Comparison of wavefront sensing and ablation imprinting for FEL focus diagnostics at FLASH2.

Extreme ultraviolet (EUV) photon beam characterization techniques, Hartmann wavefront sensing and single shot ablation imprinting, were compared along the caustic of a tightly focused free-electron laser (FEL) beam at beamline FL24 of FLASH2, the Free-electron LASer in Hamburg at DESY. The transverse coherence of the EUV FEL was determined by a Young's double pinhole experiment and used in a back-propagation algorithm which includes partial coherence to calculate the beam intensity profiles along the caustic from the wavefront measurements. A very good agreement of the profile structure and size is observed for different wavelengths between the back-propagated profiles, an indirect technique, and ablation imprints. As a result, the Hartmann wavefront sensor including its software MrBeam is a very useful, single shot pulse resolved and fast tool for non-invasive determination of focal spot size and shape and also for beam profiles along the caustic.

Transition from Paediatric to Adult Care in CAH: 20 Years of Experience at a Tertiary Referral Center.

Transition medicine aims at the coordinated transfer of young patients with a chronic disease from paediatric to adult care. The present study reflects 20 years of experience in transitioning patients with congenital adrenal hyperplasia (CAH) in a single center setting. Our endocrine transition-clinic was established in 2002 and offers joint paediatric and adult consultations. Data were evaluated retrospectively from 2002 to 2005 and 2008 to present. Fifty-nine patients (29 males) were transferred. Median age was 18.4 years (17.6-23.6). Ninety percent of the patients presented with 21-hydroxlase-deficiency (21-OHD), 38 patients (23 m) with salt-wasting (sw), 7 (1 m) with simple-virilising (sv) and 8 (3 m) with the non-classic (nc) form. Rarer enzyme deficiencies were found in 6 cases: 17α-OHD (2 sisters), P450-oxidoreductase-deficiency (2 siblings), 3ß-hydroxysteroid-dehydrogenase-deficiency (1 m) and 11ß-OHD (1 female). Thirty-four patients (57.6%, 20 m) are presently still attending the adult clinic, 1 patient (1.7%, m) moved away and 24 (40.7%, 8 m) were lost to follow-up (13 sw-21-OHD, 6 sv-21-OHD, 5 nc-21-OHD). Thirty-seven patients (62.7%) attended the adult clinic for >2 years after transfer, 17 (28.8%) for >10 years. In the lost to follow-up group, median time of attendance was 16.3 months (0-195.2). Defining a successful transfer as two or more visits in the adult department after initial consultation in the transition clinic, transfer was efficient in 84.7% of the cases. A seamless transfer to adult care is essential for adolescents with CAH. It requires a continuous joint support during the transition period, remains challenging, and necessitates adequate funding.

The beam transport system for the Small Quantum Systems instrument at the European XFEL: optical layout and first commissioning results.

The Small Quantum Systems instrument is one of the six operating instruments of the European XFEL, dedicated to the atomic, molecular and cluster physics communities. The instrument started its user operation at the end of 2018 after a commissioning phase. The design and characterization of the beam transport system are described here. The X-ray optical components of the beamline are detailed, and the beamline performances, transmission and focusing capabilities are reported. It is shown that the X-ray beam can be effectively focused as predicted by ray-tracing simulations. The impact of non-ideal X-ray source conditions on the focusing performances is discussed.

High-Resolution Table-Top NEXAFS Spectroscopy.

A table-top near-edge X-ray absorption fine structure (NEXAFS) spectroscopy system consisting of a soft X-ray source and an integrated spectrometer with a significantly improved resolution is presented. The soft X-ray source is based on a long-term stable and nearly debris-free picosecond laser-induced plasma generated in a pulsed krypton gas jet target. Photon energies ranging from 250 to 1000 eV can be used for the absorption spectroscopy of thin samples. The newly designed spectrometer accomplishes a spectral resolution of E/ΔE = 1535 at 430 eV, being close to typical synchrotron setups. Moreover, a simultaneous multi-edge analysis is possible. The performance of the new system is demonstrated by investigating the fine structure of the K- and L-absorption edges of various elements (carbon, calcium, oxygen, iron, nickel, and copper) for different types of samples. An excellent agreement with synchrotron spectra is achieved.

