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ZusammenfassungEin wichtiges Ziel bei der Behandlung der Nebenniereninsuffizienz ist die Prävention der Nebennierenkrise (auch akute Nebenniereninsuffizienz oder Addison-Krise genannt). Um in Österreich eine bessere Implementierung sowie Harmonisierung der Maßnahmen zur Prävention und Therapie der Nebennierenkrise zu erreichen, wurde dieses Konsensusdokument erarbeitet. Folgende Maßnahmen werden grundsätzlich für alle Patient*innen mit Nebenniereninsuffizienz empfohlen und in diesem Manuskript ausführlich erörtert: 1. Versorgung mit einer Notfallkarte („steroid emergency card“) sowie evtl. auch mit einem Armband oder einer Halskette (oder Ähnlichem) mit medizinischem Alarmhinweis „Nebenniereninsuffizienz, benötigt Glukokortikoide“. 2. Versorgung mit einem Hydrocortison-Notfallkit zur Injektion (alternativ auch Suppositorien/Zäpfchen zur Notfallapplikation) sowie ausreichenden oralen Glukokortikoiddosen für Stresssituationen/Erkrankungen. 3. Schulung von Patient*innen und Angehörigen zur Steigerung der Glukokortikoidtherapie in Stresssituationen bzw. bei Erkrankungen („sick day rules“) und zur Selbstinjektion von Hydrocortison. 4. Versorgung mit einer Behandlungsleitlinie (Informationszettel) zur Prävention und Therapie der Nebennierenkrise, welche bei Bedarf auch dem Gesundheitspersonal gezeigt werden soll. 5. Versorgung mit einer Notfall-Telefonnummer des behandelnden endokrinologischen Teams und/oder medizinisch geschulter Betreuungspersonen bzw. Angehöriger. 6. Regelmäßige (vorzugsweise jährliche) Wiederholung der Schulungsmaßnahmen. Dieses Konsensusdokument beinhaltet auch ausführliche Empfehlungen für die perioperative Glukokortikoidtherapie sowie für diverse andere Stresssituationen.

SummaryGiven the growing use of immune checkpoint inhibitor (ICI) therapy in oncology, the prevalence of endocrine side effects is rapidly increasing. As clinicians are nowadays frequently confronted with these side effects in routine clinical care, awareness, better knowledge of endocrine irAEs and their clinical presentation and diagnosis is crucial for an adequate management. In this short-review we give a compact overview of the recent recommendations for the management of endocrine irAE related to ICIs and highlight difficulties and uncertainties in current clinical practice.

Objectives To determine the relaxation times of the sodium nucleus, and to investigate the repeatability of quantitative, in vivo TSC measurements using sodium magnetic resonance imaging (23Na-MRI) in human skeletal muscle and explore the discriminatory value of the method by comparing TSCs between healthy subjects and patients with Addison’s disease. Materials and methods In this prospective study, ten healthy subjects and five patients with Addison’s disease were involved. 23Na-MRI data sets were acquired using a density-adapted, three-dimensional radial projection reconstruction pulse sequence (DA-3DPR) with a modification for the relaxation times measurements. Differences in TSC between muscle groups and between healthy participants were analysed using a nonparametric Friedman ANOVA test. An interclass correlation coefficient (ICC) was used as the repeatability index. Wilcoxon rank sum test was used for evaluation of differences in TSC between study participants. Results The mean T1 in the gastrocnemius medialis (GM), the tibialis anterior (TA), and the soleus (S) was 25.9 ± 2.0 ms, 27.6 ± 2.0 ms, and 28.2 ± 2.0 ms, respectively. The mean short component of T2*, T2*short were GM: 3.6 ± 2.0 ms; TA: 3.2 ± 0.5 ms; and S: 3.0 ± 1.0 ms, and the mean long component of T2*, T2*long, were GM: 12.9 ± 0.9 ms; TA: 12.8 ± 0.7 ms; and S: 12.9 ± 2.0 ms, respectively. In healthy volunteers, TSC values in the GM were 19.9 ±0.1 mmol/L, 13.8 ±0.2 mmol/L in TA, and 12.6 ± 0.2 mmol/L in S, and were significantly different (p = 0.0005). The ICCs for GM, TA and S were 0.784, 0.818, 0.807, respectively. In patients with Addison’s disease, TSC in GC, TA, and S were 10.2 ± 1.0 mmol/L, 8.4 ± 0.6 mmol/L, and 7.2 ± 0.1 mmol/L, respectively. Conclusions TSC quantification in a healthy subject’s calf at 7.0 T is reliable; the technique is able to distinguish sodium level differences between muscles and between healthy subjects and Addison’s disease patients.

The central autonomic network, which is connected to the limbic system structures including the amygdala (AMY) and anterior hippocampus (aHIP), regulates the sympathetic and parasympathetic modulation of visceromotor, neuroendocrine, pain, and behavior manifestations during stress responses. Heart rate variability (HRV) is useful to estimate the cardiac autonomic tone. The levels of phosphorylation on the Ser831 and Ser845 sites of the GluA1 subunit of the AMPAr (P-GluA1-Ser845 and P-GluA1-Ser831) are useful markers of synaptic plasticity. The relation between synaptic plasticity in the human limbic system structures and autonomic regulation in humans is unknown. This study investigated the association between HRV and neurochemistry biomarkers of synaptic plasticity in AMY and aHIP. HRV indices were obtained from the resting state electrocardiogram of patients with drug-resistant mesial temporal lobe epilepsy (MTLE, n = 18) and the levels of P-GluA1-Ser845 and P-GluA1-Ser831 in the AMY and aHIP resected during the epilepsy surgery. A backward stepwise multiple linear regression models were used to analyze the association between HRV and synaptic plasticity biomarkers controlling for imbalances in the distribution of sociodemographic, clinical, neuroimaging, and neurosurgical variables. P-GluA1-Ser845 levels in AMY show a negative association (p

