Altered brainstem responses to modafinil in schizophrenia: implications for adjunctive treatment of cognition.

Candidate pro-cognitive drugs for schizophrenia targeting several neurochemical systems have consistently failed to demonstrate robust efficacy. It remains untested whether concurrent antipsychotic medications exert pharmacodynamic interactions that mitigate pro-cognitive action in patients. We used functional MRI (fMRI) in a randomized, double-blind, placebo-controlled within-subject crossover test of single-dose modafinil effects in 27 medicated schizophrenia patients, interrogating brainstem regions where catecholamine systems arise to innervate the cortex, to link cellular and systems-level models of cognitive control. Modafinil effects were evaluated both within this patient group and compared to a healthy subject group. Modafinil modulated activity in the locus coeruleus (LC) and ventral tegmental area (VTA) in the patient group. However, compared to the healthy comparison group, these effects were altered as a function of task demands: the control-independent drug effect on deactivation was relatively attenuated (shallower) in the LC and exaggerated (deeper) in the VTA; in contrast, again compared to the comparison group, the control-related drug effects on positive activation were attenuated in LC, VTA and the cortical cognitive control network. These altered effects in the LC and VTA were significantly and specifically associated with the degree of antagonism of alpha-2 adrenergic and dopamine-2 receptors, respectively, by concurrently prescribed antipsychotics. These sources of evidence suggest interacting effects on catecholamine neurons of chronic antipsychotic treatment, which respectively increase and decrease sustained neuronal activity in LC and VTA. This is the first direct evidence in a clinical population to suggest that antipsychotic medications alter catecholamine neuronal activity to mitigate pro-cognitive drug action on cortical circuits

Ein Beitrag zum Nachweis unterschiedlicher Malatpools in Beeren der Rebe

Zur Frage, ob es unterschiedlich verfügbare Malatpools gibt, wurden reifende Weinbeeren in zwei voneinander verschiedenen Versuchsreihen (Stielapplikation und Injektion) mit 14C-Apfelsäure gefüttert. Danach wird bei reifenden Beeren (Phase IV) die ins Beereninnere applizierte Apfelsäure - nahezu unabhängig vom Reifegrad - weniger stark metabolisiert (40-47 % Veratmungs-CO2/20 h) als die durch den Beerenstiel zugeführte Apfelsäure (78-95 % Veratmung/20 h). Bei grünen Beeren (Phasen I-III) ist eine Veratmung und damit Metabolisierung von injiziertem Malat kaum feststellbar. Die Bildungsrate von Zucker aus Apfelsäure (Gluconeogenese) ist beim Injektionsversuch, der eingelagertes Malat simulieren soll, etwas höher als beim Aufnahmeversuch.Die Versuchsergebnisse werden dahingehend gedeutet, daß es einen aktiven Malatpool gibt, in dem die über den Beerenstiel eintransportierte Apfelsäure unabhängig vom Reifestadium ständig veratmet wird, und daßein inaktiver Malatpool im Beereninneren existiert.Die im Beereninneren bereits abgelagerte Apfelsäure ist bei grünen Beeren nahezu unmetabolisierbar; sie wird erst nach Weichwerden der Beeren infolge der Permeabilitätssteigerung besser an die Beerenperipherie transportiert und abgebaut. Die möglichen Faktoren für die veränderte Permeabilität werden angesprochen.Investigations on the existence of different malate pools in grape berriesIn order to demonstrate the existence of differently available malate pools, ripening grape berries were fed with 14C-malic acid in two different experimental series (pedicel application and injection). The results show that malic acid injected into ripening grapes (Phase IV) is - nearly independent of the stage of ripeness - metabolized less rapid (40-47 % respiration-CO2/20 h) than is malic acid applicated through the pedicel (78-95 1/o respiration-CO2/20 h). In green berries (Phase I-III) respiration, i. e. metabolization, of injected malate can scarcely be established. The rate of sugar formation from malate (gluconeogenesis) is less intensive in the pedicel application experiment than in the injection experiment which is to be simulating the malate incorporated.The results are interpreted as follows: There is an active malate pool, where malic acid imported through the pedicel is steadily respired, independently of the stage of ripeness.An inactive malate pool exists in the interior of the berries.Malic acid already incorporated in the interior of the berries is almost not metabolized in green berries. Owing to an increase in permeability, it is transported to the berry periphery and dissimilated only with berry ripenjng. Possible factors of the change in permeability are discussed

