High-Precision Determination of Oxygen K_{α} Transition Energy Excludes Incongruent Motion of Interstellar Oxygen.

We demonstrate a widely applicable technique to absolutely calibrate the energy scale of x-ray spectra with experimentally well-known and accurately calculable transitions of highly charged ions, allowing us to measure the K-shell Rydberg spectrum of molecular O_{2} with 8 meV uncertainty. We reveal a systematic ∼450 meV shift from previous literature values, and settle an extraordinary discrepancy between astrophysical and laboratory measurements of neutral atomic oxygen, the latter being calibrated against the aforementioned O_{2} literature values. Because of the widespread use of such, now deprecated, references, our method impacts on many branches of x-ray absorption spectroscopy. Moreover, it potentially reduces absolute uncertainties there to below the meV level.

An unexpectedly low oscillator strength as the origin of the Fe XVII emission problem.

Highly charged iron (Fe(16+), here referred to as Fe XVII) produces some of the brightest X-ray emission lines from hot astrophysical objects, including galaxy clusters and stellar coronae, and it dominates the emission of the Sun at wavelengths near 15 ångströms. The Fe XVII spectrum is, however, poorly fitted by even the best astrophysical models. A particular problem has been that the intensity of the strongest Fe XVII line is generally weaker than predicted. This has affected the interpretation of observations by the Chandra and XMM-Newton orbiting X-ray missions, fuelling a continuing controversy over whether this discrepancy is caused by incomplete modelling of the plasma environment in these objects or by shortcomings in the treatment of the underlying atomic physics. Here we report the results of an experiment in which a target of iron ions was induced to fluoresce by subjecting it to femtosecond X-ray pulses from a free-electron laser; our aim was to isolate a key aspect of the quantum mechanical description of the line emission. Surprisingly, we find a relative oscillator strength that is unexpectedly low, differing by 3.6σ from the best quantum mechanical calculations. Our measurements suggest that the poor agreement is rooted in the quality of the underlying atomic wavefunctions rather than in insufficient modelling of collisional processes.

X-ray resonant photoexcitation: linewidths and energies of Kα transitions in highly charged Fe ions.

Photoabsorption by and fluorescence of the Kα transitions in highly charged iron ions are essential mechanisms for x-ray radiation transfer in astrophysical environments. We study photoabsorption due to the main Kα transitions in highly charged iron ions from heliumlike to fluorinelike (Fe24+ to Fe17+) using monochromatic x rays around 6.6 keV at the PETRA III synchrotron photon source. Natural linewidths were determined with hitherto unattained accuracy. The observed transitions are of particular interest for the understanding of photoexcited plasmas found in x-ray binary stars and active galactic nuclei.

A new benchmark of soft X-ray transition energies of Ne , CO 2 , and SF 6 : paving a pathway towards ppm accuracy.

Abstract: A key requirement for the correct interpretation of high-resolution X-ray spectra is that transition energies are known with high accuracy and precision. We investigate the K-shell features of Ne , CO 2 , and SF 6 gases, by measuring their photo ion-yield spectra at the BESSY II synchrotron facility simultaneously with the 1s-np fluorescence emission of He-like ions produced in the Polar-X EBIT. Accurate ab initio calculations of transitions in these ions provide the basis of the calibration. While the CO 2 result agrees well with previous measurements, the SF 6 spectrum appears shifted by ∼ 0.5 eV, about twice the uncertainty of the earlier results. Our result for Ne shows a large departure from earlier results, but may suffer from larger systematic effects than our other measurements. The molecular spectra agree well with our results of time-dependent density functional theory. We find that the statistical uncertainty allows calibrations in the desired range of 1-10 meV, however, systematic contributions still limit the uncertainty to ∼ 40-100 meV, mainly due to the temporal stability of the monochromator energy scale. Combining our absolute calibration technique with a relative energy calibration technique such as photoelectron energy spectroscopy will be necessary to realize its full potential of achieving uncertainties as low as 1-10 meV.

STED nanoscopy reveals molecular details of cholesterol- and cytoskeleton-modulated lipid interactions in living cells.

