotype at the haplotype block containing the WFS1 gene modulated insulin secretion and was associated with an increased risk of type 2 diabetes.

Laser spectroscopy on forbidden transitions in trapped highly charged Ar(13+) ions.

We demonstrate resonant fluorescence laser spectroscopy in highly charged ions (HCI) stored in an electron beam ion trap by investigating the dipole-forbidden 1s(2)2s(2)2p (2)P(3/2)-(2)P(1/2) transition in boronlike Ar(13+) ions. Forced evaporative cooling yielded a high resolving power, resulting in an accurate wavelength determination to λ=441.255 68(26) nm. By applying stronger cooling and two-photon excitation, new optical frequency standards based upon ultrastable transitions in such HCI could be realized in the future, e.g., for the search of time variations of the fine-structure constant.

Suppression of the vacuum space-charge effect in fs-photoemission by a retarding electrostatic front lens.

The performance of time-resolved photoemission experiments at fs-pulsed photon sources is ultimately limited by the e-e Coulomb interaction, downgrading energy and momentum resolution. Here, we present an approach to effectively suppress space-charge artifacts in momentum microscopes and photoemission microscopes. A retarding electrostatic field generated by a special objective lens repels slow electrons, retaining the k-image of the fast photoelectrons. The suppression of space-charge effects scales with the ratio of the photoelectron velocities of fast and slow electrons. Fields in the range from -20 to -1100 V/mm for Ekin = 100 eV to 4 keV direct secondaries and pump-induced slow electrons back to the sample surface. Ray tracing simulations reveal that this happens within the first 40 to 3 µm above the sample surface for Ekin = 100 eV to 4 keV. An optimized front-lens design allows switching between the conventional accelerating and the new retarding mode. Time-resolved experiments at Ekin = 107 eV using fs extreme ultraviolet probe pulses from the free-electron laser FLASH reveal that the width of the Fermi edge increases by just 30 meV at an incident pump fluence of 22 mJ/cm2 (retarding field -21 V/mm). For an accelerating field of +2 kV/mm and a pump fluence of only 5 mJ/cm2, it increases by 0.5 eV (pump wavelength 1030 nm). At the given conditions, the suppression mode permits increasing the slow-electron yield by three to four orders of magnitude. The feasibility of the method at high energies is demonstrated without a pump beam at Ekin = 3830 eV using hard x rays from the storage ring PETRA III. The approach opens up a previously inaccessible regime of pump fluences for photoemission experiments.

The TRIXS end-station for femtosecond time-resolved resonant inelastic x-ray scattering experiments at the soft x-ray free-electron laser FLASH.

We present the experimental end-station TRIXS dedicated to time-resolved soft x-ray resonant inelastic x-ray scattering (RIXS) experiments on solid samples at the free-electron laser FLASH. Using monochromatized ultrashort femtosecond XUV/soft x-ray photon pulses in combination with a synchronized optical laser in a pump-probe scheme, the TRIXS setup allows measuring sub-picosecond time-resolved high-resolution RIXS spectra in the energy range from 35 eV to 210 eV, thus spanning the M-edge (M1 and M2,3) absorption resonances of 3d transition metals and N4,5-edges of rare earth elements. A Kirkpatrick-Baez refocusing mirror system at the first branch of the plane grating monochromator beamline (PG1) provides a focus of (6 × 6) µm2 (FWHM) at the sample. The RIXS spectrometer reaches an energy resolution of 35-160 meV over the entire spectral range. The optical laser system based on a chirped pulse optical parametric amplifier provides approximately 100 fs (FWHM) long photon pulses at the fundamental wavelength of 800 nm and a fluence of 120 mJ/cm2 at a sample for optical pump-XUV probe measurements. Furthermore, optical frequency conversion enables experiments at 400 nm or 267 nm with a fluence of 80 and 30 mJ/cm2, respectively. Some of the first (pump-probe) RIXS spectra measured with this setup are shown. The measured time resolution for time-resolved RIXS measurements has been characterized as 287 fs (FWHM) for the used energy resolution.

Time- and momentum-resolved photoemission studies using time-of-flight momentum microscopy at a free-electron laser.