Biochemisch-physiologisdle Untersuchungen an Traubenbeeren III. Stoffwechsel von zugeführten 14C-Verbindungen und die Bedeutung des Säure-Zucker-Metabolismus für die Reifung von Traubenbeeren

Zum Studium des Stoffwechsels reifender Traubenbeeren führten wir traubentragenden Trieben und isolierten Trauben zunächst in Dunkelversuchen 1.4-  14C-Weinsäure, uniform markierte  14C-Glucose und  14C-Glutaminsäure sowie 1- 14C-Acetat zu. In Mitt. II (2) haben wir über die Verteilung und Veratmung dieser Verbindungen berichtet. Zur Charakterisierung des Stoffwechsels der markierten Verbindungen haben wir die Fraktionen Beerenextrakte chromatographisch in die Stoffgruppen Neutralstoffe (Zucker), organische Säuren, Aminosäuren und weiter in Einzelsubstanzen aufgetrennt und deren Radioaktivität gemessen. In gleicher Weise sind auch die Beerenextrakte der Versuche mit isolierten Trauben nach Zufuhr von 3-14C-Äpfelsäure und nach Fixierung von  14CO2 im Hellen und Dunkeln aufgearbeitet und untersucht worden.Äpfel- und Weinsäure haben voneinander verschiedene Stoffwechselwege. Aus Glucose und Glutaminsäure entstehen wenig Weinsäure und vergleichsweise viel Äpfelsäure, während aus Acetat hauptsächlich Äpfelsäure gebildet wird. Unter den experimentellen Bedingungen wurde Weinsäure ausschließlich veratmet, wogegen Äpfelsäure neben der Veratmung markierte Metabolite aller 3 Stoffgruppen bildet. Aus Äpfelsäure werden wie aus Acetat und Glutaminsäure in den Dunkelversuchen Zucker gebildet; im Hellversuch ist die Zuckerbildung aus Äpfelsäure stark vermehrt. Unter Berücksichtigung der bevorzugten Bildung von Säuren bei der C02-Dunkelfixierung und von Zuckern während der C02-Hellfixierung werden die Bildungsmechanismen für Säuren und Zucker diskutiert. Die Umwandlung von Säuren in Zucker in reifenden Traubenbeeren ist damit sichergestellt. Die Versuche mit 14C-Verbindungen werden weitergeführt

Der Einfluß von Blatt- und Wurzelgallen der Reblaus (Dactylosphaera vitifolii Shimer) auf das Verteilungsmuster der Assimilate in Reben (Vitis rupestris 187 G.)

An 1jährigen Rebstecklingen (Vitis rupestris 187 G.) in Hydroponikkultur, die sowohl ober- wie unterirdisch von der Reblaus befallen oder nur an Blättern bzw. Wurzeln vergallt oder gänzlich reblausfrei waren, wurde mit Hilfe von 14C02 der Einfluß der Reblausvergallung auf die Bildung und Verteilung von Assimilaten untersucht. Blattvergallung hatte stets eine Retention radioaktiv markierter Verbindungen im Blattbereich und einen verminderten Export von Assimilaten nach dem Wurzelbereich zur Folge.Wurzelvergallung war ebenfalls mit einer Anreicherung von 14Cin den Nodositäten verbunden, die jedoch nicht das Ausmaß der für die Blattgallen geschätzten Werte erreichte und zu einer Verarmung der normalen Wurzelpartien an radioaktiven Substanzen führte.Die von einer Rebe durchschnittlich inkorporierte Gesamtmenge an 14C unterschied sich zwischen den einzelnen Versuchsvarianten nicht oder nicht einschneidend. Die gesteigerte Akkumulation von Assimilaten in den - photosynthetisch nur schwach aktiven - Blattgallen läßt auf eine Intensivierung der Photosyntheseleistung in den normalen Bezirken der verganten Blätter schließen.Die Bedeutung der ReblausvergaHung für das Verteilungsmuster der Assimilate wird unter dem Aspekt von Source-Sink-Beziehungen diskutiert.The effects of phylloxera leaf and root galls on the pattern of assimilate distributionin grapevine (Dactylosphaera vitifolii Shimer on Vitis rupestris 187 G.)Young grapevine cuttings growing in hydroponic culture and galled by phylloxera on both leaves and roots, on leaves only, on roots only, or not infested at all were exposed to 14C02 for 1 h and the distribution of radioactivity incorporated into the various plant parts 24 h after the beginning of photosynthesis was studied.Galling of leaves always resulted in a retention of labelled substances in the leaves and a reduced export of assimilates to the roots.14C was also accumulated in the root galls, its level, however, being lower than that estimated for the leaf galls. Root galling was accompanied by a decrease of labelled compounds in the unchanged parts of the roots.The mean total amount of 14C incorporated by a grapevine plant was similar in the four experimental groups. lt is concluded that the rise of radioactivity in the leaf galls which, according to former experiments, show only weak photosynthesis is due to an increase of photosynthesis in the normal leaf parts.The effects of phylloxera galls on the pattern of assimilate distribution were discussed in terms of source-to-sink relationships