Details about molecular membrane dynamics in living cells, such as lipid-protein interactions, are often hidden from the observer because of the limited spatial resolution of conventional far-field optical microscopy. The superior spatial resolution of stimulated emission depletion (STED) nanoscopy can provide new insights into this process. The application of fluorescence correlation spectroscopy (FCS) in focal spots continuously tuned down to 30 nm in diameter distinguishes between free and anomalous molecular diffusion due to, for example, transient binding of lipids to other membrane constituents, such as lipids and proteins. We compared STED-FCS data recorded on various fluorescent lipid analogs in the plasma membrane of living mammalian cells. Our results demonstrate details about the observed transient formation of molecular complexes. The diffusion characteristics of phosphoglycerolipids without hydroxyl-containing headgroups revealed weak interactions. The strongest interactions were observed with sphingolipid analogs, which showed cholesterol-assisted and cytoskeleton-dependent binding. The hydroxyl-containing headgroup of gangliosides, galactosylceramide, and phosphoinositol assisted binding, but in a much less cholesterol- and cytoskeleton-dependent manner. The observed anomalous diffusion indicates lipid-specific transient hydrogen bonding to other membrane molecules, such as proteins, and points to a distinct connectivity of the various lipids to other membrane constituents. This strong interaction is different from that responsible for forming cholesterol-dependent, liquid-ordered domains in model membranes.

Measurement of anomalously strong emission from the 1s-9p transition in the spectrum of H-like phosphorus following charge exchange with molecular hydrogen.

We have measured K-shell x-ray spectra of highly ionized argon and phosphorus following charge exchange with molecular hydrogen at low collision energy in an electron beam ion trap using an x-ray calorimeter array with ∼6 eV resolution. We find that the emission at the high end of the Lyman series is greater by a factor of 2 for phosphorus than for argon, even though the measurement was performed concurrently and the atomic numbers are similar. This does not agree with current theoretical models and deviates from the trend observed in previous measurements.

Spectral cross-cumulants for multicolor super-resolved SOFI imaging.

Super-resolution optical fluctuation imaging provides a resolution beyond the diffraction limit by analysing stochastic fluorescence fluctuations with higher-order statistics. Using nth order spatio-temporal cross-cumulants the spatial resolution and the sampling can be increased up to n-fold in all spatial dimensions. In this study, we extend the cumulant analysis into the spectral domain and propose a multicolor super-resolution scheme. The simultaneous acquisition of two spectral channels followed by spectral cross-cumulant analysis and unmixing increases the spectral sampling. The number of discriminable fluorophore species is thus not limited to the number of physical detection channels. Using two color channels, we demonstrate spectral unmixing of three fluorophore species in simulations and experiments in fixed and live cells. Based on an eigenvalue/vector analysis, we propose a scheme for an optimized spectral filter choice. Overall, our methodology provides a route for easy-to-implement multicolor sub-diffraction imaging using standard microscopes while conserving the spatial super-resolution property.

Simple, compact, high-resolution monochromatic x-ray source for characterization of x-ray calorimeter arrays.

X-ray calorimeters routinely achieve very high spectral resolution, typically a few eV full width at half maximum (FWHM). Measurements of calorimeter line shapes are usually dominated by the natural linewidth of most laboratory calibration sources. This compounds the data acquisition time necessary to statistically sample the instrumental line broadening and can add systematic uncertainty if the intrinsic line shape of the source is not well known. To address these issues, we have built a simple, compact monochromatic x-ray source using channel cut crystals. A commercial x-ray tube illuminates a pair of channel cut crystals that are aligned in a dispersive configuration to select the Kα1 line of the x-ray tube anode material. The entire device, including the x-ray tube, can be easily hand-carried by one person and may be positioned manually or using a mechanical translation stage. The output monochromatic beam provides a collimated image of the anode spot with magnification of unity in the dispersion direction (typically 100 µm-200 µm for the x-ray tubes used here) and is unfocused in the cross-dispersion direction so that the source image in the detector plane appears as a line. We measured output count rates as high as 10 count/s/pixel for the Hitomi soft x-ray spectrometer, which had 819 µm square pixels. We implemented different monochromator designs for energies of 5.4 keV (one design) and 8.0 keV (two designs), which have effective theoretical FWHM energy resolution of 0.125 eV, 0.197 eV, and 0.086 eV, respectively; these are well-suited for optimal calibration measurements of state-of-the art x-ray calorimeters. We measured an upper limit for the energy resolution of our Cr Kα1 monochromator of 0.7 eV FWHM at 5.4 keV, consistent with the theoretical prediction of 0.125 eV.