Time-resolved photoemission with ultrafast pump and probe pulses is an emerging technique with wide application potential. Real-time recording of nonequilibrium electronic processes, transient states in chemical reactions, or the interplay of electronic and structural dynamics offers fascinating opportunities for future research. Combining valence-band and core-level spectroscopy with photoelectron diffraction for electronic, chemical, and structural analyses requires few 10 fs soft X-ray pulses with some 10 meV spectral resolution, which are currently available at high repetition rate free-electron lasers. We have constructed and optimized a versatile setup commissioned at FLASH/PG2 that combines free-electron laser capabilities together with a multidimensional recording scheme for photoemission studies. We use a full-field imaging momentum microscope with time-of-flight energy recording as the detector for mapping of 3D band structures in (kx, ky, E) parameter space with unprecedented efficiency. Our instrument can image full surface Brillouin zones with up to 7 Å-1 diameter in a binding-energy range of several eV, resolving about 2.5 × 105 data voxels simultaneously. Using the ultrafast excited state dynamics in the van der Waals semiconductor WSe2 measured at photon energies of 36.5 eV and 109.5 eV, we demonstrate an experimental energy resolution of 130 meV, a momentum resolution of 0.06 Å-1, and a system response function of 150 fs.

Winteraceous pollen in the lower cretaceous of Israel: early evidence of a magnolialean angiosperm family.

Pollen of the primitive angiosperm family Winteraceae has been discovered in the Aptian-Albian of Israel, extending the fossil record of this phylogenetically important family of flowering plants from the uppermost Upper Cretaceous back some 40 million years to the upper Lower Cretaceous. This appears to represent the earliest known record of a magnolialean angiosperm family and is convincing evidence for the existence in the Early Cretaceous of an extant family of angiosperms.

Non-linear soft x-ray methods on solids with MUSIX-the multi-dimensional spectroscopy and inelastic x-ray scattering endstation.

With the intense and coherent x-ray pulses available from free-electron lasers, the possibility to transfer non-linear spectroscopic methods from the laser lab to the x-ray world arises. Advantages especially regarding selectivity and thus information content as well as an improvement of signal levels are expected. The use of coherences is especially fruitful and the example of coherent x-ray/optical sum-frequency generation is discussed. However, many non-linear x-ray methods still await discovery, partially due to the necessity for extremely adaptable and versatile instrumentation that can be brought to free-electron lasers for the analysis of the spectral content emitted from the sample into a continuous range of emission angles. Such an instrument (called MUSIX) is being developed and employed at FLASH, the free-electron laser in Hamburg and is described in this contribution together with first results.

Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity.

We investigated the involvement of extracellular signal-regulated protein kinases (ERK) within spinal neurons in producing pain hypersensitivity. Within a minute of an intense noxious peripheral or C-fiber electrical stimulus, many phosphoERK-positive neurons were observed, most predominantly in lamina I and IIo of the ipsilateral dorsal horn. This staining was intensity and NMDA receptor dependent. Low-intensity stimuli or A-fiber input had no effect. Inhibition of ERK phosphorylation by a MEK inhibitor reduced the second phase of formalin-induced pain behavior, a measure of spinal neuron sensitization. ERK signaling within the spinal cord is therefore involved in generating pain hypersensitivity. Because of its rapid activation, this effect probably involves regulation of neuronal excitability without changes in transcription.

Human mesenchymal stromal cells inhibit platelet activation and aggregation involving CD73-converted adenosine.

BACKGROUND: Mesenchymal stromal cells (MSCs) are promising cell therapy candidates. Clinical application is considered safe. However, minor side effects have included thromboembolism and instant blood-mediated inflammatory reactions suggesting an effect of MSC infusion on hemostasis. Previous studies focusing on plasmatic coagulation as a secondary hemostasis step detected both procoagulatory and anticoagulatory activities of MSCs. We now focus on primary hemostasis and analyzed whether MSCs can promote or inhibit platelet activation. METHODS: Effects of MSCs and MSC supernatant on platelet activation and function were studied using flow cytometry and further platelet function analyses. MSCs from bone marrow (BM), lipoaspirate (LA) and cord blood (CB) were compared to human umbilical vein endothelial cells or HeLa tumor cells as inhibitory or activating cells, respectively. RESULTS: BM-MSCs and LA-MSCs inhibited activation and aggregation of stimulated platelets independent of the agonist used. This inhibitory effect was confirmed in diagnostic point-of-care platelet function analyses in platelet-rich plasma and whole blood. Using inhibitors of the CD39-CD73-adenosine axis, we showed that adenosine produced by CD73 ectonucleotidase activity was largely responsible for the LA-MSC and BM-MSC platelet inhibitory action. With CB-MSCs, batch-dependent responses were obvious, with some batches exerting inhibition and others lacking this effect. CONCLUSIONS: Studies focusing on plasmatic coagulation suggested both procoagulatory and anticoagulatory activities of MSCs. We now show that MSCs can, dependent on their tissue origin, inhibit platelet activation involving adenosine converted from adenosine monophosphate by CD73 ectonucleotidase activity. These data may have strong implications for safety and risk/benefit assessment regarding MSCs from different tissue sources and may help to explain the tissue protective mode of action of MSCs. The adenosinergic pathway emerges as a key mechanism by which MSCs exert hemostatic and immunomodulatory functions.