Sketch-To-Solution: An Exploration of Viscous CFD with Automatic Grids

Numerical simulation of the Reynolds-averaged NavierStokes (RANS) equations has become a critical tool for the design of aerospace vehicles. However, the issues that affect the grid convergence of three dimensional RANS solutions are not completely understood, as documented in the AIAA Drag Prediction Workshop series. Grid adaption methods have the potential for increasing the automation and discretization error control of RANS solutions to impact the aerospace design and certification process. The realization of the CFD Vision 2030 Study includes automated management of errors and uncertainties of physics-based, predictive modeling that can set the stage for ensuring a vehicle is in compliance with a regulation or specification by using analysis without demonstration in flight test (i.e., certification or qualification by analysis). For example, the Cart3D inviscid analysis package has automated Cartesian cut-cell gridding with output-based error control. Fueled by recent advances in the fields of anisotropic grid adaptation, error estimation, and geometry modeling, a similar work flow is explored for viscous CFD simulations; where a CFD application engineer provides geometry, boundary conditions, and flow parameters, and the sketch-to-solution process yields a CFD simulation through automatic, error-based, grid adaptation

Results of the Anaconda endovascular graft in abdominal aortic aneurysm with a severe angulated infrarenal neck

Objective: Proximal neck anatomy of an abdominal aortic aneurysm (AAA), especially a severe angulated neck of more than 60 degrees, predicts adverse outcome in endovascular aneurysm repair. In the present study, we evaluate the feasibility of the use of the Anaconda endovascular graft (Vascutec, Terumo, Inchinnan, Scotland) for treating infrarenal AAA with a severe angulated neck (>60 degrees) and report the midterm outcomes. Methods: In total, nine Dutch hospitals participated in this prospective cohort study. From December 2005 to January 2011, a total of 36 AAA patients, 30 men and six women, were included. Mean and median follow-up were both 40 months. Results: Mean infrarenal neck angulation was 82 degrees. Successful deployment was reached in 34 of 36 patients. Primary technical success was achieved in 30 of 36 patients (83%). There was no aneurysm-related death. Four-year primary clinical success was 69%. In the first year, eight clinical failures were reported including four leg occlusions which could be solved using standard procedures. After the first year, three patients with additional failures occurred; two of them were leg occlusions. Four patients needed conversion to open AAA exclusion. In six of 36 patients, one or more reinterventions were necessary. Three of them were performed for occlusion of one Anaconda leg and two were for occlusion of the body. Conclusions: The use of the Anaconda endovascular graft in AAA with a severe angulated infrarenal neck is feasible but has its side effects. Most clinical failures occur in the first year. Thereafter, few problems occur, and midterm results are acceptable. Summarizing the present experiences, we conclude that open AAA repair is still a preferable option in patients with challenging aortic neck anatomy and fit for open surgery

Quantum Effects in Neural Networks

We develop the statistical mechanics of the Hopfield model in a transverse field to investigate how quantum fluctuations affect the macroscopic behavior of neural networks. When the number of embedded patterns is finite, the Trotter decomposition reduces the problem to that of a random Ising model. It turns out that the effects of quantum fluctuations on macroscopic variables play the same roles as those of thermal fluctuations. For an extensive number of embedded patterns, we apply the replica method to the Trotter-decomposed system. The result is summarized as a ground-state phase diagram drawn in terms of the number of patterns per site, $\alpha$, and the strength of the transverse field, $\Delta$. The phase diagram coincides very accurately with that of the conventional classical Hopfield model if we replace the temperature T in the latter model by $\Delta$. Quantum fluctuations are thus concluded to be quite similar to thermal fluctuations in determination of the macroscopic behavior of the present model.Comment: 34 pages, LaTeX, 9 PS figures, uses jpsj.st