Laser Doppler imaging for intraoperative human brain mapping.

The identification and accurate location of centers of brain activity are vital both in neuro-surgery and brain research. This study aimed to provide a non-invasive, non-contact, accurate, rapid and user-friendly means of producing functional images intraoperatively. To this end a full field Laser Doppler imager was developed and integrated within the surgical microscope and perfusion images of the cortical surface were acquired during awake surgery whilst the patient performed a predetermined task. The regions of brain activity showed a clear signal (10-20% with respect to the baseline) related to the stimulation protocol which lead to intraoperative functional brain maps of strong statistical significance and which correlate well with the preoperative fMRI and intraoperative cortical electro-stimulation. These initial results achieved with a prototype device and wavelet based regressor analysis (the hemodynamic response function being derived from MRI applications) demonstrate the feasibility of LDI as an appropriate technique for intraoperative functional brain imaging.

The Warm Electron Beam Ion Trap (WEBIT): An instrument for ground calibration of space-borne x-ray spectrometers.

The warm electron beam ion trap (WEBIT) at Lawrence Livermore National Laboratory is being developed as a pre-launch, ground calibration source for space-borne, high-throughput, high-resolution x-ray spectrometers, such as the x-ray imaging and spectroscopy mission Resolve quantum calorimeter. Historically, calibration sources for calorimeter spectrometers have relied on characteristic line emission from x-ray tubes, fluorescing metals, and radioactive sources. The WEBIT, by contrast, relies on emission from x-ray transitions in highly charged ions, for example, hydrogen-like and helium-like ions, whose energies are well known and whose line shapes are relatively simple. The WEBIT can create astrophysically relevant ions whose x-ray emission falls in the 0.3-12 keV science bandpass of Resolve and has a portable design advantageous for a calibration source. The WEBIT will be used to help calibrate Resolve's instrumental line shape and gain scale as a function of various operational parameters during both detector subsystem level testing and instrumental level testing.

Characterization of an atomic hydrogen source for charge exchange experiments.

We characterized the dissociation fraction of a thermal dissociation atomic hydrogen source by injecting the mixed atomic and molecular output of the source into an electron beam ion trap containing highly charged ions and recording the x-ray spectrum generated by charge exchange using a high-resolution x-ray calorimeter spectrometer. We exploit the fact that the charge exchange state-selective capture cross sections are very different for atomic and molecular hydrogen incident on the same ions, enabling a clear spectroscopic diagnostic of the neutral species.

Calibration of the microcalorimeter spectrometer on-board the Hitomi (Astro-H) observatory (invited).

The Hitomi Soft X-ray Spectrometer (SXS) was a pioneering non-dispersive imaging x-ray spectrometer with 5 eV FWHM energy resolution, consisting of an array of 36 silicon-thermistor microcalorimeters at the focus of a high-throughput soft x-ray telescope. The instrument enabled astrophysical plasma diagnostics in the 0.3-12 keV band. We introduce the SXS calibration strategy and corresponding ground calibration measurements that took place from 2012-2015, including both the characterization of the microcalorimeter array and measurements of the x-ray transmission of optical blocking filters.

Predictive value of cardiac autonomic neuropathy in diabetic patients with or without silent myocardial ischemia.