Improved gas-jet based extreme ultraviolet, soft X-ray laser plasma source.

We present a new nozzle design for an improved brilliance of laser-produced gas plasmas emitting in the soft X-ray and extreme ultraviolet spectral regime. A rotationally asymmetric gas jet is formed by employing two closely adjacent nozzles facing each other under the angle of 45°. The generated three-dimensional gas density distribution is tomographically analyzed using a Hartmann-Shack wavefront sensor. A comparison with numerical simulations accomplishes an optimization of the nozzle arrangement. The colliding gas jets create an optimized gas distribution with increased density, leading to a significant brilliance enhancement of the extreme ultraviolet, soft X-ray plasma.

Evaluation of coercive measures in different psychiatric hospitals: the impact of institutional characteristics.

BACKGROUND: Epidemiological studies have demonstrated considerable differences in the use of coercive measures among psychiatric hospitals; however, the underlying reasons for these differences are largely unclear. We investigated to what extent these differences could be explained by institutional factors. METHODS: Four psychiatric hospitals with identical responsibilities within the mental health care system, but with different inpatient care organizations, participated in this prospective observational study. We included all patients admitted over a period of 24 months who were affected by mechanical restraint, seclusion, or compulsory medication. In addition to the patterns of coercive measures, we investigated the effect of each hospital on the frequency of compulsory medication and the cumulative duration of mechanical restraint and seclusion, using multivariate binary logistic regression. To compare the two outcomes between hospitals, odds ratios (OR) with corresponding 95% confidence intervals (CI) were calculated. RESULTS: Altogether, coercive measures were applied in 1542 cases, corresponding to an overall prevalence of 8%. The frequency and patterns of the modalities of coercive measures were different between hospitals, and the differences could be at least partially related to institutional characteristics. For the two hospitals that had no permanently locked wards, certain findings were particularly noticeable. In one of these hospitals, the probability of receiving compulsory medication was significantly higher compared with the other institutions (OR 1.9, CI 1.1-3.0 for patients < 65 years; OR 8.0, CI 3.1-20.7 for patients ≥65 years); in the other hospital, in patients younger than 65 years, the cumulative duration of restraint and seclusion was significantly longer compared with the other institutions (OR 2.6, CI 1.7-3.9). CONCLUSIONS: The findings are compatible with the hypothesis that more open settings are associated with a more extensive use of coercion. However, due to numerous influencing factors, these results should be interpreted with caution. In view of the relevance of this issue, further research is needed for a deeper understanding of the reasons underlying the differences among hospitals.

Passive compensation of laser-induced higher-order aberrations in high-power NIR optics.

We report a method for passive compensation of thermally induced focal shifts and higher-order aberrations of NIR laser processing optics. Theoretical considerations are made on the elimination of aberrations including polarization effects using a multi-stage compensation element with optical flats of both positive and negative dn/dT. A compensation layout is designed and optimized utilizing numerical simulations of thermo-optic effects. Based on these findings, optical elements for compensation of an F-Theta objective are manufactured. By means of wavefront measurements and beam caustic measurements the feasibility of simultaneous passive compensation of focal shifts and higher-order aberrations is demonstrated.

Papillary Thyroid Cancer and Coexisting Autoimmune Thyroiditis.