Die Nebenniereninsuffizienz (NNI) ist eine seltene, unbehandelt jedoch potenziell lebensbedrohlich verlaufende Erkrankung. Aufgrund der vor allem anfanglich unspezifischen klinischen Symptomatik ist es fur die behandelnden Arztinnen und Arzte wichtig, die Moglichkeit einer NNI als Differenzialdiagnose bei zunehmender Schwache, Gewichtsabnahme, Mudigkeit, aber auch Hyponatriamie und Hypoglykamie in Betracht zu ziehen. Die Therapie der NNI ist eine moglichst physiologische Glukokortikoidsubstitution, wobei hier Hydrocortison aufgrund seiner kurzen Halbwertszeit der Vorzug gegeben werden sollte. Auf eine adaquate Dosisadaptierung bei Sondersituationen ist zur Vermeidung von Nebennierenkrisen unbedingt zu achten. Bei der primaren NNI ist zusatzlich noch die Mineralokortikoidtherapie von Relevanz, wahrend bei der sekundaren und tertiaren NNI die anderen Hypophysenhormonachsen kontrolliert und bei Bedarf im Verlauf substituiert werden sollten.

Background Despite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, patients suffering from primary adrenal insufficiency (AI) have an increased mortality, mainly due to cardiovascular diseases. Only little knowledge exists on the contribution of MC substitution to the cardiovascular risk. Therefore, this study investigates the impact of plasma renin concentration on parameters of micro- and macrovascular function. Methods 26 patients with primary AI [female = 18, age: 51 (28; 78) years; BMI: 24 (18; 40) kg/m2; disease duration: 18 (5; 36) years] were included in this cross-sectional analysis. Intima media thickness (IMT) and pulse wave velocity (PWV) were investigated to assess macrovascular remodeling and arterial stiffness. Microvascular function was estimated by post-occlusive reactive hyperemia using laser Doppler fluxmetry. Baseline perfusion, biological zero, peak perfusion, time to peak and recovery time were recorded. Patients were grouped according to their median plasma renin concentration of previous visits (Reninhigh vs Reninlow) and were compared to a group of healthy women [age: 44 (43; 46) years; BMI: 24.2 (21.8; 27.5)]. Results PWV was significantly higher in AI patients compared to controls [9.9 (5; 18.5) vs 7.3 (6.8; 7.7) m/s; p low time to peak perfusion was significantly longer [6.0 (3; 15) vs 3.5 (1.5; 11) s; p high and Reninlow. No impact of GC dose was observed. Conclusions Microvascular function is not impaired in patients with primary AI under adequate replacement therapy, although higher renin concentrations are associated with subclinical improvements. No relation between RAAS activity and macrovascular function is observed, while arterial stiffness might be increased in primary AI.

Der Artikel stellt Dieter Janz als Neurologen vor, der nach 1950 die Auffassung von Epilepsie in Deutschland grundlegend reformierte und modernisierte. Sein wissenschaftlicher Akzent lag auf der Entwicklung einer klinisch basierten Differenzierung epileptischer Syndrome, worunter besonders die umfassende Beschreibung der juvenilen myoklonischen Epilepsie (Impulsiv-Petit mal, Janz-Syndrom) hervorragt. Sein Buch „Die Epilepsien“ besticht durch die tiefschurfende Analyse vieler Krankengeschichten und des Anfallserlebens der Patienten. Den Heidelberger Jahren als angehender Neurologe, dann Oberarzt folgte die Berufung nach Berlin, wo er eine neurologische Abteilung mit rehabilitativer und psychosomatischer Ausrichtung aufbaute, die aber auch auf den Gebieten der klinischen Pharmakologie der Antiepileptika, der Video-EEG-Diagnostik und der Epilepsiegenetik sich intensiv in die internationalen Entwicklungen einbrachte. Bemerkenswert ist seine eingehende Auseinandersetzung mit der existenziellen und theologischen Dimension der Epilepsie bei Dostojewskij und Raffael. Seine letzten Jahre widmete er vornehmlich der Herausgabe der Schriften und des Briefwechsels Victor v. Weizsackers.

Psoriasis is a chronic inflammatory skin disease that involves numerous types of immune cells and cytokines resulting in an inflammatory feedback loop and hyperproliferation of the epidermis. A more detailed understanding of the underlying pathophysiology has revolutionized anti-psoriatic treatment and led to the development of various new drugs targeting key inflammatory cytokines such as IL-17A and IL-23. Successfully treated psoriatic lesions often resolve completely, leaving nothing visible to the naked eye. However, such lesions tend to recur within months at the exact same body sites. What is left behind at the cellular and molecular levels that potentially reinitiates psoriasis? Here, we elucidate the cellular and molecular “scar” and its imprints left after clinical resolution of psoriasis treated with anti-TNFα, anti-IL-17, or anti-IL-23 antibodies or phototherapy. Hidden cytokine stores and remaining tissue-resident memory T cells (TRMs) might hold the clue for disease recurrence.

Fumaric acid esters are recommended in European guidelines for induction and maintenance treatment of patients with moderate to severe plaque psoriasis. A systemic medication with pure dimethyl fumarate without monoethyl fumarate salts was recently licensed in Europe. The efficacy and safety of pure dimethyl fumarate were assessed in patients with severe (physician global assessment) plaque psoriasis in Austria in the BRIDGE trial. In this double blind, randomized, placebo-controlled trial patients received 16-week treatment with pure dimethyl fumarate in a head to head comparison with dimethyl fumarate with monoethyl fumarate salts, which is licensed in Germany. In this post hoc analysis the efficacy and safety were assessed in patients with severe psoriasis in Austria. Efficacy measures significantly improved in both active treatment arms compared to placebo in 65 patients after 16 weeks of treatment. Physician global assessment of clear/almost clear in the dimethyl fumarate group was non-inferior to the dimethyl fumarate with monoethyl fumarate salts group 2 months after end of treatment. No serious adverse reaction occurred in patients with dimethyl fumarate in contrast to the second active treatment. Efficacy outcome was paralleled by quality of life improvements. This is the first report of dimethyl fumarate in a severely affected population with plaque psoriasis. Dimethyl fumarate is effective and safe in the systemic treatment of adults with severe psoriasis (physician global assessment).