OBJECTIVE: The aim of this study was to determine the predictive value of silent myocardial ischemia (SMI) and cardiac autonomic neuropathy (CAN) in asymptomatic diabetic patients. RESEARCH DESIGN AND METHODS: We recruited 120 diabetic patients with no history of myocardial infarction or angina, a normal 12-lead electrocardiogram (ECG), and two or more additional risk factors. SMI assessment was carried out by means of an ECG stress test, a thallium-201 myocardial scintigraphy with dipyridamole, and 48-h ECG monitoring. CAN was searched for by standardized tests evaluating heart rate variations. Accurate follow-up information for 3-7 years (mean 4.5) was obtained in 107 patients. RESULTS: There was evidence of SMI in 33 patients (30.7%). CAN was detected in 33 of the 75 patients (38.9%) who were tested, and a major cardiac event occurred in 11 of them. Among these 75 patients, the proportion of major cardiac events in the SMI+ patients was not significantly higher than that in the SMI- patients (6 of 25 vs. 5 of 50 patients), whereas it was significantly higher in the CAN+ patients than in the CAN- patients (8 of 33 vs. 3 of 42 patients; P = 0.04), with a relative risk of 4.16 (95% CI 1.01-17.19) and was the highest in the patients with both SMI and CAN (5 of 10 patients). After adjusting for SMI, there was a significant association between CAN and major cardiac events (P = 0.04). CONCLUSIONS: In asymptomatic diabetic patients, CAN appears to be a better predictor of major cardiac events than SMI. The risk linked to CAN appears to be independent of SMI and is the highest when CAN is associated with SMI.

Postprandial cholesteryl ester transfer and high density lipoprotein composition in normotriglyceridemic non-insulin-dependent diabetic patients.

Altered postprandial HDL metabolism is a possible cause of defective reverse cholesterol transport and increased cardiovascular risk in diabetic patients with a normal fasting lipoprotein profile. Ten normolipidemic, normoponderal non-insulin dependent diabetes mellitus (NIDDM) patients and seven controls received a 980 kcal meal containing 78 g lipids with 100 000 IU vitamin A. Chylomicron clearance was not different, but area under the curve (AUC) for retinyl palmitate in chylimicron-free serum (remnant clearance) was greater in patients (P < 0.02). LCAT activity increased postprandially to the same extent in both groups. In control subjects, cholesteryl ester transfer protein (CETP) activity (CETA) also increased by 20% (P < 0.01 at 6 h) in parallel with a 20% decrease in HDL2-CE (r = -0.55, P = 0.009). In NIDDM patients, on the contrary, CETA which was 35% higher in the fasting state (P < 0.005), decreased postprandially yet HDL2-CE remained unchanged. Postprandial HDL3 of controls were enriched with phospholipid (PL) (30.3 +/- 2.6% at 6 h) with respect to fasting (25.6 +/- 2.5%, P < 0.01) and to NIDDM-HDL3 (25.8 +/- 1.7% at 6 h, P < 0.01). These results show that variation in plasma CETA has little impact on HDL2-CE in NIDDH subjects. They support the concept that, in controls, the combined enrichment of HDL3 with PL, increased LCAT and CETA create the conditions for stimulation of cell cholesterol efflux and CE transfer to apo B lipoproteins. In NIDDM, because of the lesser HDL3 enrichment with PL and of the inverse trend of CETA, these conditions fail to occur, depriving the patients of a potentially efficient mechanism of unesterified cholesterol (UC) clearance, despite their strictly normal preprandial profile.

GH deficiency in adults: an epidemiological approach.

OBJECTIVE: The prevalence of adult onset GH deficiency (GH-D) is poorly documented. Epidemiological data are now required to estimate the financial cost of GH treatment in adults. The aim of the present study was to estimate the prevalence of GH-D, from a cohort of 1652 adult patients with hypothalamo-pituitary diseases. DESIGN: The hormonal status of all patients presenting with pituitary diseaseand observed during the year 1994 in 15 endocrine units was retrospectively analyzed, irrespective of the date of disease onset, of the nature and date of pituitary investigations, and whether or not they included specific testing of the GH axis. Of the whole population of 1652 patients, a selected group (RG2) was chosen after exclusion of patients with active acromegaly (n=1414). RESULTS: GH stimulation tests had been performed in 549 patients of the RG2 group and a documented GH-D was found in 301. A relationship between the value of the GH peak and the number of pituitary deficits was evaluated. For instance, it was shown that 93% of patients with three deficits had GH-D. These results constituted the basis for estimating the number of GH-D in the group of untested patients. The number of GH-D deduced from the number of established GH-D (n=301) and from the number of GH-D hypothesized from other pituitary deficits (n=406) was 707 cases. Prevalence and annual incidence were calculated from data recorded in a referral center with a well-defined catchment area, Marseilles (Bouches du Rhône department). We projected a prevalence of 2638 for France and an annual incidence of 12 GH-D per million of the adult population.