Histological findings often display an association between papillary thyroid carcinomas (PTC) and autoimmune thyroiditis (AIT) and so differ significantly from follicular thyroid carcinomas (FTC). The aim of this interdisciplinary, retrospective study was to evaluate the association of AIT in patients with PTC and FTC and a control group of benign nodular goiters. One hundred thyroidectomies with histologically confirmed differentiated thyroid carcinomas, 67 with PTC and 33 with FTC, were submitted for examination. The two control groups consisted of 60 patients with euthyroid nodular goiter, displaying no signs for malignancy (no surgery) and 100 patients (second control group) with surgery of a benign nodular goiter. Controls were collected to obtain data about the incidence of significantly increased TPOAbs in the first group and of lymphocytic infiltrates (LI) in the second group. High TPOAbs were found in 35% (23/67) of patients with PTC. LI were detected by histology in 48% (32/67) of PTC. Ten patients (10/32) of this group showed the clinical and histological manifestation of a classic AIT with diffuse dense LI as well as diffuse hypoechogeneity in ultrasonography. In 7/32 cases, the histological report described focal dense LI (fAIT) and in 15/32 cases scant scattered LI. AIT and fAIT, together 25% of all PTC (17/67), showed germinal centers and can therefore be characterized as chronic autoimmune thyroiditis. In this group, high TPOAb could be detected in 94% (16/17). Scan scattered LI without germinal centers (15/32) do not represent a fAIT, although TPOAb are high in 47% (7/15). The younger age group (<45 years) showed significantly more often high TPOAbs (p<0.023) in comparison with the age-group older than 60 years. In contrast to PTC, only 4/33 (12%) patients with FTC had high TPOAb levels. We conclude that in contrast to benign euthyroid goiters and to FTC, different degrees of LI are often associated with high TPOAb levels and seem to be significantly increased in PTC, particularly prominent in younger age. There is a high coincidence between LI and high TPOAb levels. In the presence of hypoechoic thyroid nodule, signs of thyroid autoimmunity such as the presence of high TPOAbs, lymphocytic infiltration in cytology, and/or characteristic ultrasonic features, are arguments that might favor the decision for surgery if a cytologically indeterminate thyroid nodule is found and focal autonomy is excluded by szintiscan.

Hartmann wavefront sensors and their application at FLASH.

Different types of Hartmann wavefront sensors are presented which are usable for a variety of applications in the soft X-ray spectral region at FLASH, the free-electron laser (FEL) in Hamburg. As a typical application, online measurements of photon beam parameters during mirror alignment are reported on. A compact Hartmann sensor, operating in the wavelength range from 4 to 38 nm, was used to determine the wavefront quality as well as aberrations of individual FEL pulses during the alignment procedure. Beam characterization and alignment of the focusing optics of the FLASH beamline BL3 were performed with λ(13.5 nm)/116 accuracy for wavefront r.m.s. (w(rms)) repeatability, resulting in a reduction of w(rms) by 33% during alignment.

The BH3 mimetic drug ABT-737 induces apoptosis and acts synergistically with chemotherapeutic drugs in thyroid carcinoma cells.

BACKGROUND: Patients with dedifferentiated and anaplastic thyroid carcinomas that do not take up radioiodine are resistant to chemotherapeutic treatment and external irradiation and thus are difficult to treat. Direct induction of apoptosis is a promising approach in these apoptosis-resistant tumor cells. The BH3 mimetic ABT-737 belongs to a new class of drugs that target anti-apoptotic proteins of the BCL-2 family and facilitate cell death. The purpose of this study was to investigate the effect of ABT-737 alone or in combination with chemotherapeutic drugs on thyroid carcinoma cell lines. METHODS: A total of 16 cell lines derived from follicular, papillary, and anaplastic thyroid carcinomas were treated with ABT-737. Cell viability was measured with MTT assay. Cell death was determined by cell cycle phase distribution and subG1 peak analyses, determination of caspase 3/7 activity and caspase cleavage products, lactate dehydrogenase (LDH) liberation assays and LC3 analysis by western blot. RESULTS: The number of viable cells was decreased in all cell lines examined after ABT-737 treatment, with IC50 values ranging from 0.73 to 15.6 µM. Biochemical markers of apoptosis like caspase activities, caspase cleavage products and DNA fragmentation determined as SubG1 peak were elevated after ABT-737 treatment, but no LC3 cleavage was induced by ABT-737 indicating no autophagic processes. In combination with doxorubicin and gemcitabine, ABT-737 showed synergistic effects on cell viability. CONCLUSIONS: With these experiments we demonstrated the efficacy of the BH3 mimetic drug ABT-737 against dedifferentiated thyroid carcinoma cells of various histological origins and showed synergistic effects with chemotherapeutic drugs. ABT-737-treated cells underwent an apoptotic cell death. ABT-737 and related BH3 mimetic drugs, alone or in combination, may thus be of value as a new therapeutic option for dedifferentiated thyroid carcinomas.

Toroidal grating astigmatism of high-harmonics characterized by EUV Hartmann sensor.

The beam transport of single high-order harmonics in a monochromator arrangement is studied. A toroidal grating combines spectral filtering and focusing in order to produce a small individual spot for each harmonic. Here, the effect of small deviations from perfect alignment is investigated. Experimentally, a Hartmann sensor monitors the EUV wavefront while the grating is subjected to an online alignment procedure. The obtained results are confirmed by a simple theoretical description employing optical matrix methods.