The Atomic Clock Ensemble in Space is a fundamental physics mission of the European Space Agency to be launched in August 2021. It relies on a high-performance clock onboard the International Space Station (ISS), a network of high-performance clocks on ground, a dedicated 2-way microwave link (MWL) enabling space-to-ground and ground-to-ground clock comparisons, as well as an optical link (ELT). PHARAO/SHM (Projet d’Horloge Atomique par Refroidissement d’Atomes en Orbite/Space Hydrogen Maser), the clock onboard the ISS, has a relative frequency accuracy at the $${10}^{-16}$$ level, a relative frequency stability (Allan deviation) equal to $${10}^{-13}/\sqrt{\tau }$$ ( $$\tau$$ being the integration time in seconds) and a time deviation of 12 picoseconds after one day of integration. The MWL is designed to reach a time deviation below 7 ps after one day of integration. While space-to-ground clock comparisons will enable precise tests of the gravitational redshift, tests of deviations from General Relativity at the $${10}^{-6}$$ level, and tests of local Lorentz invariance at the $${10}^{-10}$$ level, ground-to-ground clock comparisons will enable a search of the time variation of fundamental constants with uncertainty at the $${10}^{-17}$$ level after one year. In this contribution, we review the mission setup with a particular emphasis on the MWL, discuss the simulation and data analysis software developed to investigate mission performance, focusing on its primary scientific objective: the test of the gravitational redshift.

Atomic Clock Ensemble in Space (ACES) is a mission designed to test Einstein’s theory of General Relativity from the International Space Station (ISS). A primary frequency standard based on laser cooled caesium atoms (PHARAO) and an active H-maser (SHM) generate a clock signal that is distributed to a network of clocks on the ground to perform space-to-ground comparison. With a fractional frequency stability of 1 × 10−16 after 10 days of integration time and an accuracy of 1 – 2 × 10−16, ACES will provide an absolute measurement of the gravitational redshift, it will search for time variations of fundamental constant, and perform Standard Model Extension (SME) tests. The ACES payload is currently completing its qualification tests before flying. The mission status, the latest test results, and the ACES performance for testing General Relativity are discussed.

Aktuelle Leitlinien empfehlen, im Rahmen der Abklarung einer Hyponatriamie eine primare Hypothyreose auszuschliesen. Die Evidenz aus groseren Studien und damit die Bedeutung fur den klinischen Alltag sind hierfur jedoch nicht eindeutig und durchaus kritisch zu hinterfragen. Es gibt verschiedene Erklarungsmechanismen, wie die Schilddrusenunterfunktion eine Hyponatriamie auslosen konnte. Ein Ansatz geht davon aus, dass der bei hypothyreoten Patienten erhohte ADH-Spiegel uber eine Wasserretention zu einer Hyponatriamie fuhren konnte. Ein weiterer Ansatz beruft sich auf eine reduzierte Herzfunktion, welche durch eine Schilddrusenunterfunktion ausgelost werden kann. Dies sowie mogliche Veranderungen in der Niere, insbesondere eine reduzierte glomerulare Filtrationsrate, konnten eine Hyponatriamie erklaren. Ob diese Mechanismen jedoch auch fur den medizinischen Alltag von Relevanz sind bzw. eine Schilddrusenunterfunktion alleine ausreicht, um eine klinisch relevante Hyponatriamie zu induzieren, ist unklar. Eine kurzlich von uns publizierte Studie an einem grosen Patientenkollektiv mit Hyponatriamie konnte keinen wesentlichen Einfluss einer Hypothyreose zeigen. In Zusammenschau der vielen Studien zu dieser Thematik lasst sich folgern, dass eine Hypothyreose als alleiniges Krankheitsbild, wenn uberhaupt, sehr selten fur eine klinisch relevante Hyponatriamie verantwortlich sein durfte. Bei Patienten mit einem verminderten Natriumspiegel gibt es viele alternative Ursachen, welche nicht ubersehen werden sollten.

The frequency stability and uncertainty of the latest generation of optical atomic clocks is now approaching the one part in $$10^{18}$$ level. Comparisons between earthbound clocks at rest must account for the relativistic redshift of the clock frequencies, which is proportional to the corresponding gravity (gravitational plus centrifugal) potential difference. For contributions to international timescales, the relativistic redshift correction must be computed with respect to a conventional zero potential value in order to be consistent with the definition of Terrestrial Time. To benefit fully from the uncertainty of the optical clocks, the gravity potential must be determined with an accuracy of about $$0.1\,\hbox {m}^{2}\,\hbox {s}^{-2}$$ , equivalent to about 0.01 m in height. This contribution focuses on the static part of the gravity field, assuming that temporal variations are accounted for separately by appropriate reductions. Two geodetic approaches are investigated for the derivation of gravity potential values: geometric levelling and the Global Navigation Satellite Systems (GNSS)/geoid approach. Geometric levelling gives potential differences with millimetre uncertainty over shorter distances (several kilometres), but is susceptible to systematic errors at the decimetre level over large distances. The GNSS/geoid approach gives absolute gravity potential values, but with an uncertainty corresponding to about 2 cm in height. For large distances, the GNSS/geoid approach should therefore be better than geometric levelling. This is demonstrated by the results from practical investigations related to three clock sites in Germany and one in France. The estimated uncertainty for the relativistic redshift correction at each site is about $$2 \times 10^{-18}$$ .

