Medical treatment of Cushing’s disease with concurrent diabetes mellitus

Cushing’s disease (CD) is a severe endocrine disorder characterized by chronic hypercortisolaemia secondary to an overproduction of adrenocorticotropic hormone (ACTH) by a pituitary adenoma. Cortisol excess impairs normal glucose homeostasis through many pathophysiological mechanisms. The varying degrees of glucose intolerance, including impaired fasting glucose, impaired glucose tolerance, and Diabetes Mellitus (DM) are commonly observed in patients with CD and contribute to significant morbidity and mortality. Although definitive surgical treatment of ACTH-secreting tumors remains the most effective therapy to control both cortisol levels and glucose metabolism, nearly one-third of patients present with persistent or recurrent disease and require additional treatments. In recent years, several medical therapies demonstrated prominent clinical efficacy in the management of patients with CD for whom surgery was non-curative or for those who are ineligible to undergo surgical treatment. Cortisol-lowering medications may have different effects on glucose metabolism, partially independent of their role in normalizing hypercortisolaemia. The expanding therapeutic landscape offers new opportunities for the tailored therapy of patients with CD who present with glucose intolerance or DM, however, additional clinical studies are needed to determine the optimal management strategies. In this article, we discuss the pathophysiology of impaired glucose metabolism caused by cortisol excess and review the clinical efficacy of medical therapies of CD, with particular emphasis on their effects on glucose homeostasis

Lew Karsawin und die russische 'Einzigartigkeit'

'Zweifelsohne gilt der seit 1917 in staatlicher Form ausgetragene Ost-West-Konflikt heute als überwunden. Weitaus schwieriger verhält es sich allerdings mit einer Bewertung der Entwicklung 'unterhalb' dieser Ebene. Die gegenwärtige Entwicklung in Rußland verdeutlicht, daß das Ost-West-Verhältnis bis heute von einer latenten Konflikthaftigkeit geprägt ist. Diskussionen über die künftigen Beziehungen zwischen Rußland und Europa gewinnen an Bedeutung. Die Ost-West-Thematik nimmt neue Dimensionen an, die Auseinandersetzung wird in den Bereich der kultur- und geschichtsphilosophischen Reflexion verlagert. Lew Karsawin (1882-1952) gehört zu jenen Vertretern der russischen Geistesgeschichte, deren Anschauungen die durch viele Besonderheiten und Ambivalenzen gekennzeichnete historisch-kulturelle Tradition ihres Landes geprägt haben, ohne deren Kenntnis man insbesondere die wachsenden Schwierigkeiten der Reformprozesse in Osteuropa kaum adäquat verstehen und beurteilen kann. Als Zeitzeuge großer historischer Ereignisse (Erster Weltkrieg, Oktoberrevolution in Rußland, revolutionäre Ausbrüche in Westeuropa) konnte er diese in ganz unmittelbarer Weise in seine geschichtsphilosophische Reflexion einbeziehen. Die Analyse von Karsawins Werken vermittelt einen repräsentativen Einblick in die Diskussion über Universalität und Einzigartigkeit der russischen Geschichte. Auf der Suche nach ihrem Sinn bewegt sich Karsawin im Spannungsfeld zwischen Rationalität und Irrationalität, zwischen dem traditionellen Messianismus der 'russischen Idee' und der Akzeptanz anderer Kulturen. Er widmet sich der Frage, ob Revolutionen Ausdruck spontaner Naturgewalt oder aber göttlicher Vorsehung sind, ob sie von den Volksmassen getragen werden oder aber von deren Führern. Es drängen sich historische Parallelen zwischen der Französischen Revolution, der russischen Oktoberrevolution und der Perestroika Gorbatschows auf. Das gegenwärtig wachsende Interesse an Karsawin wird zu einem nicht geringen Teil durch dessen Zusammenarbeit mit den Eurasien begründet, deren führender Theoretiker er von 1926 bis 1929 in Paris war. Unter diesem Namen wurden in der russichen Emigration nach 1917 jene konzeptionellen Ansätze bekannt, die eine Art dritten Weg in bezug auf die Interpretation der russischen Geschichte im Verhältnis zwischen Ost und West - bei stärkerer Gewichtung Asiens - suchten. Als Quellen dienen vorwiegend Karsawins Werke, die z. T. in jüngster Zeit wieder veröffentlicht wurden, and andere relevante russische Publikationen.' (Autorenreferat)'Without doubt, the East/West conflict that had been carried out since 1917 between states on both sides can nowadays by considered a thing of the past. It is much more difficult, however, to assess the evolution of this situation 'below' his level. Contemporary developments in Russia make it clear that East/West relations are still characterized by a latent conflict potential even today. Debates about future relations between Russia and Europe are gaining in importance. Discussion of the East/West topic is taking on new dimensions, the arguments are shifting into the realm of philosophical reflection on culture and history. Lev Karsavin (1882-1952) was one of those protagonists in the history of the Russian mind whose views have impressed themselves upon the historico-cultural tradition of their country, a tradition marked by many peculiarities and ambivalences and without knowledge of which it is virtually impossible accurately to comprehend and assess in particular the worsening difficulties being experienced by the reform processes in Eastern Europe. As a contemporary withness to great historical events (the First World War, the October Revolution in Russia, revolutionary outbreaks in Western Europe) he was able to incorporate these events in all immediacy into his philosophical reflection on history. An analysis of Karsavin's works conveys a representative insight into the discussion about the universality and uniqueness of Russian history.In search of its meaning, Karsavin is torn between the opposite poles of rationality and irrationality, between the traditional messianism of the 'Russian idea' and the acceptance of other cultures. He devotes himself to the question as to whether revolutions are the expression of spontaneous natural forces or are instead dictated by divine providence, whether they are carried out by the masses of the people or rather by their leaders. Historical parallels become apparent between the French Revolution, the Russian October Revolution, and Gorbachev's Perestroika. The growing interest in Karsavin today is due to no mean extent to his collaboration with the Eurasians, whose leading theoretician in Paris he was from 1926 to 1929. This is the name given to those conceptual approaches adopted among Russian emigrants as of 1917 in search of a kind of third path to facilitate the interpretation of Russian history betwixt and between East and West - with greater emphasis on Asia.' (author's abstract

