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  • 1
    ISSN: 1527-3458
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: SL651498 (6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2, 9-dihydro-1H-pyrido[3,4-b]indol-1-one) was identified as a drug development candidate from a research program designed to discover subtype-selective GABAA receptor agonists for the treatment of generalized anxiety disorder and muscle spasms. The drug displays high affinity for rat native GABAA receptors containing α1 (Ki= 6.8 nM) and α2 (Ki= 12.3 nM) subunits, and weaker affinity for α5-containing GABAA receptors (Ki= 117 nM). Studies on recombinant rat GABAA receptors confirm these findings and indicate intermediate affinity for the α3β2γ2 subtype. SL651498 behaves as a full agonist at recombinant rat GABAA receptors containing α2 and α3 subunits, and as a partial agonist at recombinant GABAA receptors expressing α1 and α5 subunits. SL651498 produced anxiolytic-like and skeletal muscle relaxant effects qualitatively similar to those of benzodiazepines (BZs) [minimal effective dose (MED): 1 to 10 mg/kg, i.p. and 3 to 10 mg/kg, p.o.]. However, unlike these latter drugs, SL651498 induced muscle weakness, ataxia or sedation at doses much higher than those having anxiolytic-like activity (MED: 30 to 100 mg /kg, i.p. or p.o.). Moreover, in contrast to BZs, SL651498 did not produce tolerance to its anticonvulsant activity or physical dependence. It was much less active than BZs in potentiating the depressant effects of ethanol or impairing cognitive processes in rodents. The differential profile of SL651498 as compared to BZs may be related to its selective efficacy at the α2 and α3-containing GABAA receptors. This suggests that selectively targeting GABAA receptor subtypes can lead to drugs with increased clinical specificity. SL651498 represents a promising alternative to agents currently used for the treatment of anxiety disorders and muscle spasms without the major side effects seen with classical BZs.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature America Inc.
    Nature medicine 6 (2000), S. 929-932 
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] Infectious diseases are the main cause of neonatal morbidity and mortality in humans. The World Health Organization estimated that in 1995 approximately 8 million infants died within the first year of life from infectious diseases, including 5 million during the first week of life. Some of the ...
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Der Radiologe 40 (2000), S. 262-266 
    ISSN: 1432-2102
    Keywords: Schlüsselwörter MR-Mammographie ; Pharmakokinetische Modellierung ; 3D-Visualisierung ; Virtuelle Realität ; Key words MR mammography ; Pharmacokinetic modeling ; 3D visualization ; Virtual reality
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Background: The purpose of this study was the development of a method for fast and efficient analysis of dynamic MR images of the female breast. The image data sets were acquired with a saturation-recovery turbo-FLASH sequence which enables the detection of the kinetics of the contrast agent concentration in the whole breast with a high temporal and spatial resolution. In addition, a morphologic 3D-FLASH data set was acquired. Methods: The dynamic image datasets were analyzed by a pharmacokinetic model which enables the representation of the relevant functional tissue information by two parameters. In order to display simultaneously morphologic and functional tissue information, we developed a multidimensional visualization system, which enables a practical and intuitive human-computer interface in virtual reality. Discussions: The developed system allows the fast and efficient analysis of dynamic MR data sets. An important clinical application is the localization and definition of multiple lesions of the female breast.
    Notes: Zusammenfassung Hintergrund: Ziel dieser Arbeit war die Entwicklung einer Methode zur schnellen und effizienten Befundung dynamischer MR-Bilddatensätze der weiblichen Brust. Für die Datenakquisition wurde eine Saturation-recovery-Turbo-FLASH-Sequenz eingesetzt, die es ermöglicht, die Kinetik der Kontrastmittelanreicherung mit hoher zeitlicher und räumlicher Auflösung in der gesamten Brust zu erfassen. Zusätzlich wurde ein morphologischer 3D-FLASH-Datensatz akquiriert. Methode: Die dynamischen Bilddatensätze wurden mit einem pharmakokinetischen Modell analysiert, das es ermöglicht, die relevante funktionelle Gewebeinformation durch 2 Parameter zu repräsentieren. Zur simultanen Darstellung der morphologischen und funktionellen Gewebeinformation wurde ein multidimensionales Visualisierungssystem entwickelt, das eine praktikable und intuitive Schnittstelle zwischen Mensch und Maschine in virtueller Realität ermöglicht. Diskussion: Das entwickelte System erlaubt eine schnelle und effiziente Befundung dynamischer MR-Bildserien. Eine wichtige klinische Anwendung stellt die Lokalisation und Abgrenzung multipler Läsionen der weiblichen Brust dar.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    s.l. ; Stafa-Zurich, Switzerland
    Solid state phenomena Vol. 95-96 (Sept. 2003), p. 35-42 
    ISSN: 1662-9779
    Source: Scientific.Net: Materials Science & Technology / Trans Tech Publications Archiv 1984-2008
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-2072
    Keywords: Key words Anxiety ; Benzodiazepine ; Diazepam ; Elevated plus-maze ; Inbred and outbred mouse strains ; Light/dark test