Plasma levels of tumor necrosis factor-alpha (TNF-alpha) are essentially dependent on visceral fat amount in type 2 diabetic patients.

TNF-alpha is considered as one of the potential determinants of insulin resistance. However several data suggest that TNF-alpha expression itself, could be modulated by the degree of adiposity and/or plasma insulin levels. To clarify the determinants of plasma TNF-alpha levels in type 2 diabetes mellitus, we studied the impact of intensive insulin treatment on plasma TNF-alpha levels in 16 type 2 diabetic subjects with failure to oral antidiabetic medication (HbA1c: 10.8 +/- 1.2 %). Furthermore, we analyzed the relationship between plasma TNF-alpha levels and total or regional body fat measurements using anthropometry, bienergetic absorptiometry and computed tomography in a cohort of 33 caucasian obese type 2 diabetic subjects (BMI: 32.2 +/- 4.4 kg/m(2) ). The plasma TNF-alpha level was neither affected by plasma glucose level variations nor intensive insulin treatment despite a 37 % decrease in daily insulin needs at the end of insulin therapy (total duration: 11.5 +/- 2.0 days). The plasma TNF-alpha level was similar in men and women and unrelated to age, fasting glycemia or HbA1c. A relationship was highlighted with BMI (r =0.39, p <0.02), but not with total fat mass. This relationship was only dependent on the intra-abdominal fat mass amount as assessed by the waist-to-hip circumference ratio (r =0.52, p <0.01) and the visceral adipose tissue area (r =0.56, p <0. 01). These results show that plasma TNF-alpha levels are essentially dependent on visceral fat amount, thus suggesting that TNF-alpha could be one of the factors mediating insulin resistance and cardiovascular risk in obese type 2 diabetic patients.

Serum lipoprotein (a) concentrations in a population of 819 non-insulin-dependent diabetic patients.

Variations in serum Lp(a) concentrations were studied in a large population of non-insulin-dependent diabetic (NIDDM) patients in relation to long-term complications. Lp(a) concentrations were measured by immunonephelometry in 819 NIDDM subjects and compared with those of 128 controls. Correlations were investigated relative to plasma lipid and glycaemic parameters, body mass index (BMI) and macro- and microvascular complications. Mean absolute and relative variations of Lp(a) concentrations were studied in a subgroup of 245 patients over a one-year period. No significant differences were found between Lp(a) concentrations in NIDDM and control subjects. No relationship was evidenced with macrovascular and microvascular complications or glycaemic control. Mean relative Lp(a) variations were correlated with BMI and absolute and relative variations in triglyceridaemia. These results confirm the absence of any alterations of Lp(a) concentrations in a large cohort of NIDDM patients, either with or without micro- and macrovascular complications, but suggest a particular modulatory role for BMI and serum triglyceride variations.

Insulin and body fat distribution have no direct effect on plasma leptin levels in obese Caucasian women with and without type 2 diabetes mellitus.