N-Salicyloyl-Asparaginsäure: Eine neue phenolische Verbindung aus Reben

N-Salicyloyl-aspartic acid: a new phenolic compound in grapevinesA new phenolic compound was detected in wild vines (Vitis riparia and V. rupestris) and some of their cross-breeding hybrids and identified as N-salicyloyl-aspartic acid. It shows no effects on Botrytis, but causes a slight inhibition of Plasmopara growth. The substance has never been found in nature hitherto

Vorkommen und Inversion von Saccharose in Weinbeeren

Durch die Anwendung der HPLC-Methode zur schnellen quantitativen Erfassung von Saccharose neben Glucose und Fructose konnte gezeigt werden, daß der Saccharosegehalt in Weinbeeren zwischen 5,5 und 21 g/l Beerensaft liegt. Im zentrifugierten Beerensaft nimmt der Saccharosegehalt innerhalb von 2 Std. bei einer Temperatur von 20 °C um 1,8 bis 11,4 g/l ab. Die Saccharoseinversion wird von Temperatur, festen Beerenanteilen, pH-Wert und zusätzlich zugefügter Saccharose beeinflußt. Ein Zusatz von S02 bis 200 mg/l hat keinen Einfluß auf die Spaltgeschwindigkeit. Auch in intakten, isolierten Beeren konnten wir eine Saccharoseinversion nachweisen. Dabei konnte mit 14C-markierter Saccharose gezeigt werden, daß frisch eingewanderte Saccharose intensiver invertiert wird als bereits im Beereninnern eingelagerte. In dem bearbeiteten Untersuchungsmaterial konnten keine sortenspezifischen Unterschiede der Saccharosekonzentration oder der Invertaseaktivität aufgezeigt werden.Occurence and inversion of sucrose in grape berriesUsing HPLC as a rapid method of determining sucrose, besides glucose and fructose, it could be shown that the sucrose content in grape berries ranges between 5.5 and 21 g/l berry juice. In the centrifuged berry juice sucrose decreases from 1.8 to 11.4 g/l were observed within 2 hours at a temperature of 20 °C. The sucrose Inversion is influenced by temperature, solid berry components, pH value and by added sucrose. An addition of S02 up to 200 mg/l does not influence the inversion rate. Sucrose inversion has also been established in intact, isolated berries. By means of 14C-sucrose it could be shown that freshly imported sucrose is more intensively inverted than sucrose already incorporated inside the berries. Variety-specific differences in the sucrose concentration or in the invertase activity could not be established in the investigated material

Replica Symmetry Breaking in Attractor Neural Network Models

The phenomenon of replica symmetry breaking is investigated for the retrieval phases of Hopfield-type network models. The basic calculation is done for the generalized version of the standard model introduced by Horner [1] and by Perez-Vicente and Amit [2] which can exhibit low mean levels of neural activity. For a mean activity $\bar a =1/2$ the Hopfield model is recovered. In this case, surprisingly enough, we cannot confirm the well known one step replica symmetry breaking (1RSB) result for the storage capacity which was presented by Crisanti, Amit and Gutfreund [3] (\alpha_c^{\hbox{\mf 1RSB}}\simeq 0.144). Rather, we find that 1RSB- and 2RSB-Ans\"atze yield only slightly increased capacities as compared to the replica symmetric value (\alpha_c^{\hbox{\mf 1RSB}}\simeq 0.138\,186 and \alpha_c^{\hbox{\mf 2RSB}}\simeq 0.138\,187 compared to \alpha_c^{\hbox{\mf RS}}\simeq 0.137\,905), significantly smaller also than the value \alpha_c^{\hbox{\mf sim}} = 0.145\pm 0.009 reported from simulation studies. These values still lie within the recently discovered reentrant phase [4]. We conjecture that in the infinite Parisi-scheme the reentrant behaviour disappears as is the case in the SK-spin-glass model (Parisi--Toulouse-hypothesis). The same qualitative results are obtained in the low activity range.Comment: Latex file, 20 pages, 8 Figures available from the authors upon request, HD-TVP-94-