Towards dynamical network biomarkers in neuromodulation of episodic migraine

Computational methods have complemented experimental and clinical neursciences and led to improvements in our understanding of the nervous systems in health and disease. In parallel, neuromodulation in form of electric and magnetic stimulation is gaining increasing acceptance in chronic and intractable diseases. In this paper, we firstly explore the relevant state of the art in fusion of both developments towards translational computational neuroscience. Then, we propose a strategy to employ the new theoretical concept of dynamical network biomarkers (DNB) in episodic manifestations of chronic disorders. In particular, as a first example, we introduce the use of computational models in migraine and illustrate on the basis of this example the potential of DNB as early-warning signals for neuromodulation in episodic migraine.Comment: 13 pages, 5 figure

Verbindungen des Formeltyps M2El2(OtBu)8

By simple salt-exchange processes the starting materials Na2El2(OtBu)6 (El = Ge, Sn, Pb) can be transformed to germanates, stannates and plumbates of divalent magnesium and divalent transition metals. Two types of compounds are formed in these reactions: MEl2(OtBU)6 [El = Ge, M = Mg (1A), Cr (1B), Mn (1C), Zn (1 F); El = Pb, M Mn (3C), M = Zn (3 F)] and M2El2(OtBu)8 [El = Ge, M = Co (1d), Ni (1e); El = Sn, M = Mg (2a), Cr (2b), Mn (2c), Co (2d), Ni (2e); El = Pb, M = Co (3d)]. Single-crystal X-ray diffraction studies have been performed on 1C, 1d, 2a, 2b, 2c, 2d, and 2e, and the structures have been solved. In 1C the Mn atom occupies the center of an elongated O6 octahedron, the germanium(II) atoms displaying pyramidal coordination by three oxygen atoms. The central molecular cage can be described as two MnO3Ge trigonal bipyramids sharing the common central Mn atom and being wrapped by tert-butyl groups linked to the oxygen atoms. The other compounds of the MEl2(OtBU)6 formula seem to be isostructural with the exception of 3F, which displays a H-1-NMR spectrum which is not compatible with this structure. All X-ray structures of the compounds M2El2(OtBu)8 show the same feature: to a central M2(OtBU)2 four-membered ring are spirocyclically connected two M(OtBu)2El rings through the common metal atoms M. The structure is completed by the coordination of an exocyclic tert-butoxy group to the terminal El atoms. The metal atoms M are therefore quasi tetrahedrally coordinated while the Ge and Sn atoms are in pyramidal three-fold oxygen atom environments. All molecules display an El...M...M...El one-dimensional arrangement. From susceptibility measurements it is apparent, that in the compounds MEl2(OtBu)6 and M2El2(OtBu)8 the transition metal atoms are in high-spin configurations, which is also supported by the UV spectra. Analysis of the structural data of the series 2a-2e reveal important contributions of the electronic environments of the transition metal atoms to the M...M and M...Sn distances. A qualitative MO description is used to explain these features. Again it has been shown that the geometrical softness" of Ge(OtBu)3 and Pb(OtBu)3 is greater than of Sn(OtBu)3, as the former two can accomodate Cr2+ and Mn2+ in a sixfold coordination site by two units, while Sn(OtBu)3 coordinates Cr2+ and Mn2+ with only two alkoxy groups. when 1C and 2d are allowed to react with nonacarbonyldiiron Mn-Ge2(OtBu)6 . 2 Fe(CO)4 (4) and Co2Sn2(OtBu)8 . 2 Fe(CO)4 (5), respectively, are formed. Compound 4 displays presumably five metal atoms in a linear arrangement while 5 has six metallic elements arranged in one dimension. The latter fact has been unambigously proved by an X-ray structure determination

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Detection of Pseudomonas aeruginosa Metabolite Pyocyanin in Water and Saliva by Employing the SERS Technique

Pyocyanin (PYO) is a metabolite specific for Pseudomonas aeruginosa. In the case of immunocompromised patients, it is currently considered a biomarker for life-threating Pseudomonas infections. In the frame of this study it is shown, that PYO can be detected in aqueous solution by employing surface-enhanced Raman spectroscopy (SERS) combined with a microfluidic platform. The achieved limit of detection is 0.5 μM. This is ~2 orders of magnitude below the concentration of PYO found in clinical samples. Furthermore, as proof of principle, the SERS detection of PYO in the saliva of three volunteers was also investigated. This body fluid can be collected in a non-invasive manner and is highly chemically complex, making the detection of the target molecule challenging. Nevertheless, PYO was successfully detected in two saliva samples down to 10 μM and in one sample at a concentration of 25 μM. This indicates that the molecules present in saliva do not inhibit the efficient adsorption of PYO on the surface of the employed SERS active substrates

Preisregulierung von verschreibungspflichtigen Arzneimitteln in der gesetzlichen Krankenversicherung nach dem GKV-Wettbewerbsstärkungsgesetz