Treatment of malignant phaeochromocytoma with a combination of cyclophosphamide, vincristine and dacarbazine: own experience and overview of the contemporary literature.

OBJECTIVE: Malignant phaeochromocytomas are rare and highly aggressive tumours. This retrospective study evaluated the outcome of combined chemotherapy with cyclophosphamide, vincristine and dacarbazine (also known as CVD regimen). METHODS: Patients with histologically and radiologically confirmed malignant phaeochromocytoma who were treated with the CVD regimen for progressive disease were retrospectively identified from chart review. Treatment cycles were usually repeated at 21-day intervals, with cyclophosphamide (750 mg/m(2) ), vincristine (1·4 mg/m(2) ) and dacarbazine (600 mg/m(2) ) on day 1, and dacarbazine only (600 mg/m(2) ) on day 2. The main outcome measures were best response during treatment and progression-free survival. RESULTS: Eight patients (4 males; median age 55·5 (range 31-77) years) with progressive disease underwent a median of 6 (range 3-11) cycles. Best treatment responses were as follows: partial response, n = 2 (25%); stable disease, n = 3 (38%); and progressive disease, n = 3 (38%). The median progression-free survival was 5·4 (range 2·5-26·8) months. After the initial administration of 6 cycles, two patients received a second course of chemotherapy with another 6 cycles after new progressive disease had been detected. Subsequently, these patients were progression-free for another 6·0 and 6·4 months. Mild gastrointestinal symptoms and fatigue were the most common adverse events. CONCLUSION: Although objective tumour response rates were lower than previously reported in small series, the CVD regimen allowed disease stabilization for a substantial period of time and may therefore be considered as a treatment option in advanced stages. To improve disease outcome, however, new therapeutic approaches and larger multicentre studies are needed.

Induction of atypical cell death in thyroid carcinoma cells by the indirubin derivative 7-bromoindirubin-3'-oxime (7BIO).

BACKGROUND: The indirubin derivative 7-bromoindirubin-3'-oxime (7BIO) has already shown anticancer properties by causing cell death in some tumour cell lines and may be a new therapeutic option for treatment-resistant tumour cells. Since dedifferentiated and anaplastic thyroid carcinomas do not take up radioiodine and are insensitive to chemotherapeutic treatment and external radiation, direct cell death induction in these tumour cells may be a promising approach. We thus investigated the effect of 7BIO on thyroid carcinoma cell lines of different histological origins and characterized the type of cell death induction by 7BIO. METHODS: Cell viability was measured with MTT assay. Cell death was analysed by caspase 3/7 activity, lactate dehydrogenase liberation, caspase cleavage products, DNA fragmentation, cell cycle phase distribution and LC3B analysis. RESULTS: After 7BIO treatment, cell viability was reduced in all 14 thyroid carcinoma cell lines investigated. Treated cells showed DNA fragmentation, cell cycle arrest and lactate dehydrogenase liberation but no LC3B cleavage. Caspase activation following 7BIO treatment was found in five of six cell lines investigated. Interestingly, inhibition of caspases had no effect on viability of the cells after 7BIO incubation. CONCLUSIONS: Our results indicate that 7BIO efficiently killed dedifferentiated thyroid carcinoma cells. It induced a non-classical kind of cell death that was caspase-independent and includes DNA fragmentation. 7BIO and related indirubin components thus may have value as a new therapeutic option for dedifferentiated thyroid cancer irrespective of the exact target molecules and the kind of cell death they induce.

Sorafenib inhibits intracellular signaling pathways and induces cell cycle arrest and cell death in thyroid carcinoma cells irrespective of histological origin or BRAF mutational status.