To prove the feasibility and safety of a conversion to once-daily injected GLP1 agonist (lixisenatide) and long-acting basal insulin analogue (glargine) in patients with T2DM and poorly controlled glycemia previously treated with multiple injections of premixed insulins (iPremix) in an outpatient setting. Nine patients with T2DM currently receiving iPremix formulations and poor glycemic control were switched to once-daily injected lixisenatide (Lixi) and basal insulin analogue glargine (iGlar) for a 12-week period. Efficacy was defined as A1c reduction of at least 0.4% and weight loss of 0.5 kg or higher. Five of nine patients achieved A1c reductions of 0.4% (4 mmol/mol) or higher and six of nine patients a weight loss of 0.5 kg or higher. A mean A1C reduction of 0.5% ± 0.5% (6 mmol/mol) and mean weight loss of −1.4 ± 3.6 kg were observed in all patients. Total daily insulin dose after 12 weeks declined from 56 ± 26 IU with iPremix formulations to 47 ± 17 IU in patients taking combined iGlar and Lixi. Corrections with fast acting insulin glulisine (iGlu) were necessary in two patients on a regular basis and in four patients on an irregular basis (2.3 IU mean total daily dose). Two patients did not need additional iGlu. Postprandial glucose profiles were lower in the combined group compared with iPremix throughout the day, which resolved in the afternoon. No metabolic derangements occurred. Mild hypoglycemia and gastrointestinal symptoms were the most often reported adverse events affecting three patients. The conversion to once-daily injected GLP1 agonist Lixi and basal iGlar could safely be performed in an outpatient setting and was associated with better postprandial glycemic control throughout the day, except dinner, compared to iPremix. Clinical Trial Registration: EU clinical trials register EudraCT number 2013-005334-37 and ClinicalTrials.gov NCT02168491. Funding: Sponsored by the Medical University of Vienna and in part supported by Sanofi-Aventis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

TYK2 is a member of the JAK family of tyrosine kinases that is involved in chromosomal translocation-induced fusion proteins found in anaplastic large cell lymphomas (ALCL) that lack rearrangements activating the anaplastic lymphoma kinase (ALK). Here we demonstrate that TYK2 is highly expressed in all cases of human ALCL, and that in a mouse model of NPM-ALK-induced lymphoma, genetic disruption of Tyk2 delays the onset of tumors and prolongs survival of the mice. Lymphomas in this model lacking Tyk2 have reduced STAT1 and STAT3 phosphorylation and reduced expression of Mcl1, a pro-survival member of the BCL2 family. These findings in mice are mirrored in human ALCL cell lines, in which TYK2 is activated by autocrine production of IL-10 and IL-22 and by interaction with specific receptors expressed by the cells. Activated TYK2 leads to STAT1 and STAT3 phosphorylation, activated expression of MCL1 and aberrant ALCL cell survival. Moreover, TYK2 inhibitors are able to induce apoptosis in ALCL cells, regardless of the presence or absence of an ALK-fusion. Thus, TYK2 is a dependency that is required for ALCL cell survival through activation of MCL1 expression. TYK2 represents an attractive drug target due to its essential enzymatic domain, and TYK2-specific inhibitors show promise as novel targeted inhibitors for ALCL.

The prevalence of obesity and metabolic syndrome increases in patients with type 1 diabetes mellitus (T1DM). In the general population this is linked with ectopic lipid accumulation in liver (HCL) and skeletal muscle (IMCL), representing hallmarks in the development of insulin resistance. Moreover, hepatic mitochondrial activity is lower in newly diagnosed patients with T1DM. If this precedes later development of diabetes related fatty liver disease is currently not known. This study aims to investigate energy metabolism in liver (kATP) and skeletal muscle (kCK) and its impact on HCL, IMCL, cardiac fat depots and heart function in 10 patients with long standing T1DM compared to 11 well-matched controls by 31P/1H magnetic resonance spectroscopy. HCL was almost 70% lower in T1DM compared to controls (6.9 ± 5% vs 2.1 ± 1.3%; p = 0.030). Also kATP was significantly reduced (0.33 ± 0.1 s−1vs 0.17 ± 0.1 s−1; p = 0.018). In T1DM, dose of basal insulin strongly correlated with BMI (r = 0.676, p = 0.032) and HCL (r = 0.643, p = 0.045), but not with kATP. In the whole cohort, HCL was significantly associated with BMI (r = 0.615, p = 0.005). In skeletal muscle kCK was lower in patients with T1DM (0.25 ± 0.05 s−1vs 0.31 ± 0–04 s−1; p = 0.039). No significant differences were found in IMCL. Cardiac fat depots as well as heart function were not different. Our results in patients with long standing T1DM show that HCL is lower compared to matched controls, despite reduced energy metabolism in liver and skeletal muscle.

We estimated the dynamic cell metabolic activity and the distribution of the pH value and oxygen concentration in tissue samples cultured in vitro by using real-time sensor records and a numerical simulation of the underlying reaction-diffusion processes. As an experimental tissue model, we used chicken spleen slices. A finite element method model representing the biochemical processes and including the relevant sensor data was set up. By fitting the calculated results to the measured data, we derived the spatiotemporal values of the pH value, the oxygen concentration and the absolute metabolic activity (extracellular acidification and oxygen uptake rate) of the samples. Notably, the location of the samples in relation to the sensors has a great influence on the detectable metabolic rates. The long-term vitality of the tissue samples strongly depends on their size. We further discuss the benefits and limitations of the model.