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Natural strain differences exist in mice for behavioural traits such as emotional reactivity. Objective: The present experiments compared the behavioural profiles of nine strains of mice (BALB/c, C57BL/6, C3H, CBA, DBA/2, NMRI, NZB, SJL, Swiss) in two models of anxiety after the administration of the benzodiazepine diazepam. Methods: The tests used were the light/dark choice task and the elevated plus-maze, two well-validated anxiolytic screening tests. Results: In vehicle-treated animals, differences on variables designed to measure anxiety-related behaviours were observed in both tests. In the light/dark test, the strains could be divided into three distinct groups: two non-reactive strains (NZB and SJL), an intermediate-reactive group (C3H, CBA, DBA/2, NMRI, C57BL/6 and Swiss), and one highly reactive strain (BALB/c). In the elevated plus-maze, SJL, NMRI, CBA and, to a lesser extent, C3H strains of mice, consistently showed low levels of anxiety-related behaviours. Intermediate levels were seen in the Swiss and BALB/c strains, and high levels of emotional reactivity were seen in C57BL/6, DBA/2 and NZB. The strain distribution between the light/dark and the elevated plus-maze tests shows similarities and differences, suggesting that each of these experimental procedures represents a different set of behaviours. Marked differences between a number of strains of mice in their sensitivity to the anxiolytic-like action of diazepam were observed in both the light/dark and the elevated plus-maze tests. Mice of the BALB/c, Swiss and, to a lesser extent, CBA and C3H strains were responsive to diazepam in both tests, although in the case of CBA mice, effects may have been contaminated by behavioural suppression. SJL mice were largely unresponsive to the action of the benzodiazepine in both tests, whereas in C57, DBA/2, NMRI and NZB mice, diazepam produced positive effects only in the elevated plus-maze. Conclusion: The finding of differential strain distributions both with and without diazepam treatment in the light/dark and the elevated plus-maze tests, indicates that not all strains of mice are suitable for investigating the effects of GABA/BZ receptor ligands. This study may thus provide a useful guide for choosing the best strain of mice for studying the pharmacology of fear-related behaviours.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-1211
    Keywords: Differential display Immune response Mucosal immunity Sheep Sp17 Rotavirus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract. One approach to understanding the physiologically relevant events during the induction of an immune response is to identify genes that are expressed when the immune system first encounters antigen. Such an investigation requires a naive but fully functional immune system, and the fetal lamb provides these conditions during the last trimester of gestation. 'Intestinal segments,' containing a jejunal Peyer's patch, were surgically prepared in fetal lambs (〉120 days gestation) and individual 'intestinal segments' were injected with either culture medium or infectious bovine rotavirus. Peyer's patch tissue was collected 18 h postinfection. Histology and virus culture confirmed that bovine rotavirus had infected the mucosal epithelium. RNA was extracted from jejunal Peyer's patch tissue and mRNA differential display was used to identify genes expressed following rotavirus infection. Ten cDNAs were identified by differential display and these cDNAs were isolated, cloned, and sequenced. One of the cDNAs sequenced, displayed homology to the gene encoding the sperm surface protein Sp17. Differential expression of this gene in antigen-exposed jejunal Peyer's patches was confirmed by Northern blot and RT-PCR. The complete sequence for sheep Sp17 mRNA was obtained from a λ cDNA library, prepared from the jejunal Peyer's patch of a young lamb. Sp17 expression was detected by RT-PCR in a variety of mucosa-associated lymphoid tissues but not in primary or other secondary lymphoid tissues. Thus, the fetal lamb model may be appropriate for identifying genes relevant to mucosal immunity.
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  • 7
    ISSN: 1439-099X
    Keywords: Schlüsselwörter: Tumormikrozirkulation ; Blutfluss ; Dynamische MR-Messungen ; Rektumkarzinom ; Präoperative Strahlentherapie ; Perfusionsindex ; Prognosefaktor ; Key Words: Tumor microcirculation ; Blood flow ; Dynamic MR imaging ; Rectal carcinoma ; Preoperative chemoradiation ; Perfusion index ; Prognostic factor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Purpose: The aim of our study was to evaluate in vivo the influence of tumor microcirculation data on therapy outcome. Patients and Methods: Tumor perfusion data of primary rectal carcinoma (n = 14, cT3) who underwent preoperative chemoradiation have been analyzed (Table 1). The perfusion data were acquired at the beginning and at the end of therapy by use of an ultrafast T1-mapping sequence on a whole-body magnetic resonance imager. The gadolinium-DTPA concentration-time-curves were evaluated for arterial blood and tumor before, during and after intravenous constant rate infusion and from that the perfusion index (PI) was calculated. Subsequent resection of the tumors allowed for a correlation of perfusion index values with the pathological classification. Results: Nine patients showed a T downstaging (ypT0–2, group 1), 5 patients did not (ypT3, group 2). The initial mean perfusion index value of group 1 (n = 9) was 8.2 ml/min/100 g (±2) and for group 2 (n = 5) 10.4 ml/min/100 g (±0.4). The difference in perfusion index values before chemoradiation between group 1 and group 2 was significant different (p = 0.012, Mann-Whitney test). The perfusion index value at the end of therapy of group 1 (n = 6) was 9.6 ml/min/100 g (±2.8) and for group 2 (n = 4) 10.7 ml/min/100 g (±1.6). The difference in perfusion index values after chemoradiation between group 1 and group 2 was not significant different (Table 2). Conclusion: Our used perfusion index value combines 2 parameters: tumor perfusion and extraction fraction. Therefore a significant negative influence on therapy outcome of high perfusion index values could be explained possibly by areas with a high portion of high perfusion (e.g. av-shunts) and a low extraction fraction (= low exchange of nutrients). However, we could show a significant negative influence of high perfusion index values on therapy outcome (p = 0.012). Because the tumor stage has a significant influence on tumor-free survival, there is a possibility for using initial perfusion index values as a new prognostic factor in rectal carcinoma without sphincter infiltration undergoing a preoperative chemoradiation. To examine this hypotheses a prospective trial is in preparation.