Der Bundesverband der Arzneimittel-Hersteller e.V. hat einen Forschungsauftrag zur Preisregulierung von erstattungsfähigen Arzneimitteln im generikafähigen Markt in der GKV nach dem GKV-WSG vergeben. Ausgangspunkt ist, dass das Scharfstellen der Rabattverträge zu einem aggressiven Preiswettbewerb (effektive Marktpreise nach Rabatt) geführt hat, der in einer steigenden Marktkonzentration münden kann. Vor diesem Hintergrund wird untersucht, welche Entwicklungen auf dem generikafähigen Markt aus oligopoltheoretischer Sicht zu erwarten sind. Anschließend wird ein möglicher Vorschlag für einen zentralen Ansatz der Steuerung des generikafähigen Arzneimittelmarktes entwickelt. Die oligopoltheoretischen Analysen zeigen, dass eine Entwicklung vorstellbar ist, in der zunächst ein intensiver Preiswettbewerb herrscht, da das Gut generikafähiges Arzneimittel von den Krankenkassen als relevanten Nachfragern als homogen angesehen wird und bei den Krankenkassen von einer sehr hohen Preiselastizität der Nachfrage ausgegangen werden kann (Bertrand'scher Preiswettbewerb). Ein solcher Bertrand'scher Preiswettbewerb, bei dem der Preis bis auf die Grenzkosten sinkt, ist in der Realität auf längere Sicht auf oligopolistischen Märkten jedoch selten vorzufinden. Implizite oder gar explizite Preisabsprachen der Oligopolisten führen zu Gewinnmaximierungen zu Gunsten der noch auf dem Markt tätigen Anbieter und zu Lasten der gesellschaftlichen Wohlfahrt sowie der aus dem Markt ausgeschiedenen Unternehmen. Die Wahrscheinlichkeit der Bildung von Preiskartellen bzw. impliziten Preisabsprachen wird umso größer, je kleiner die Anzahl der Oligopolisten ist. Insofern ist eine Entwicklung vorstellbar, in der der Bertrand'sche Preiswettbewerb bei zunehmender Marktkonzentration von einem Preiskartell oder impliziten Preisabsprachen abgelöst wird. Als weniger wahrscheinlich ist eine Einschränkung des Preiswettbewerbs durch Produktdifferenzierung anzusehen. Vor diesem Hintergrund wird in Fachkreisen auch diskutiert, die gegenwärtige Kombination von zentraler Erstattungs-und Preisregulierung mit dezentralem Preiswettbewerb durch ein durchgängig zentrales System zu ersetzen. In diesem Papier wird ein mögliches Modell skizziert, wie ein solcher zentraler Ansatz ausgestaltet sein könnte. ... --

The Causal Effect of Malaria on Stunting: A Mendelian Randomization and Matching Approach

Background Previous studies on the association of malaria and stunted growth delivered inconsistent results. These conflicting results may be due to different levels of confounding and to considerable difficulties in elucidating a causal relationship. Randomized experiments are impractical and previous observational studies have not fully controlled for potential confounding including nutritional deficiencies, breastfeeding habits, other infectious diseases and socioeconomic status. Methods This study aims to estimate the causal effect between malaria episodes and stunted growth by applying a combination of Mendelian randomization, using the sickle cell trait, and matching. We demonstrate the method on a cohort of children in the Ashanti Region, Ghana. Results We found that the risk of stunting increases by 0.32 (P-value: 0.004, 95% CI: 0.09, 1.0) for every malaria episode. The risk estimate based on Mendelian randomization substantially differs from the multiple regression estimate of 0.02 (P-value: 0.02, 95% CI: 0.003, 0.03). In addition, based on the sensitivity analysis, our results were reasonably insensitive to unmeasured confounders. Conclusions The method applied in this study indicates a causal relationship between malaria and stunting in young children in an area of high endemicity and demonstrates the usefulness of the sickle cell trait as an instrument for the analysis of conditions that might be causally related to malaria

Label-free detection of Phytophthora ramorum using surface-enhanced Raman spectroscopy

In this study, we report on a novel approach for the label-free and species-specific detection of the plant pathogen Phytophthora ramorum from real samples using surface enhanced Raman scattering (SERS). In this context, we consider the entire analysis chain including sample preparation, DNA isolation, amplification and hybridization on SERS substrate-immobilized adenine-free capture probes. Thus, the SERS-based detection of target DNA is verified by the strong spectral feature of adenine which indicates the presence of hybridized target DNA. This property was realized by replacing adenine moieties in the species-specific capture probes with 2-aminopurine. In the case of the matching capture and target sequence, the characteristic adenine peak serves as an indicator for specific DNA hybridization. Altogether, this is the first assay demonstrating the detection of a plant pathogen from an infected plant material by label-free SERS employing DNA hybridization on planar SERS substrates consisting of silver nanoparticles