To demonstrate the overlap of the hepatic and bile phosphorus (31P) magnetic resonance (MR) spectra and provide evidence of phosphatidylcholine (PtdC) contribution to the in vivo hepatic 31P MRS phosphodiester (PDE) signal, suggested in previous reports to be phosphoenolpyruvate (PEP). Phantom measurements to assess the chemical shifts of PEP and PtdC signals were performed at 7 T. A retrospective analysis of hepatic 3D 31P MR spectroscopic imaging (MRSI) data from 18 and five volunteers at 3 T and 7 T, respectively, was performed. Axial images were inspected for the presence of gallbladder, and PDE signals in representative spectra were quantified. Phantom experiments demonstrated the strong pH-dependence of the PEP chemical shift and proved the overlap of PtdC and PEP (~2 ppm relative to phosphocreatine) at hepatic pH. Gallbladder was covered in seven of 23 in vivo 3D-MRSI datasets. The PDE gall/γ-ATPliver ratio was 4.8-fold higher (p = 0.001) in the gallbladder (PDEgall/γ-ATPliver = 3.61 ± 0.79) than in the liver (PDEliver/γ-ATPliver = 0.75 ± 0.15). In vivo 7 T 31P MRSI allowed good separation of PDE components. The gallbladder is a strong source of contamination in adjacent 31P MR hepatic spectra due to biliary phosphatidylcholine. In vivo 31P MR hepatic signal at 2.06 ppm may represent both phosphatidylcholine and phosphoenolpyruvate, with a higher phosphatidylcholine contribution due to its higher concentration. • In vivo 31 P MRS from the gallbladder shows a dominant biliary phosphatidylcholine signal at 2.06 ppm. • Intrahepatic 31 P MRS signal at 2.06 ppm may represent both intrahepatic phosphatidylcholine and phosphoenolpyruvate. • In vivo 31 P MRS has the potential to monitor hepatic phosphatidylcholine.

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In past decades, type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease developed into a global public health disease with an endemic scale. Although up to now the pathogenesis of T2DM is still poorly understood, ectopic lipid accumulation is one of the strongest predictors for T2DM and is closely associated with insulin resistance. This review aims (i) to overview recent literature on the impact of intracellular lipid deposition, (ii) to point out changes in ectopic fat accumulation during diabetes progression or shortly after initializing individual therapy, and finally (iii) to expose unsolved questions and future perspectives in the role of ectopic lipids for the development of insulin resistance and T2DM.

Saturation transfer (ST) phosphorus MR spectroscopy (31P MRS) enables in vivo insight into energy metabolism and thus could identify liver conditions currently diagnosed only by biopsy. This study assesses the reproducibility of the localized 31P MRS ST in liver at 7 T and tests its potential for noninvasive differentiation of non-alcoholic fatty liver (NAFL) and steatohepatitis (NASH). After the ethics committee approval, reproducibility of the localized 31P MRS ST at 7 T and the biological variation of acquired hepato-metabolic parameters were assessed in healthy volunteers. Subsequently, 16 suspected NAFL/NASH patients underwent MRS measurements and diagnostic liver biopsy. The Pi-to-ATP exchange parameters were compared between the groups by a Mann–Whitney U test and related to the liver fat content estimated by a single-voxel proton (1H) MRS, measured at 3 T. The mean exchange rate constant (k) in healthy volunteers was 0.31 ± 0.03 s−1 with a coefficient of variation of 9.0 %. Significantly lower exchange rates (p

Es ist allgemein ublich, EEG-Befunde als freien Text zu schreiben. Dies ist mit dem Nachteil einer erheblichen Interobserver-Variabilitat verbunden. Deshalb wurde von einer Expertengruppe, bestehend aus Neurophysiologen und Neurologen, im Rahmen einer europaischen Konsenserklarung ein Standard der EEG-Befundung publiziert: das „standardised computer-based organised reporting of the EEG“ (SCORE). Der EEG-Auswerter kann mit diesem Protokoll EEG beschreiben und befunden, indem er definierte Begriffe auswahlt, die in thematischen Zusammenhangen prasentiert sind. Nach Dateneingabe wird der Befund automatisch erstellt. Das Programm SCORE ist zur EEG-Auswertung von Patienten sowohl im Kindes- als auch im Erwachsenenalter geeignet. Da das Neugeborenen-EEG eine andere Herangehensweise der Befundung erfordert, wurde fur diese Altersgruppe eine spezifische Maske entwickelt. Es gibt inzwischen eine fertige frei verfugbare deutsche Version. Das Programm SCORE ermoglicht eine den klinischen Belangen angepasste Standardisierung der EEG-Befundung, kann im Rahmen der EEG-Ausbildung junger Neurologen sowie Neuropadiater eingesetzt werden und kann als ubiquitar verfugbare Datenbank auserdem die Basis fur eine multinationale Zusammenarbeit in klinischer Forschung darstellen.

Dendritic cells (DCs) have been implicated in the pathogenesis of psoriasis but the roles for specific DC subsets are not well defined. Here we show that DCs are required for psoriasis-like changes in mouse skin induced by the local injection of IL-23. However, Flt3L-dependent DCs and resident Langerhans cells are dispensable for the inflammation. In epidermis and dermis, the critical DCs are TNF-producing and IL-1β-producing monocyte-derived DCs, including a population of inflammatory Langerhans cells. Depleting Ly6Chi blood monocytes reduces DC accumulation and the skin changes induced either by injecting IL-23 or by application of the TLR7 agonist imiquimod. Moreover, we find that IL-23-induced inflammation requires expression of CCR6 by DCs or their precursors, and that CCR6 mediates monocyte trafficking into inflamed skin. Collectively, our results imply that monocyte-derived cells are critical contributors to psoriasis through production of inflammatory cytokines that augment the activation of skin T cells., Imiquimod exacerbates IL-23-induced skin inflammation and models psoriasis in mice. Here the authors show that this pathology is not dependent on resident dendritic cells, but on CCR6-induced immigration of monocyte-derived cells.

Background: Previous work has indicated that extracorporeal photochemotherapy (ECP) may be a safe and effective treatment in patients with severe atopic dermatitis. Methods: We performed a prospective study to investigate the effect of a defined 20-week ECP protocol in patients with severe, refractory atopic dermatitis. The patient inclusion criteria included (i) disease duration of at least 1 year, (ii) SCORAD > 45, and (iii) resistance to first-line therapy, including topical steroids, topical calcineurin inhibitors, and one form of phototherapy (UVA, UVB, or PUVA) or one second-line therapy, including systemic steroids or cyclosporine. Ten patients (4 women and 6 men; age range 29 to 61 years) were enrolled and treated with two sessions of standard ECP in 2-week intervals for 12 weeks and 4-week intervals thereafter until week 20. The patients’ clinical status and response was determined by SCORAD at baseline and every 2 weeks, and quality of life was assessed every 4 weeks using SKINDEX, SF-36, and FACT scores. Results: There was a statistically significant (p = 0.015) reduction of the mean SCORAD by 10.3 (95% CI, 2.5 to 18.0) from 64.8 at baseline to 54.5 (i.e., 15.9% reduction) at week 20. In a subset of patients (all of female sex), the relative reduction in SCORAD after ECP was more than 25% at week 20. Improvement in quality of life measured by SKINDEX, SF-36, and FACT did not reach statistical significance. Conclusions: We detected a small but significant therapeutic effect of ECP in patients with severe, refractory atopic dermatitis.

Polymorphic light eruption (PLE) is a very frequent photodermatosis in Europe whose pathogenesis may involve resistance to UV-induced immune suppression and simultaneous immune reactions against skin photoneoantigens. We performed a randomized, double-blind, placebo-controlled intra-individual half-body trial to investigate the protective effect of an after-sun (AS) lotion containing DNA-repair enzymes (photolyase from Anacystis nidulans and Micrococcus luteus extract with endonuclease activity). Fourteen PLE patients were exposed to suberythemal doses of solar-simulated UV radiation on 4 consecutive days at 4 symmetrically located PLE-prone test fields per patient. The test fields were treated with (i) active AS lotion or (ii) a placebo lotion immediately after each UV exposure, or (iii) an SPF30 sunscreen before UV exposure or left untreated. All test fields were exposed to photoactivating blue light 1 h after each UV exposure. As shown by a newly established specific PLE test score (AA + SI + 0.4P [range, 0-12], where AA is affected area score [range, 0-4], SI is skin infiltration score [range, 0-4], and P is pruritus score on a visual analogue scale [range, 0-10]), PLE symptoms were significantly fewer on test sites treated with active AS lotion than on untreated (P = 0.00049) or placebo-treated test sites (P = 0.024). At 144 h after first UV exposure (the time point of maximal PLE symptoms), the mean test scores for untreated, active AS lotion-treated, and placebo-treated test fields were 4.39, 1.73 (61% reduction; 95% confidence interval (CI), 36% to 85%), and 3.20 (27% reduction; 95% CI, 3% to 51%), respectively. Pretreatment with SPF30 sunscreen completely prevented PLE symptoms in all patients. The present results indicate that DNA damage may trigger PLE and that the application of topical liposomes containing DNA repair enzymes to increase DNA repair may effectively prevent PLE.

We discuss perspectives for new tests of general relativity which are based on recent technological developments as well as new ideas. We focus our attention on tests performed with atomic clocks and do not repeat arguments present in the other contributions to the present volume. In particular, we present the scientific motivations of the space projects ACES and SAGAS., Contribution for "The Nature of Gravity" (eds. F. Everitt et al)

Der nachfolgende Aufsatz beschaftigt sich mit der Statistikausbildung, wie sie an deutschen Hochschulen im Bereich Wirtschaftswissenschaften ublicherweise anzutreffen ist. Wir zeigen neue Wege auf, um die teilweise verstaubten Lehrmethoden an die heutigen technologischen Moglichkeiten anzupassen. Dabei stehen reale Datenbeispiele und die Umsetzung am Rechner im Vordergrund. Neben einer allgemeinen Diskussion gehen wir in medias res und fuhren aus, wie die Vorschlage in die Tat umgesetzt werden konnen.

Chronic exposure to ultraviolet radiation (UVR) plays a significant role in aging and carcinogenesis of the skin. Sensory nerve fibers densely innervate all layers of the skin and get in close anatomical as well as functional contact with cellular components of the epidermis and dermis. In this review, we address the impact of acute and chronic UVR exposure on the cutaneous sensory nervous system and its mediators. We suggest that skin cell-derived nerve growth factor (NGF) and skin nerve-derived neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) may play a central role in intrinsic aging as well as extrinsic (photo-) aging of the skin. In addition, we discuss the possible role of these mediators in photocarcinogenesis.

The frequencies of a cryogenic sapphire oscillator and a hydrogen maser are compared to set new constraints on a possible violation of Lorentz invariance. We give a detailed description of microwave resonators operating in Whispering Gallery modes and then apply it to derive explicit models for Lorentz violating effects in our experiment. Models are calculated in the theoretical framework of Robertson, Mansouri and Sexl and in the standard model extension (SME) of Kostelecky and co-workers. We constrain the parameters of the Mansouri and Sexl test theory to $1/2 - \beta_{MS} + \delta_{MS} = (1.2 \pm 2.2) \times 10^{-9}$ and $\beta_{MS} - \alpha_{MS} - 1 = (1.6 \pm 3.0) \times 10^{-7}$ which is of the same order as the best results from other experiments for the former and represents a 70 fold improvement for the latter. These results correspond to an improvement of our previously published limits [Wolf P. et al., Phys. Rev. Lett. {\bf 90}, 6, 060402, (2003)] by about a factor 2., Comment: 21 pages, 6 figures, accepted for General Relativity and Gravitation (January, 2004). New version with slight changes following the referee's suggestions

Endothelin is an endothelium-derived peptide with potent vasoconstrictor and mitogenic properties. Since studies concerning the immunocytochemical localization of endothelin are often inconsistent we tried to clear up some of these discrepancies by comparing specificity and labeling patterns of different endothelin antibodies. Monoclonal and polyclonal endothelin antibodies ( n=7) were examined concerning their reactivity with endothelins and heart tissues by immunoblotting. Using immunofluorescence microscopy reactivities with human non-failing hearts, failing hearts, and cultured endothelial cells were examined. Specificity of labelings was assessed by absorption controls and functional controls using endothelial cells conditioned to produce different amounts of endothelin. As shown by immunoblotting five out of seven endothelin antibodies revealed both specific endothelin reactivity and negligible non-specific reactivities with heart proteins. Immunocytochemistry showed vascular reactivity of N-terminal endothelin antibodies to be associated with alpha-smooth muscle actin expression. One N-terminal antibody showed additional nuclear reactivity, and one C-terminal antibody vimentin-like labeling patterns. Although these reactivities were abolished in absorption controls these labelings had to be graded non-specific because functional specificity of endothelin antibodies could not be proven. The remaining antibodies revealed no endothelial reactivity even after tyramide signal amplification. Cellular endothelin concentrations ranged around 2,000-fold below the detection limit of immunocytochemical methods. Discrepancies in endothelin immunocytochemistry may originate from false-positive results and from expression levels of endothelin below the detection limit of immunocytochemical methods.

Erythema ab igne (EAI) is a red-brown netlike hyperpigmentation due to repetitive exposure to submaximal heat over a long period of time. This rash is typically seen on the anterior lower legs of people who sit in front of open fireplaces or coal stoves and on the trunk of patients with chronic disorders who seek pain relief by long-term use of hot-water bottles or heating pads. EAI can not only be a diagnostic sign for underlying internal diseases including malignant tumors but can also give rise to cutaneous malignancies. We report on a 75-year-old female patient who developed several thermal keratoses and squamous cell carcinomas at the site of erythema ab igne caused by chronic heat exposure over several years.

Objective: In the treatment of epilepsy, as in all areas of drug therapy, generic formulations are becoming more important as pressure to reduce drug costs increases. In clinical practice, the interchangeability of reference and generic preparations is often assumed. However, in individual patients with a narrow therapeutic range, switching to another formulation of an antiepileptic agent with low water solubility and nonlinear pharmacokinetics may lead to breakthrough seizures or toxicity The purpose of this study was to examine the bioequivalence and clinical effects after switch of equal daily dosages of two commercially available sustained-release preparations of carbamazepine (CBZ). Patients and Study Design: This was a nonblinded intra-individual trial in 14 patients aged 18 to 52 years with focal epilepsy who had been receiving mono-therapy with the reference preparation of sustained-release carbamazepine (mean dosage 1985 mg/day given twice daily) for at least 35 days. After a minimum of 3 further days, the reference preparation (denoted CBZ-R) was immediately replaced by an identical dosage of the generic preparation (denoted CBZ-G). Under steady-state conditions, for each preparation we determined area under the serum concentration-time curve (AUC), maximum serum concentration (Cmax), minimum serum concentration (Cmin) and peak-trough fluctuation (PTF) of carbamazepine and carbamazepine 10,11-epoxide. Results: One patient dropped out because of intolerable adverse effects with CBZ-G. For carbamazepine, the data for the remaining 13 patients, expressed as CBZ-G/CBZ-R, were: AUC 111.5% [90% confidence interval (CI) 105.6-117.8%]; PTF 90.9% (90% CI 73.4-112.8%); Cmax110.1% (90% CI 100.4-117.0%). These data indicate a higher bioavailability for CBZ-G. For carbamazepine 10,11-epoxide, about 20% higher average concentrations were measured with CBZ-G. Applying the usual inclusion rule [90% CI within the range 80 to 125% (AUC) or 70to 143% (PTF and Cmax) of the reference preparation], the two formulations can be considered as bioequivalent. In contrast, we observed marked adverse effects, such as dizziness, nausea, ataxia, diplopia and nystagmus, in eight of the remaining 13 patients after switching to CBZ-G. Conclusions: Proof of bioequivalence between reference and generic preparations of antiepileptic drugs does not mean that they are freely interchangeable. Generic formulations with proven bioequivalence to branded preparations can be used, for example, at the beginning of treatment or in poorly controlled patients with serum concentrations in the mid range. The results demonstrate that the usual rules for bioequivalence and the range of acceptability for preparations of carbamazepine are problematic.

Primary cardiac cell cultures of newborn rats containing approximately 50% (by cell number) spontaneously contracting cardiomyocytes were used to study the role of protein N-glycosylation for the binding of dihydropyridine (DHP) to the voltage-dependent L-type calcium channel. This binding is not influenced by the accompanying non-muscle cells. Exposure of the cells up to 6 micrograms/ml of the N-glycosylation inhibitor tunicamycin for a 44 h period resulted in a decrease of the specific DHP binding sites (Bmax) to 46.0 +/- 17.2% of the untreated control. Similar effects were observed after enzymatic deglycosylation using N-glycosidase F (PNGase F). The results suggest that a posttranslational modification of parts of the cardiac L-type Ca+2 channel by N-glycosylation is an important determinant for the binding of Ca+2 antagonists of the DHP-type to the alpha 1 subunit which itself is not glycosylated. The results suggest a participation of N glycosylation in the assembling of the subunits to the functional channel and/or its turnover. However, a possible effect of tunicamycin on the expression of the Ca channel as an alternative mechanism cannot be excluded.

Background Several types of cognitive or combined cognitive-motor intervention types that might influence physical functions have been proposed in the past: training of dual-tasking abilities, and improving cognitive function through behavioral interventions or the use of computer games. The objective of this systematic review was to examine the literature regarding the use of cognitive and cognitive-motor interventions to improve physical functioning in older adults or people with neurological impairments that are similar to cognitive impairments seen in aging. The aim was to identify potentially promising methods that might be used in future intervention type studies for older adults. Methods A systematic search was conducted for the Medline/Premedline, PsycINFO, CINAHL and EMBASE databases. The search was focused on older adults over the age of 65. To increase the number of articles for review, we also included those discussing adult patients with neurological impairments due to trauma, as these cognitive impairments are similar to those seen in the aging population. The search was restricted to English, German and French language literature without any limitation of publication date or restriction by study design. Cognitive or cognitive-motor interventions were defined as dual-tasking, virtual reality exercise, cognitive exercise, or a combination of these. Results 28 articles met our inclusion criteria. Three articles used an isolated cognitive rehabilitation intervention, seven articles used a dual-task intervention and 19 applied a computerized intervention. There is evidence to suggest that cognitive or motor-cognitive methods positively affects physical functioning, such as postural control, walking abilities and general functions of the upper and lower extremities, respectively. The majority of the included studies resulted in improvements of the assessed functional outcome measures. Conclusions The current evidence on the effectiveness of cognitive or motor-cognitive interventions to improve physical functioning in older adults or people with neurological impairments is limited. The heterogeneity of the studies published so far does not allow defining the training methodology with the greatest effectiveness. This review nevertheless provides important foundational information in order to encourage further development of novel cognitive or cognitive-motor interventions, preferably with a randomized control design. Future research that aims to examine the relation between improvements in cognitive skills and the translation to better performance on selected physical tasks should explicitly take the relation between the cognitive and physical skills into account.

Correction for ‘Patients with polymorphic light eruption have decreased serum levels of 25-hydroxyvitamin-D(3) that increase upon 311 nm UVB photohardening’ by Peter Wolf et al., Photochem. Photobiol. Sci., 2012, 11, 1831–1836.

Mandatory generic substitution of antiepileptic drugs is an increasingly common practice that has many physicians and patients concerned because of the potential for breakthrough seizures and adverse effects. Do the same concerns apply to the treatment of newly diagnosed epilepsy? Peter Wolf investigates.

Phase III testing of aminolevulinic acid (ALA) in topical photodynamic therapy (PDT) has resulted in US Federal Drug Administration approval of the treatment for actinic keratosis on face and scalp. A 20% ALA solution (Levulan®, KerastickTM ) is applied by a specially designed dermal applicator to the skin for 14 to 18 hours before exposure to blue light of wavelength 417nm (exposure time 1000 seconds; light dose, 10 J/cm2). ALA preferentially penetrates the abnormal stratum corneum of diseased skin, localizes in dysplastic and neoplastic tissue and leads to extensive endogenous protoporphyrin IX (PpIX) production in cells. Subsequent activation of PpIX by visible light destroys cells by the production of cytotoxic reactive oxygen species. In the phase III study, 1 or 2 exposures to ALA PDT cleared 72% of actinic keratoses on face and scalp as assessed 12 weeks after the initial treatment. Importantly, previous studies had revealed that actinic keratoses on the face and scalp responded significantly better to ALA-PDT than lesions on other body sites.[1,2] The adverse event profile of ALA PDT seems to be favourable. The major short term adverse effects are burning and stinging during PDT and transient localized erythema and edema after PDT. In contrast to other forms of PDT, systemic photosensitization and/or phototoxic reactions at distant sites do not occur in the setting of topical ALA PDT. Treatment of actinic keratoses is necessary because these lesions are potential precursors of squamous cell carcinoma. The standard armamentarium of treatments includes curettage and electrodesiccation, C02 laser ablation, cryosurgery, topical chemotherapy with fluorouracil (5FU) and now ALA PDT. The choice of treatment modality depends not only on the location, size and extent of lesion(s), but also on the physician’s and patient’s experience with the therapeutic technique. ALA PDT seems to be particularly useful in the treatment of multiple and widespread actinic keratoses which has previously been the domain of 5FU treatment. In contrast to 5FU, which has to be applied daily for, on average, up to 10 to 12 weeks and often induces strong inflammatory reactions at exposure sites, the reaction to ALA PDT is usually moderate and short lasting. However, the real clinical value of ALA PDT will be upheld by the long term disease-free rates after treatment and ultimately by patients’ acceptance of this treatment. In these aspects, our results[1] and those of other investigators promise ALA PDT a bright future in the treatment of actinic keratoses. ▲

The power density of synchrotron radiation emitted by the electron storage ring BESSY (755 MeV) in the soft X-ray range was measured in an exposure chamber used for the irradiation of polymer films with the aid of a calorimeter. The experimental data were compared with data calculated with the aid of the Schwinger equation. According to the emittance of the storage ring the electron beam has a finite vertical and horizontal extension and an angular divergence. The broadening effect can be accounted for by a smearing parameter s. Compared with theoretical data obtained on the basis of s=0 (point source), the maxima of the experimental data were lower by a few percent, typically: 5.2% when the beam passed a filter combination (3.6 μm Al+7.5 μm Kapton). Excellent agreement between experiment and theory was found by assuming s=0.4. With respect to “homogeneous” irradiations of polymer films which were scanned continuously up and down through the beam, it was concluded that fairly correct values of the power density were calculated with s=0, if the vertical amplitude was larger than ±4 mm at a distance between radiation source and polymer film of 10.67 m.

Der CO2-Laser vom Typ Sharplan 791 ist dank seiner Dosierbarkeit und Fokussierbarkeit ein gut geeignetes Gerat, um am Nervensystem des Menschen prazise und sicher schneiden, koagulieren und vaporieren zu konnen. Dies hat sich im Tierexperiment erwiesen und bei 22 Patienten bestatigt.