Slow Transition Path Times Reveal a Complex Folding Barrier in a Designed Protein

De-novo designed proteins have received wide interest as potential platforms for nano-engineering and biomedicine. While much work is being done in the design of thermodynamically stable proteins, the folding process of artificially designed proteins is not well-studied. Here we used single-molecule force spectroscopy by optical tweezers to study the folding of ROSS, a de-novo designed 2x2 Rossmann fold. We measured a barrier crossing time in the millisecond range, much slower than what has been reported for other systems. While long transition times can be explained by barrier roughness or slow diffusion, we show that isotropic roughness cannot explain the measured transition path time distribution. Instead, this study shows that the slow barrier crossing of ROSS is caused by the population of three short-lived high-energy intermediates. In addition, we identify incomplete and off-pathway folding events with different barrier crossing dynamics. Our results hint at the presence of a complex transition barrier that may be a common feature of many artificially designed proteins

Auto- and cross-power spectral analysis of dual trap optical tweezer experiments using Bayesian inference

The thermal fluctuations of micron-sized beads in dual trap optical tweezer experiments contain complete dynamic information about the viscoelastic properties of the embedding medium and—if present—macromolecular constructs connecting the two beads. To quantitatively interpret the spectral properties of the measured signals, a detailed understanding of the instrumental characteristics is required. To this end, we present a theoretical description of the signal processing in a typical dual trap optical tweezer experiment accounting for polarization crosstalk and instrumental noise and discuss the effect of finite statistics. To infer the unknown parameters from experimental data, a maximum likelihood method based on the statistical properties of the stochastic signals is derived. In a first step, the method can be used for calibration purposes: We propose a scheme involving three consecutive measurements (both traps empty, first one occupied and second empty, and vice versa), by which all instrumental and physical parameters of the setup are determined. We test our approach for a simple model system, namely a pair of unconnected, but hydrodynamically interacting spheres. The comparison to theoretical predictions based on instantaneous as well as retarded hydrodynamics emphasizes the importance of hydrodynamic retardation effects due to vorticity diffusion in the fluid. For more complex experimental scenarios, where macromolecular constructs are tethered between the two beads, the same maximum likelihood method in conjunction with dynamic deconvolution theory will in a second step allow one to determine the viscoelastic properties of the tethered element connecting the two beads

Phase engineering in tantalum sulfide monolayers on Au(111)