    Notes: Fragestellung: Ziel unserer Untersuchung war es, den Einfluss in vivo erhobener Tumormikrozirkulationsdaten auf ein Therapieansprechen zu evaluieren. Patienten und Methode: Bei primären Rektumkarzinomen (n = 14, cT3) wurden Tumorperfusionsdaten bei Beginn und am Ende einer präoperativen kombinierten Radiochemotherapie mittels ultraschneller T1-Mapping-Sequenzen an einem 1,5-Tesla-Ganzkörperkernspintomographen erhoben. Gadolinium-DTPA-Konzentrations-Zeit-Kurven wurden vor, während und nach einem prolongierten Bolus im arteriellen Blut und im Tumor erhoben und daraus der Perfusionsindex (PI) berechnet. Die anschließende chirurgische Resektion ermöglichte eine pathologische Klassifizierung und somit einen Vergleich der Perfusionsindexwerte mit dem Therapieansprechen. Ergebnisse: Bei neun Patienten konnte ein Tumor-Downstaging (ypT0–2) (Gruppe 1), bei fünf Patienten kein Tumor-Downstaging (ypT3) (Gruppe 2) nachgewiesen werden. Der mittlere Perfusionsindexwert für Gruppe 1 (n = 9) betrug 8,2 mg/min/100 g (± 2) und für Gruppe 2 (n = 5) 10,4 ml/min(100 g (±0,4). Es zeigte sich ein signifikanter Unterschied Gruppe 1 versus Gruppe 2 bezüglich Tumor-Downstaging (p = 0,012). Der bei Therapieende erhobene mittlere Perfusionsindexwert für Gruppe 1 (n = 6) betrug 9,6 ml/min/100 g (± 2,8) und für Gruppe 2 (n = 4) 10,7 ml/min/100 g ± 1,6). Hier konnte kein signifikanter Unterschied nachgewiesen werden. Schlussfolgerung: Der Perfusionsindexwert kombiniert zwei Parameter: Tumorperfusion und Extraktionsfraktion. Der überraschende negative Einfluss hoher Perfusionsindexwerte auf ein Therapieansprechen kann somit möglicherweise durch einen hohen Anteil an Arealen hoher Perfusion (eventuell arteriovenösen Shunts) mit niedriger Extraktionsfraktion (= minimaler Stoffaustausch) erklärt werden. Wir konnten aufzeigen, dass hohe Perfusionsindexwerte bei Therapiebeginn einen signifikanten negativen Einfluss (p = 0,012) auf ein Therapieansprechen haben. Da das Tumorstadium einen signifikanten Einfluss auf die tumorfreie Überlebenszeit hat, könnte möglicherweise der Perfusionsindexausgangswert als neuer Prognosefaktor bei primären Rektumkarzinomen ohne Sphinkterinfiltration, die präoperativ mit einer kombinierten Radiochemotherapie behandelt werden, zugezogen werden. Zur Überprüfung dieser Hypothese ist eine prospektive Studie in Vorbereitung.
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  • 8
    Title: Meshfree methods for partial differential equations /; 26
    Contributer: Griebel, Michael
    Edition: 1
    Publisher: Berlin [u.a.] :Springer,
    Year of publication: 2003
    Series Statement: Lecture notes in computational science and engineering 26
    ISBN: 3-540-43891-2
    Type of Medium: Book
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  • 9
    Title: Meshfree Methods for Partial Differential Equations II /; 43
    Contributer: Griebel, Michael , Schweitzer, Marc A.
    Edition: 1. Ed.
    Publisher: Berlin :Springer,
    Year of publication: 2004
    Pages: VIII,303 S.
    Series Statement: Lecture notes in computational science and engineering 43
    ISBN: 3-540-23026-2
    Type of Medium: Book
    Language: English
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