Prevalence of risk factors of coronary heart disease in Turks living in Germany: The Giessen Study.

Turkish people represent the majority of immigrants in Germany. Even though a high proportion of Turks has been living in Germany since about 20 years, little is known about risk factors of coronary heart disease (CHD) in this population. In this study a sample of 325 male and 155 female Turks are investigated, who voluntarily underwent a health check-up in Germany. Data about the presence of CHD, risk factors and blood parameters were collected. Mean residence time was 21 and 17 years (males/females). A low percentage of female participants was observed compared to the general Turkish population in Germany. Age adjusted prevalence of CHD reached 9.5% in males and 6.7% in females, respectively. Dyslipoproteinemia (DLP) showed the highest prevalence of all risk factors investigated in both genders. Total cholesterol (TC) levels were comparable to those of other western countries and remarkably higher than reported for the population in Turkey. Besides this, low high density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-I (ApoA-I) levels could be found in the majority of the sample. The highest odds ratios for CHD were estimated for stress and hypertension in males and obesity in females. It is concluded that Turkish immigrants in Germany showed an assimilation of lipid pattern to western populations. However, reasons for low HDL-C levels remain unclear. Changes in the lipid metabolism chiefly seem to contribute to the risk factor pattern of Turkish immigrants in Germany.

Sympathetic nervous system modulation of tumor metastases and host defense mechanisms.

The sympathetic nervous system can signal cells of the immune system through release of norepinephrine (NE), and may thus modulate several aspects of immune reactivity. We have examined the consequences of chemical denervation using 6-hydroxydopamine (6-OHDA) on the response of BALB/c mice to tumor cell challenge. In this study, chemical axotomy prior to the intravenous (i.v.) injection of the alveolar carcinoma line 1 significantly increased the number of pulmonary metastases. In contrast, axotomy performed after i.v. injection of tumor cells had no effect on the number of lung metastases. Line 1 tumor cells have been reported to be susceptible to lysis by natural killer (NK) cells. To examine possible mechanisms through which prior axotomy leads to increased lung metastases, we tested the effects of axotomy on in vitro and in vivo NK cell activity. No differences in NK cell activity were found between 6-OHDA- and vehicle-treated mice. Line 1 tumor cell growth in vitro was unaffected by both 6-OHDA and NE, and the tumor cells do not express beta-adrenergic receptors. Priming mice with lethally irradiated line 1 cells significantly reduced the number of lung metastases following challenge with live tumor cells; axotomy did not alter this decrease in metastases associated with priming. In summary, chemical axotomy of mice prior to injection of alveolar carcinoma cells resulted in an increased number of pulmonary metastases that was not correlated with alterations in either NK cell cytotoxicity or the putative immunological consequences of in vivo priming.

Sympathetic nervous system modulation of the immune system. III. Alterations in T and B cell proliferation and differentiation in vitro following chemical sympathectomy.

Functional changes in lymph node (LN) and spleen lymphocytes were examined following sympathetic denervation of adult mice with 6-hydroxydopamine (6-OHDA). Sympathectomy reduced in vitro proliferation to concanavalin A (ConA) by LN cells and decreased LN Thy-1+ and CD4+ T cells. At the same time, ConA-induced interferon-gamma (IFN-gamma) production was increased, but interleukin-2 (IL-2) production was not altered. After sympathectomy, lipopolysaccharide (LPS)-stimulated proliferation of LN B cells was enhanced, in parallel with an increase in the proportion of sIgM+ cells. LPS-induced polyclonal IgM secretion was decreased, whereas polyclonal IgG secretion was dramatically enhanced. In the spleen, ConA and LPS responsiveness was reduced after sympathectomy, as was IL-2 and IFN-gamma production. The decreased proliferation was not associated with changes in splenic T and B cell populations. The uptake blocker desipramine prevented the 6-OHDA-induced changes in spleen and LN, indicating that these alterations were dependent upon neuronal destruction. These results provide evidence for heterogeneity of sympathetic nervous system regulation of T and B lymphocyte function and for organ-specific influences on immune function.

Spinal administration of adrenergic agents produces analgesia in amphibians.