BACKGROUND: Patients with dedifferentiated or anaplastic thyroid carcinomas currently lack appropriate treatment options. Kinase inhibitors are among the most promising new agents as alternative strategies. The BRAF- and multi-kinase inhibitor, sorafenib, has already shown antitumor effects in thyroid carcinoma patients in a phase III clinical trial. In this study we aim to better characterize molecular effects and efficacy of sorafenib against thyroid carcinoma cells with various histological origins and different BRAF mutational status. Analysis of different signaling pathways affected by sorafenib may contribute to assist a more specific therapy choice with fewer side effects. Twelve thyroid carcinoma cell lines derived from anaplastic, follicular and papillary thyroid carcinomas with wildtype or mutationally activated BRAF were treated with sorafenib. Growth inhibition, cell cycle arrest, cell death induction and inhibition of intracellular signaling pathways were then comprehensively analyzed. METHODS: Cell viability was analyzed by MTT assay, and the cell cycle was assessed by flow cytometry after propidium iodide staining. Cell death was assessed by lactate dehydrogenase liberation assays, caspase activity assays and subG1 peak determinations. Inhibition of intracellular pathways was analyzed in dot blot and western blot analyses. RESULTS: Sorafenib inhibited proliferation of all thyroid carcinoma cell lines tested with IC50 values ranging between 1.85 and 4.2 µM. Cells derived from papillary carcinoma harboring the mutant BRAF (V600E) allele were slightly more sensitive to sorafenib than those harboring wildtype BRAF. Cell cycle analyses and caspase assays showed a sorafenib-dependent induction of apoptosis in all cell lines, whereas increased lactate dehydrogenase release suggested cell membrane disruption. Sorafenib treatment caused a rapid inhibition of various MAP kinases in addition to inhibiting AKT and receptor tyrosine kinases. CONCLUSIONS: Sorafenib inhibited multiple intracellular signaling pathways in thyroid carcinoma cells, which resulted in cell cycle arrest and the initiation of apoptosis. Sorafenib was effective against all thyroid carcinoma cell lines regardless of their tumor subtype origin or BRAF status, confirming that sorafenib is therapeutically beneficial for patients with any subtype of dedifferentiated thyroid cancer. Inhibition of single intracellular targets of sorafenib in thyroid carcinoma cells may allow the development of more specific therapeutic intervention with less side effects.

Prediction of therapy response in acromegalic patients under pegvisomant therapy within the German ACROSTUDY cohort.

PURPOSE: This study aimed at investigating predicting factors for therapy response under growth hormone receptor antagonist therapy with a focus on subjective and patient-oriented measures. METHODS: Observational, multicenter nested-cohort study including 271 selected patients with the diagnosis of acromegaly and a minimum of one-year follow-up period within the German ACROSTUDY cohort (total cohort: n = 514). Outcome measures were the change of the biomarker IGF-1 (IGF-1 change and IGF-1 normalisation) between baseline and after 1 year of pegvisomant therapy (12 ± 6 months). Main predictors were patient-assessed subjective measures according to the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) in conjugation with age, gender, BMI, max. dosage of pegvisomant at follow-up and IGF-1 before the start of pegvisomant therapy. RESULTS: The mean age of the study population was 51.2 (13.9) years and the mean BMI was 29.5 (5.1) kg/m(2). In adjusted analyses, none of the individual perceived health (PASQ) scores, but age, BMI and IGF-1 at baseline were predictive for an IGF-1 decrease after 1 year of pegvisomant therapy and BMI and IGF-1, but equally none of the PASQ items, were predicting IGF-1 normalisation. CONCLUSIONS: Age, BMI and baseline IGF-1 but not subjective perceived health measures predict therapy response under second line medical therapy with pegvisomant.

Coronary atherosclerosis burden, but not transient troponin elevation, predicts long-term outcome in recreational marathon runners.