Leptin, a hormone produced by adipose tissue, is potentially involved in the regulation of adiposity. The effects of insulin and body fat distribution on human plasma leptin have not yet been clearly defined. The present study investigated the relationships between plasma leptin and total and regional body fat parameters measured by anthropometry and bienergetic absorptiometry associated or not with computed tomography, taking glucose metabolism into account. A cohort of 51 obese Caucasian women (23 with normal glucose tolerance, 11 with impaired glucose tolerance, and 17 with Type 2 diabetes) was analysed. All non-diabetic subjects had an oral glucose tolerance test together with plasma glucose and insulin measurements. Moreover, a subgroup of 7 diabetic subjects with failure to oral antidiabetic treatment was submitted to about 12 days of intensive subcutaneous insulin therapy. Plasma leptin was essentially dependent on total body fat mass (r = 0.83, p < 0.0001, for the whole population), but not related to adipose tissue distribution. An independent correlation between leptin adjusted on body fat mass and fasting insulinaemia (R = 0.72, p < 0.02) or C-peptide (R = 0.62, p < 0.03) was found significant only in the diabetic group. Insulin treatment was associated with a moderate and transient increase of plasma leptin. The relative variations of plasma leptin levels were strongly negatively correlated with those of free fatty acids. The present data confirm that plasma leptin is not dependent on body fat distribution and suggest an indirect effect of insulin on leptin secretion in clinical conditions.

Influence of endogenous and environmental factors on variations of serum lipoprotein (a) concentrations in a large population of insulin-treated diabetic patients.

Variations of serum Lp(a) concentrations were studied in a large population of insulin-treated diabetic patients in relation to the type of diabetes, insulin treatment and long-term complications. Lp(a) concentrations were measured by immunonephelometry in 740 diabetic patients [493 insulin-dependent diabetic (IDDM) patients and 247 insulin-treated Type 2 diabetic (ITD) patients]. Concentrations and distributions were compared with those of 128 non-diabetic controls. Correlations were investigated with lipidic and glycaemic parameters, daily lipid intake, body mass index (BMI), macrovascular and nephropathic complications, and insulin therapy. Both groups of insulin-treated patients (IDDM and ITD) displayed significantly higher Lp(a) concentrations when compared to controls. No relationship was found with macrovascular complications and nephropathy, except in IDDM patients in whom Lp(a) was elevated when creatinine concentration was above 120 mumol/L. Mean variations of Lp(a) were correlated with BMI and triglyceride variations in IDDM patients and only with triglycerides in ITD patients. These results suggest a direct and/or indirect (via serum triglycerides) potential role of exogenous insulin in the modulation of serum Lp(a) concentrations. BMI and lipid daily fat intake could be considered as additional modulating factors of Lp(a) serum concentrations in ITD patients.

Short-term intensive insulin therapy in insulin-requiring diabetes: effectiveness and factors predicting success.

Insulin-requiring diabetes (IRD) is a condition of permanent blood glucose imbalance which occurs despite a regulated diet and treatment with maximum doses of oral anti-diabetic drugs (glibenclamide 15 mg/d + metformin 1,700 mg/d). This report describes the results of a 2-year prospective study in 75 IRD patients treated to eliminate their insulin requirement. All had residual endogenous insulin secretion (REIS) (urinary C peptide > 80 micrograms/24 h and/or basal C peptide > 2.4 ng/ml) and were treated for 10 days by subcutaneous insulin infusion via a portable pump. REIS was measured, and insulin resistance was determined by an insulin tolerance test (ITT) to define their insulin sensitivity index (DG/G) before and after 10-day intensive therapy. The patients were monitored as outpatients, and the attempt at remission was considered to be a failure (F) or a success (S). Thirty of the 75 patients (40%) were in remission at 1 year, and 14/67 (21%) at 2 years. No clinical criterion differentiated successes from failures at 1 year, nor was the initial degree of blood glucose imbalance or the REIS predictive of the metabolic changes that occurred after insulin therapy. However, the drop in the insulin requirement (IR) (-26% for F and -39% for S, p < 0.05) and the increases in the DG/G index (+68 +/- 51% for F and 176 +/- 50% for S, p < 0.01) after insulin therapy were indicative of their condition 1 year later. Receiving operating characteristic curves showed that a 35% decrease in IR and an 80% increase in DG/G were indicative of a successful outcome at 1 year, with a specificity and sensitivity of about 70%. It is concluded that a decrease in daily IR and an increase in the DG/G index during insulin treatment are prognostic indicators of the course of insulin-requiring diabetics after temporary intensive insulin treatment.