We prepare monolayers of tantalum sulfide on Au(111) by evaporation of Ta in a reactive background of H$_2$S. Under sulfur-rich conditions, monolayers of 2H-TaS$_2$ develop, whereas under sulfur-poor conditions TaS forms, a structure that can be derived from 2H-TaS$_2$ by removal of the bottom S layer. We analyse the alignment of the layers with respect to the substrate and the relation with the domains in the Au(111) herringbone reconstruction using scanning tunneling microscopy (STM). With the help of density functional theory (DFT) calculations we can determine the registry of the two phases with the substrate. We develop a growth process that allows preparation of uniquely oriented 2H-TaS$_2$ on Au(111). 2H-TaS$_2$ and TaS have a remarkably similar in-plane lattice structure and we observe the formation of lateral 2H-TaS$_2$-TaS heterostructures with atomically well-defined and defect-free boundaries. We observe mirror twin boundaries within 2H-TaS$_2$ along the S- and Ta-edge

Impact of Quenching Failure of Cy Dyes in Differential Gel Electrophoresis

Background: Differential gel electrophoresis (DIGE) is a technology widely used for protein expression analysis. It is based on labelling with fluorescent Cy dyes. In comparative fluorescence gel electrophoresis experiments, however, unspecific labelling using N-hydroxy-succinimide-ester-based labelling protocols was recently detected. Cross-talk was observed due to failure of the quenching process. Here, the impact of this effect for DIGE experiments was investigated. Methodology/Principal Findings: Experiments to test quenching efficiency were performed in replicate using Escherichia coli lysate. Parameters such as the amount of dye and quencher were varied. Labelling and quenching were reversed in one experiment. Differences in protein spot volumes due to limited quenching were determined. For some spots twice the volume was detected underscoring the importance of proper control of silencing of active dye. Conclusions/Significance: It could be demonstrated that uncontrolled labelling increased protein spot volume, even doubling it in some cases. Moreover, proteins responded differently to the protocol. Such unpredictable and unspecific processes are not acceptable in protein regulation studies so that it is necessary to validate the correct amount of quencher for individual samples before the DIGE experiment is performed. Increase of the concentration of lysine, which is used as quencher, from 10 mM to 2500 mM, was sufficient to silence the dye. Alternatively, active dye molecules can be removed by filtration

Do position and species identity of neighbours matter in 8–15-year-old post harvest mesic stands in the boreal mixedwood?

Neighbourhood competition indices (NCI), where position and species identity of neighbours are known, have been used to investigate growth and competitive interactions among adult trees. In this study, we used NCI in 8–15-year-old stands following clear-cutting in a boreal mixedwood forest of eastern Canada to improve our understanding of early successional forest dynamics. Trees of increasing diameter from the center (≥1 cm) to the edge (≥5 cm) were mapped in twenty-five circular 450m2 plots. Target trees (DBH≥1 cm) were sampled in plot center to determine their annual radial stem growth. For each species, we compared a set of growth models using either a spatially explicit NCI or a non-spatial competition index. Both types of indices estimated a species-specific competition coefficient for each pair of competitor–target species. NCI were selected as the best competition model for all target species although differences in variance explained relative to the non-spatial index were small. This likely indicates that competition occurs at the local level but that the high density and the relative uniformity of these young stands creates similar neighbourhoods for most trees in a given stand. The effective neighbourhood radius for competitors varied among species and was smaller for shade tolerant species. Intraspecific neighbours were the strongest competitors for most species. Aspen (Populus tremuloides) was a weak competitor for all species as opposed to balsam fir (Abies balsamea) which was a strong competitor in all cases. These results are in contradiction with some widely used forest policies in North America (e.g. free-to-grow standards) that consider broadleaf species, such as aspen, as the strongest competitors. For these early successional forests, the decision regarding the use of spatial or non-spatial competition indices should rest on the intended use. For even-age management, spatial indices might not justify their use in highdensity stands but they are needed for the simulation of novel harvest techniques creating complex stand structure

Osilodrostat — an emerging drug for the medical management of Cushing’s disease

Cushing’s disease (CD) is a rare endocrine disorder characterized by the overproduction of adrenocorticotropic hormone (ACTH) by pituitary adenoma followed by hypercortisolaemia with severe complications. Although transsphenoidal resection of the defined pituitary adenoma has been the treatment of choice for the past decades, it does not always result in long-term remission — 10–30% of cases show ineffective surgical treatment or tumour recurrence even after initial success. Pharmacological therapies for cortisol reduction are often required for those who either cannot undergo pituitary surgery or when the surgery has failed, and patients still present with the persistent disease. Osilodrostat is a potent oral steroidogenesis inhibitor that has lately been shown as an effective adjuvant therapy in the management of patients with CD. In this article, we review the recent reports on the efficacy and safety of osilodrostat in clinical settings