Direct intraspinal injection of the catecholamines epinephrine and norepinephrine, and the alpha-adrenergic agents dexmedetomidine and clonidine, produced a dose-dependent elevation of pain thresholds in the Northern grass frog, Rana pipiens. Significant analgesic effects were noted for at least 4 h. The analgesic effect of intraspinal dexmedetomidine or epinephrine was blocked by systemic pretreatment with the alpha 2-adrenoceptor antagonists, yohimbine and atipamezole, but not with the alpha 1-adrenoceptor antagonist, prazosin. Dose-response analyses showed that dexmedetomidine, epinephrine, norepinephrine had similar analgesic potencies, but clonidine was significantly less potent. Analgesia was observed without accompanying motor or sedative effects. These results suggest that alpha 2-adrenoceptor mechanisms which mediate analgesia may have evolved early in vertebrate evolution and that descending epinephrine-containing fibers in the amphibian nervous system may be the source of endogenous catecholamines regulating nociceptive sensitivity in the amphibian spinal cord.

Increased pulmonary metastases and natural killer cell activity in mice following handling.

We have demonstrated that holding BALB/c female mice for two minutes per day for two weeks prior to injection of line 1, a BALB/c derived alveolar carcinoma, results in a significant increase in pulmonary metastases compared to unhandled controls. Handling did not affect splenic in vitro or in vivo natural killer (NK) cell activity but, surprisingly, was associated with increased NK cell activity in the lungs of these handled mice. These results demonstrate that a simple psychosocial manipulation may effect the metastatic process. The implications of these findings and potential mechanisms are discussed.

The effects of handling on antibody production, mitogen responses, spleen cell number, and lymphocyte subpopulations.

The effects of a simple psychosocial manipulation, handling, on immune function in BALB/c.ByJ mice were studied. Handling for two minutes/day prior to immunization was shown to be associated with a decreased primary IgG antibody response to the protein antigen keyhole limpet hemocyanin. Handling was also associated with decreased T cell proliferative responses to Concanavalin A. No reliable changes in spleen cell number or lymphocyte subsets were found. These findings demonstrate that simply picking up an animal results in modulation of the immune response. These data are also of interest for their obvious methodological implications.

Cefoxitin sodium: solution and solid-state chemical stability studies.

Studies were undertaken to provide the basic physicochemical information necessary for preparing a suitable parenteral formulation of cefoxitin sodium. Emphasis was placed on the physico-chemical properties of the compound in solution and in the solid state. Cefoxitin sodium is very soluble in water and exhibits apparent first-order decomposition in this medium at pH 3-9. Maximum stability in water is at pH 5-7. Under these pH conditions, cefoxitin sodium loses about 10% of its activity in 2 days at 25 degrees. Thermal decomposition rates for amorphous and crystalline cefoxitin sodium samples were determined. Amorphous cefoxitin sodium was considerably less stable than its corresponding crystalline form. Solid-state decomposition plots are biphasic, displaying initial rapid losses followed by a slower decay period. The extent of loss in the crystalline solid at the end of the more rapid initial phase can be correlated with the water content of the solid.

Physician and other ambulatory care services in Germany.

The Germany multipayer universal health insurance plan in 1992 consumed 8.7% of its nation's total expenditures. Nevertheless, its macromanaged approach has allowed until recently for pluralism, decentralization, and self-regulation among providers and sickness funds (not-for-profit, third party payers). With 34.8% more physicians per 1,000 persons, German doctors provided twice as many patient contacts per capita than in the United States. Due to economic constraints and increases in payroll taxes, the Federal Republic of Germany's parliament, with its 1993 health reform plan, virtually froze all payments to providers for a 3-year period. Among other contentious provisions were the following: (1) limiting the entry of new physicians into municipalities that are considered by government health manpower planning experts to be oversupplied in that specialty; (2) requiring community-based physicians to participate in controlling pharmaceutical costs; and (3) eliminating some of the German traditional barriers between their in- and out-of-hospital physicians. This article focuses on how the Germans now micromanage their physician and other ambulatory care services within a macromanaged system that, in terms of patient access, benefits, quality, and cost, should be the envy of the Americans.

Importing budget systems from other countries: what can we learn from the German drug budget and the British GP fundholding?

The rising costs of pharmaceutical expenditures are a common problem for policy makers in most European countries. In two countries, budget systems for pharmaceutical spending exist(ed). In Great Britain, between 1991 and 1999 GP fundholders were responsible for prescribing costs, and in Germany an overall expenditure cap for pharmaceutical prescribing has been used since 1993. These two examples are analysed in order to identify the conditions that are needed for successfully implementing budget systems for prescribing costs in other countries. It is argued, that a good budget system balances the provision of enough information for budget holders to monitor their expenditures on the one hand, against an explosive increase of transaction costs on the other hand. Apart from that, it makes doctors responsible only for expenditures that they themselves can actually control, and does not provide them with an incentive to use that discretionary power by shifting expenditures to other health care sectors. A good information infrastructure is needed for the implementation of budget systems in general. For the introduction of fundholding, a number of additional criteria need to be met, such as having gate-keeping GPs with personal lists and having a single-payer system.