We determined the prognostic value of transient increases in high-sensitive serum troponin I (hsTnI) during a marathon and its association with traditional cardiovascular risk factors and imaging-based risk markers for incident coronary events and all-cause mortality in recreational marathon runners. Baseline data of 108 marathon runners, 864 age-matched controls and 216 age- and risk factor-matched controls from the general population were recorded and their coronary event rates and all-cause mortality after 6 ± 1 years determined. hsTnI was measured in 74 marathon finishers before and after the race. Other potential predictors for coronary events, i.e., Framingham Risk Score (FRS), coronary artery calcium (CAC) and presence of myocardial fibrosis as measured by magnetic resonance imaging-based late gadolinium enhancement (LGE), were also assessed. An increase beyond the 99 % hsTnI-threshold, i.e., 0.04 µg/L, was observed in 36.5 % of runners. FRS, CAC, or prevalent LGE did not predict hsTnI values above or increases in hsTnI beyond the median after the race, nor did they predict future events. However, runners with versus without LGE had higher hsTnI values after the race (median (Q1/Q3), 0.08 µg/L (0.04/0.09) versus 0.03 µg/L (0.02/0.06), p = 0.039), and higher increases in hsTnI values during the race (median (Q1/Q3), 0.05 µg/L (0.03/0.08) versus 0.02 µg/L (0.01/0.05), p = 0.0496). Runners had a similar cumulative event rate as age-matched or age- and risk factor-matched controls, i.e., 6.5 versus 5.0 % or 4.6 %, respectively. Event rates in runners with CAC scores <100, 100-399, and ≥400 were 1.5, 12.0, and 21.4 % (p = 0.002 for trend) and not different from either control group. Runners with coronary events had a higher prevalence of LGE than runners without events (57 versus 8 %, p = 0.003). All-cause mortality was similar in marathon runners (3/108, 2.8 %) and controls (26/864, 3.0 % or 5/216, 2.4 %, respectively). Recreational marathon runners with prevalent myocardial fibrosis develop higher hsTnI values during the race than those without. Increasing coronary artery calcium scores and prevalent myocardial fibrosis, but not increases in hsTnI are associated with higher coronary event rates. All-cause mortality in marathon runners is similar to that in risk factor-matched controls.

Measurement and compensation of laser-induced wavefront deformations and focal shifts in near IR optics.

We demonstrate the feasibility of passive compensation of the thermal lens effect in fused silica optics, placing suitable optical materials with negative dn/dT in the beam path of a high power near IR fiber laser. Following a brief overview of the involved mechanisms, photo-thermal absorption measurements with a Hartmann-Shack sensor are described, from which coefficients for surface/coating and bulk absorption in various materials are determined. Based on comprehensive knowledge of the 2D wavefront deformations resulting from absorption, passive compensation of thermally induced aberrations in complex optical systems is possible, as illustrated for an F-Theta objective. By means of caustic measurements during high-power operation we are able to demonstrate a 60% reduction of the focal shift in F-Theta lenses through passive compensation.

Table-top soft x-ray microscope using laser-induced plasma from a pulsed gas jet.

An extremely compact soft x-ray microscope operating in the "water window" region at the wavelength λ = 2.88 nm is presented, making use of a long-term stable and nearly debris-free laser-induced plasma from a pulsed nitrogen gas jet target. The well characterized soft x-ray radiation is focused by an ellipsoidal grazing incidence condenser mirror. Imaging of a sample onto a CCD camera is achieved with a Fresnel zone plate using magnifications up to 500x. The spatial resolution of the recorded microscopic images is about 100 nm as demonstrated for a Siemens star test pattern.

Wigner distribution measurements of the spatial coherence properties of the free-electron laser FLASH.

The four-dimensional Wigner distribution function is determined from intensity profiles measured in the focused photon beam of FLASH (Free-electron laser in Hamburg) for a variety of photon beamline settings. The Wigner formalism results in comprehensive coherence information without the requirement of simplifying assumptions on the beam. The entire four-dimensional spatial mutual coherence function, horizontal and vertical coherence lengths and the global degree of coherence are derived and compared to Young's double pinhole measurements [Opt. Express 20, 17480 (2012)].

Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide.

Wilson disease is caused by accumulation of Cu(2+) in cells, which results in liver cirrhosis and, occasionally, anemia. Here, we show that Cu(2+) triggers hepatocyte apoptosis through activation of acid sphingomyelinase (Asm) and release of ceramide. Genetic deficiency or pharmacological inhibition of Asm prevented Cu(2+)-induced hepatocyte apoptosis and protected rats, genetically prone to develop Wilson disease, from acute hepatocyte death, liver failure and early death. Cu(2+) induced the secretion of activated Asm from leukocytes, leading to ceramide release in and phosphatidylserine exposure on erythrocytes, events also prevented by inhibition of Asm. Phosphatidylserine exposure resulted in immediate clearance of affected erythrocytes from the blood in mice. Accordingly, individuals with Wilson disease showed elevated plasma levels of Asm, and displayed a constitutive increase of ceramide- and phosphatidylserine-positive erythrocytes. Our data suggest a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease.