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  • Atomic, Molecular and Optical Physics  (6,266)
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  • 1
    Publication Date: 2020-12-11
    Description: Im Mai 2009 wurde Wolfram|Alpha gestartet, ein Service, der seinen Namen von seinem Entwickler, dem britischen Mathematiker Stephen Wolfram, ableitet. Dem Benutzer soll nicht nur eine Liste von Webseiten als Ergebnis auf Anfragen geliefert werden, sondern Antworten auf konkrete Fragen geben. In diesem Report soll gezeigt werden, warum sichWolframjAlpha von Suchmaschinen abgrenzt und was die Berechnung von Antworten auf natürlichsprachliche Fragen möglich machen kann.
    Description: Wolfram|Alpha was started in May 2009 and it's a service whose name derives from the british mathematician Stephen wolfram. As a result for a request the user is not just supported with a list of websites but with answers for concrete questions. In this report it will be shown why Wolfram|Alpha seperates from search engines and moreover what makes the computation of answers for natural language queries possible.
    Keywords: ddc:004
    Language: German
    Type: reportzib , doc-type:preprint
    Format: application/pdf
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  • 2
    Publication Date: 2016-06-30
    Description: Executing applications in the Grid often requires access to multiple geographically distributed resources. In a Grid environment, these resources belong to different administrative domains, each employing its own scheduling policy. That is, at which time an activity (e.g., compute job, data transfer) is started, is decided by the resource's local management system. In such an environment, the coordinated execution of distributed applications requires guarantees on the quality of service (QoS) of the needed resources. Reserving resources in advance is an accepted means to obtain QoS guarantees from a single provider. The challenge, however, is to coordinate advance reservations of multiple resources. This work presents a system architecture and mechanisms to coordinate multiple advance reservations -- called co-reservations -- for delivering QoS guarantees to complex applications. We formally define the co-reservation problem as an optimization problem. The presented model supports three dimensions of freedom: the start time, the duration and the service level of a reservation. Requests and resources are described in a simple language. After matching the static properties and requirements of either side in a mapping, the reservation mechanism probes information about the future status of the resources. The versatile design of the probing step allows the efficient processing of requests, but also lets the resources express their preferences among the myriads of reservation candidates. Next, the best mapping is found through an implementation of the formal co-reservation model. Then, the mapping has to be secured, i.e., resources need to be allocated to a co-reservation candidate with all-or-nothing semantics. We study several goal-driven sequential and concurrent allocation mechanisms and define schemes for handling allocation failures. Finally, we introduce the concept of virtual resources for seamlessly embedding co-reservations into Grid resource management.
    Description: Die Ausführung von Anwendungen erfordert oft mehrere, geographisch verteilte Ressourcen. In Grid-Umgebungen gehören diese Ressourcen zu verschiedenen administrativen Organisationen, wobei jede ihre eigene Schedulingregeln verwendet. Das bedeutet, zu welcher Zeit eine Aktivität gestartet wird (z.B. ein Rechenjob), wird vom lokalen Ressourcenmanagementsystem entschieden. Die koordinierte Ausführung von verteilten Anwendungen erfordert Dienstgütegarantien für die benötigten Ressourcen. Das Reservieren von Ressourcen im Voraus ist ein Mittel, um Dienstgütegarantien von einem einzelnen Ressourcenanbieter zu erhalten. Die Herausforderung in dieser Arbeit ist, Vorausreservierungen von mehreren Ressourcen zu koordinieren. Es wird ein System für die Koordinierung mehrerer Vorausreservierungen -- Co-Reservierungen genannt -- für die Bereitstellung von Dienstgütegarantien vorgestellt. Wir definieren das Co-Reservierungsproblem als Optimierungsproblem. Das vorgestellte Modell unterstützt drei Freiheitsgrade: die Startzeit, die Dauer und die Dienstgüte einer Reservierung. Anfragen und Ressourcen werden in einer einfachen Sprache beschrieben. Nachdem statische Eigenschaften und Anforderungen beider Seiten überprüft wurden, ermittelt der Reservierungsmechanismus Informationen über den zukünftigen Zustand der Ressourcen. Dieser Schritt ist so allgemein gehalten, daß er sowohl ein effizientes Bearbeiten der Anfragen erlaubt als auch den Ressourcen ermöglicht ihre Präferenzen auszudrücken. Im Anschluss wird die optimale Zuweisung von Anfragen zu Ressourcen ermittelt. Im letzten Schritt muss diese Zuweisung umgesetzt werden, d.h., entweder alle oder keine Ressource wird allokiert. Es werden mehrere sequentielle und parallele Allokationsverfahren vorgestellt sowie deren Auswirkung auf verschiedene Metriken untersucht. Die Einbettung von Co-Reservierungen in das Grid-Ressourcenmanagement wird anhand des Konzeptes der virtuellen Ressource dargestellt.
    Keywords: ddc:004
    Language: English
    Type: doctoralthesis , doc-type:doctoralThesis
    Format: application/pdf
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  • 3
    Publication Date: 2016-06-30
    Description: Aktuelle Entwicklungen zeigen, dass Peer-to-Peer (P2P) Anwendungen wie Skype oder Bittorrent im Internet immer mehr an Bedeutung gewinnen. In den letzten Jahren hat es einen explosionsartigen Anstieg an Nutzern und Daten in solchen Netzen gegeben. Dabei stellt der eigentliche Dateitransfer zwischen zwei Rechnern kein großes Problem mehr dar und auch der Speicherbedarf für die große Menge an Daten kann durch die Weiterentwicklung der Hardware gut gedeckt werden. Das eigentliche Problem liegt vielmehr darin, den Rechner zu finden, der die gewünschten Daten hat. Client-Server Architekturen, wie zum Beispiel Napster, haben sich als ungünstig herausgestellt. Wenige Server, die eine große Anzahl an Clients bedienen müssen, sind einerseits sehr anfällig gegenüber Angriffen und Ausfällen (Single Point of Failure)und kommen auch nicht mit der ständig wachsenden Anzahl an Nutzern zurecht. Verteilte Hashtabellen (DHT) bieten hier einen guten Lösungsansatz, der mit einer großen Anzahl an Nutzern skaliert und ausfallsicher ist. Andere dezentrale Lösungen, wie zum Beispiel das P2P Netzwerk Gnutella haben zwar das Problem des Single Point of Failure gelöst, jedoch haben sie starke Nachteile bei der Suche nach Keys. Bei einer Suche wird ein Broadcast verwendet (jeder schickt die Anfrage an jeden weiter) und damit ein enormer Netzwerkverkehr erzeugt. In "Why Gnutella Can't Scale. No, Really" wird erklärt, dass eine Suchanfrage bei Standardeinstellungen in der Clientsoftware einen Netzwerkverkehr von 17MB erzeugt. Deswegen wird zusätzlich eine Lösung benötigt, die Keys und Values geordnet verteilt, damit sie gezielt gesucht werden können. Aus diesem Grund beschäftigt sich die folgende Arbeit mit einer völlig dezentralen Architektur, die außerdem eine sinnvolle Platzierung der Keys vornimmt. Die dezentrale Architektur hat den Vorteil, dass die Endgeräte den Hauptteil des Dienstes selbst erbringen und damit jeder zusätzliche Teilnehmer seine eigenen Ressourcen beisteuert. Diese Arbeit präsentiert Chord#, eine dezentrale, skalierbare und selbstorganisierende verteilte Hashtabelle. Chord# wurde ausgewählt, da in dieser Arbeit auch Wert auf Bereichsabfragen gelegt wurde. Diese sind zum Beispiel bei dem Chord Algorithmus nicht möglich, da dieser eine Hashfunktion für die Keys verwendet und somit die Daten zwar gleichmäßig aber unsortiert auf die Teilnehmer verteilt. Es wird in dieser Arbeit gezeigt, dass mit Hilfe von Chord# auch ohne die Hashfunktion gute Ergebnisse erzielt werden. Außerdem können durch den Verzicht auf die Hashfunktion Bereichsabfragen ermöglicht werden. Dafür wird der Chord# Algorithmus in Java implementiert (ca. 1500 Zeilen Code) und in dem Forschungsnetz PlanetLab ausführlich auf Laufzeiten, Instandhaltungskosten und Skalierung getestet.
    Description: Recent developments show that peer-to-peer (p2p) applications, such as Skype or Bittorrent have become increasingly important in the internet. Over the last years there has been a rapid growth of both users and data in such networks. However, the actual file transfer between two peers is not really an issue anymore. The same holds true for data storage, since the new hardware grants users enough space to store their data. The real problem is finding the peers that possess the desired data. Client-server architectures like Napster have proven to be ineffective addressing that problem. One or few servers being responsible for many peers are vulnerable to attacks or failures (single point of failure). Additionally, they are unable to cope with the rapidly growing number of peers. Distributed hashtables (DHT) are a good approach to solve these problems, since they scale nicely with large numbers of peers and provide a high tolerance for errors. Other decentralized solutions like the p2p network Gnutella solved the problem of Single Point of Failure but show considerable disadvantages when searching for keys. The peers in Gnutella use a broadcast (sending the message to all peers they know)resulting in massive traffic. According to "Why Gnutella Can't Scale. No, Really.", each search using standard client settings yields 17MB traffc. This calls for a different solution, distributing keys and values to peers quickly and efficiently so they can be found fast. For that reason this thesis focuses on a fully distributed architecture using organized key placement. One major advantage of distributed architecture is the fact, that the peers do most of the work themselves. This way, new peers joining the network add resources to it. This thesis presents Chord#, a scalable, self-organizing and completely decentralized DHT. It has been chosen due to its capability to allow range queries. The regular Chord algorithm does not support range queries, because of the hashfunction it uses to evenly distribute the keys among the peers. This results in similar or logical coherent keys most likely not being close together in the network. This thesis shows Chord# achieving same results as Chord - regarding performance costs - without the hashfunction. In dropping the hashfunction this algorithm allows the use of range queries. The Chord# algorithm is implemented in Java (about 1500 lines of code) and thoroughly tested in the research network PlanetLab. The results are evaluated regarding performance, maintenance and scalability.
    Keywords: ddc:004
    Language: German
    Type: masterthesis , doc-type:masterThesis
    Format: application/pdf
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  • 4
    Publication Date: 2017-11-02
    Description: One of the biggest impacts on the performance of a Distributed Hash Table (DHT), once established, is its ability to balance load among its nodes. DHTs supporting range queries for example suffer from a potentially huge skew in the distribution of their items since techniques such as consistent hashing can not be applied. Thus explicit load balancing schemes need to be deployed. Several such schemes have been developed and are part of recent research, most of them using only information locally available in order to scale to arbitrary systems. Gossiping techniques however allow the retrieval of fairly good estimates of global information with low overhead. Such information can then be added to existing load balancing algorithms that can use the additional knowledge to improve their performance. Within this thesis several schemes are developed that use global information like the average load and the standard deviation of the load among the nodes to primarily reduce the number of items an algorithm moves to achieve a certain balance. Two novel load balancing algorithms have then been equipped with implementations of those schemes and have been simulated on several scenarios. Most of these variants show better balance results and move far less items than the algorithms they are based on. The best of the developed algorithms achieves a 15-30% better balance and moves only about 50-70% of the number of items its underlying algorithm moves. This variation is also very robust to erroneous estimates and scales linearly with the system size and system load. Further experiments with self-tuning algorithms that set an algorithm’s parameter according to the system’s state show that even more improvements can be gained if additionally applied. Such a variant based on the algorithm described by Karger and Ruhl shows the same balance improvements of 15-30% as the variant above but reduces the number of item movements further to 40-65%.
    Keywords: ddc:004
    Language: English
    Type: masterthesis , doc-type:masterThesis
    Format: application/pdf
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  • 5
    Publication Date: 2020-12-15
    Description: Entwurf und Entwicklung eines eingebetteten Hauptspeicher-Datenbanksystems mit Snapshot-Reads.
    Description: Design and implementation of an embedded main memory database with snapshot reads.
    Keywords: ddc:004
    Language: German
    Type: masterthesis , doc-type:masterThesis
    Format: application/pdf
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  • 6
    Publication Date: 2016-06-30
    Description: Das Ziel dieser Arbeit ist die Schaffung einer Zugriffs-Komponente für das Grid-Datenmanagement-System ZIB-DMS, das dessen transparente Einbindung in den Verzeichnisbaum eines Linux-Systems erlaubt. Dazu wird unter Verwendung des FUSE-Rahmenwerkes ein Userspace-Dateisystem mit Anbindung an das ZIB-DMS konzipiert und implementiert. Im Fokus stehen dabei die Abbildung der erweiterten Verwaltungsmechanismen des Systems auf die limitierte Schnittstelle hierarchischer Dateisysteme und die dazu notwendigen Änderungen am ZIB-DMS.
    Description: The goal of this work is to create an access component for the Grid data management system ZIB-DMS, that allows a transparent integration into the directory tree of a Linux system. For this purpose the FUSE framework is used to design and implement a userspace file system with connections to the ZIB-DMS. The focus is on the mapping of the extended management mechanisms of the system to the limited interface of hierarchical file systems and the therefore necessary changes to ZIB-DMS.
    Keywords: ddc:004
    Language: German
    Type: masterthesis , doc-type:masterThesis
    Format: application/pdf
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  • 7
    Publication Date: 2021-01-22
    Description: We present a framework for transactional data access on data stored in a DHT. It allows to atomically read and write items and to run distributed transactions consisting of a sequence of read and write operations on the items. Items are symmetrically replicated in order to achieve durability of data stored in the SON. To provide availability of items despite the unavailability of some replicas, operations on items are quorum-based. They make progress as long as a majority of replicas can be accessed. Our framework processes transactions optimistically with an atomic commit protocol that is based on Paxos atomic commit. We present algorithms for the whole framework with an event based notation. Additionally we discuss the problem of lookup inconsistencies and its implications on the one-copy serializability property of the transaction processing in our framework.
    Keywords: ddc:004
    Language: English
    Type: reportzib , doc-type:preprint
    Format: application/pdf
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  • 8
    Publication Date: 2020-12-11
    Description: When planning teams for projects with specific goals, employees of a company have to group together so well, that all necessary knowledge for conquering the project’s challenges are met within the member’s skills. A tool that facilitates semantic web technologies can support the team recruiter, who is responsible for chosing the members of the team, in terms of finding the most efficient combinations of the company’s employees based on their expertises.
    Keywords: ddc:004
    Language: English
    Type: reportzib , doc-type:preprint
    Format: application/pdf
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  • 9
    Publication Date: 2021-01-22
    Description: Key/value stores which are built on structured overlay networks often lack support for atomic transactions and strong data consistency among replicas. This is unfortunate, because consistency guarantees and transactions would allow a wide range of additional application domains to benefit from the inherent scalability and fault-tolerance of DHTs. The Scalaris key/value store supports strong data consistency and atomic transactions. It uses an enhanced Paxos Commit protocol with only four communication steps rather than six. This improvement was possible by exploiting information from the replica distribution in the DHT. Scalaris enables implementation of more reliable and scalable infrastructure for collaborative Web services that require strong consistency and atomic changes across multiple items.
    Keywords: ddc:004
    Language: English
    Type: reportzib , doc-type:preprint
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  • 10
    Publication Date: 2022-07-19
    Description: Basierend auf einem vorhandenen Ansatz zur Einführung von anisotropen Tetraedern im Randbereich eines reinen Tetraedergitters wird ein Gittergenerator für hybride Gitter implementiert. Das hybride Gitter besteht in Randnähe primär aus anisotropen Prismen und im Inneren der Geometrie aus isotropen Tetraedern. Eine erhöhte Auflösung im Randbereich soll zu besseren Ergebnissen von numerischen Strömungssimulationen führen, für welche eine problemangepasste Diskretisierung des zu untersuchenden Gebietes benötigt wird. In dem zuvor genannten Ansatz wird eine Reihe von Übergangselementen vorgeschlagen, die an scharfen Kanten der Oberfläche platziert werden sollen. Im Rahmen dieser Diplomarbeit wird die Idee der Übergangselemente aufgegriffen und bei hybriden Gittern eingesetzt, um auch komplexe Eingabegeometrien vergittern zu können. Der ursprüngliche Gittergenerierungprozess wird überarbeitet und erweitert. Eine neue Menge an Übergangselementen wird eingeführt, es werden gekrümmte Extrusionsvektoren verwendet und es wird die Auswertung der medialen Oberfläche vorgenommen, um Überschneidungen im hybriden Gitter zu vermeiden. Der Gittergenerator wird als Modul in das Visualisierungs- und Analyseprogramm Amira implementiert und die erstellten hybriden Gitter werden auf ihre Elementqualität und die Güte der Strömungssimulationsergebnisse hin überprüft.
    Description: Based on an existing approach for the introduction of anisotropic tetrahedra near the surface boundary of a tetrahedral grid a grid generator for hybrid grids is implemented. The hybrid grid consists near the surface boundary primarily of anisotropic prisms and inside the geometry of isotropic tetrahedra. An increased resolution near the boundary should lead to better results of numerical flow simulations, which needs a problem specific discretization of the analyzed domain. In the aforementioned approach a set of transition elements is suggested, which should be placed at sharp surface corners. As a part of this diploma thesis the concept of using transition elements is applied for creating hybrid grids even for very complex input geometries. The initial grid generation process is revised and enhanced. A new set of transition elements is introduced, curved extrusion vectors are used and the medial surface is evaluated to avoid intersections in the hybrid grid. The grid generator is implemented as a module for the visualization and analysis tool Amira and the element quality of the generated hybrid grids and the quality of flow simulations performed on the grids are tested.
    Keywords: ddc:004
    Language: German
    Type: masterthesis , doc-type:masterThesis
    Format: application/pdf
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  • 11
    Publication Date: 2016-06-30
    Description: We study performance and scaling of the Berlin Quantum Chromodynamics Program (BQCD) on the SGI Altix 4700 at Leibniz Supercomputing Centre (LRZ). We employ different communication methods (MPI, MPI with two OpenMP threads per process, as well as the shmem library) and run the MPI version on the two types of nodes of that machine. For comparison with other machines we made performance measurements on an IBM p690 cluster and a Cray XT4.
    Keywords: ddc:004
    Language: English
    Type: reportzib , doc-type:preprint
    Format: application/pdf
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  • 12
    Publication Date: 2022-07-19
    Description: In dieser Arbeit wird eine Serie von Remeshing-Verfahren um die Berücksichtigung von nicht-mannigfaltigen Dreiecksvernetzungen und Merkmalskantenzügen erweitert. Die betrachteten Verfahren arbeiten im Wesentlichen lokal. Daher können die im Rahmen dieser Arbeit entwickelten Erweiterungen, die nicht-mannigfaltige Kantenzüge und Merkmalskantenzüge betreffen, separat beschrieben werden. Dabei wird ein Ansatz verfolgt, beide Arten von besonderen Kantenzügen aufgrund ihrer Gemeinsamkeiten einheitlich zu behandeln. Dieser besteht zum einen darin, eine Korrespondenz zwischen Kantenzügen auf der Eingabe- und der Ausgabefläche zu erhalten, indem die Remeshing-Operationen auf den Kantenzügen in entsprechend eingeschränkter Weise verwendet werden. Zum anderen wird beschrieben, wie die Abtastdichte der Kantenzüge dynamisch an die Abtastdichte der Umgebung angepasst werden kann, um für weitgehende Isotropie in der Nähe von Merkmalskantenzügen zu sorgen.
    Description: A unified approach for consistent remeshing of arbitrary non-manifold triangle meshes with additional user-defined feature lines is presented. The method is based on local operations only and produces meshes of high regularity and triangle quality while preserving the geometry as well as topology of the feature lines as well as the input mesh.
    Keywords: ddc:004
    Language: German
    Type: masterthesis , doc-type:masterThesis
    Format: application/pdf
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  • 13
    Publication Date: 2022-07-19
    Description: This work introduces a novel streamline seeding technique based on dual streamlines that are orthogonal to the vector field, instead of tangential. The greedy algorithm presented here produces a net of orthogonal streamlines that is iteratively refined resulting in good domain coverage and a high degree of continuity and uniformity. The algorithm is easy to implement and efficient, and it naturally extends to curved surfaces.
    Description: In dieser Arbeit wird eine neue Strategie zur Platzierung von Stromlinien vorgestellt. Hierzu werden zusätzliche duale Stromlinien verwendet, die --im Gegensatz zur üblichen Definition-- orthogonal zum Vektorfeld verlaufen. Der vorgestellte Greedy-Algorithmus berechnet ein Netz aus orthogonalen Stromlinien, welches iterativ verfeinert wird, was zu einer guten Abdeckung der Domäne und einer gleichmäßigen Verteilung der Stromlinien führt. Es handelt sich um einen einfach zu implementierenden und effizienten Algorithmus, der direkt auf gekrümmten Oberflächen anwendbar ist.
    Keywords: ddc:004
    Language: English
    Type: reportzib , doc-type:preprint
    Format: application/pdf
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  • 14
    Publication Date: 2020-12-11
    Description: In dieser Diplomarbeit wird untersucht, wie auf der Basis von Literaturreferenzen ein Zitationsgraph durch ein automatisches Verfahren aufgebaut werden kann. Zur Lösung des Problems werden Probabilistische Relationale Modelle herangezogen. Eine problemspezifische Erweiterung des Modells ermöglicht es, dass bestehende Unsicherheiten im Zitationsgraphen mit Hilfe eines Inferenzverfahrens aufgelöst werden können. Zur Evaluierung des Verfahren werden Experimente auf dem Cora-Datensatz durchgeführt.
    Keywords: ddc:004
    Language: German
    Type: masterthesis , doc-type:masterThesis
    Format: application/pdf
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  • 15
    Publication Date: 2016-06-30
    Description: Die Diplomarbeit präsentiert ein Transaktionsverfahren für strukturierte Overlay-Netzwerke, das an die Erfordernisse verteilter Informationssysteme mit relationalem Datenmodell angepasst ist. Insbesondere wird der Einsatz von Transaktionen für verteilte Wikis betrachtet, die moderne Funktionalitäten, wie Metadaten und zusätzliche Indexe für die Navigation, unterstützen. Konsistenz und Dauerhaftigkeit der gespeicherten Daten erfordert die Behandlung von Knotenausfällen. Die Arbeit schlägt dafür das Zellenmodell vor: Das Overlay wird aus replizierten Zustandsmaschinen gebildet, um Verfügbarkeit zu gewährleisten. Das Transaktionsverfahren baut darauf auf und verwendet Two-Phase-Commit mit Fehlererkennung und Widerherstellung von ausgefallenen Transaktionsmanagern. Anwendungen wird eine Auswahl an pessimistischen und hybrid-optimistischen Nebenläufigkeitskontrollverfahren geboten, die die Minimierung von Latenzeffekten und die schnelle Ausführung von Nur-Lese-Transaktionen ermöglichen. Für die Beispielanwendung Wiki wird der erforderliche Pseudocode angegeben und die verschiedenen Nebenläufigkeitskontrollverfahren hinsichtlich ihrer Nachrichtenkomplexität verglichen.
    Description: The diploma thesis presents a transaction processing scheme for structured overlay networks and uses it to develop a distributed Wiki application based on a relational data model. The Wiki supports rich metadata and additional indexes for navigation purposes. Ensuring consistency and durability requires handling of node failures. Such failures are masked by providing high availability of nodes. This in turn is achieved by constructing the overlay from replicated state machines (cell model). Atomicity is realized using two phase commit with additional support for failure detection and restoration of the transaction manager. The developed transaction processing scheme provides the application with a mixture of pessimistic, hybrid optimistic and multiversioning concurrency control techniques to minimize the impact of replication on latency and optimize for read operations. The pseudocode of the relevant Wiki functions is presented and the different concurrency control techniques are evaluated in terms of message complexity.
    Keywords: ddc:004
    Language: German
    Type: masterthesis , doc-type:masterThesis
    Format: application/pdf
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  • 16
    Publication Date: 2016-06-30
    Description: Die Arbeit präsentiert ein Transaktionsverfahren für strukturierte Overlay-Netzwerke, das an die Erfordernisse verteilter Informationssysteme mit relationalem Datenmodell angepasst ist. Insbesondere wird der Einsatz von Transaktionen für verteilte Wikis betrachtet, die moderne Funktionalitäten, wie Metadaten und zusätzliche Indexe für die Navigation, unterstützen. Konsistenz und Dauerhaftigkeit der gespeicherten Daten erfordert die Behandlung von Knotenausfällen. Die Arbeit schlägt dafür das Zellenmodell vor: Das Overlay wird aus replizierten Zustandsmaschinen gebildet, um Verfügbarkeit zu gewährleisten. Das Transaktionsverfahren baut darauf auf und verwendet Two-Phase-Commit mit Fehlererkennung und Widerherstellung von ausgefallenen Transaktionsmanagern. Anwendungen wird eine Auswahl an pessimistischen und hybrid-optimistischen Nebenläufigkeitskontrollverfahren geboten, die die Minimierung von Latenzeffekten und die schnelle Ausführung von Nur-Lese-Transaktionen ermöglichen. Für die Beispielanwendung Wiki wird der erforderliche Pseudocode angegeben und die verschiedenen Nebenläufigkeitskontrollverfahren hinsichtlich ihrer Nachrichtenkomplexität verglichen.
    Description: The report presents a transaction processing scheme for structured overlay networks and uses it to develop a distributed Wiki application based on a relational data model. The Wiki supports rich metadata and additional indexes for navigation purposes. Ensuring consistency and durability requires handling of node failures. Such failures are masked by providing high availability of nodes. This in turn is achieved by constructing the overlay from replicated state machines (cell model). Atomicity is realized using two phase commit with additional support for failure detection and restoration of the transaction manager. The developed transaction processing scheme provides the application with a mixture of pessimistic, hybrid optimistic and multiversioning concurrency control techniques to minimize the impact of replication on latency and optimize for read operations. The pseudocode of the relevant Wiki functions is presented and the different concurrency control techniques are evaluated in terms of message complexit
    Keywords: ddc:004
    Language: German
    Type: reportzib , doc-type:preprint
    Format: application/pdf
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  • 17
    Publication Date: 2016-06-30
    Description: Berlin als Stadtstaat ist Kommune und Land der Bundesrepublik zugleich und Standort vieler renommier-ter Wissenschafts- und Kultureinrichtungen. In enger Zusammenarbeit der Wissenschaftseinrichtungen mit dem IT-Dienstleistungszentrum Berlin (ITDZ, ehemals Landesbetrieb für Informationstechnik), der für die Behörden Berlins zuständigen Einrichtung, wurde seit 1993 ein landeseigenes Glasfasernetz mit einer derzeitigen Länge von 856 km Glasfaserkabel (je Kabel bis zu 144 Einzelfasern) zur gemeinsamen Nutzung von Wissenschaft und Verwaltung errichtet und weiter ausgebaut. 1994 erfolgte der offizielle Start des Berliner Wissenschaftsnetzes BRAIN (Berlin Research Area Information Network), als durch einen Beschluss des Senats von Berlin die Nutzung des landeseigenen Glasfasernetzes durch die Wissen-schaftseinrichtungen festgeschrieben wurde. Bereits 1995 wurden durch die Wissenschaftseinrichtungen auf diesem Glasfasernetz die ersten sieben Anschlüsse in ATM-Technik (Classical BRAIN-ATM) in Betrieb genommen, 1999 wurden anschließend auch erste Strecken in Ethernet-Technik (Classical BRAIN-GE) betrieben. Diese heterogenen Netze mit unterschiedlichen Netzgeräten wurden dezentral von den Netzadministratoren der beteiligten Einrichtungen nach globalen Absprachen betreut. Die dezentrale Administration erschwerte das Management und die Erweiterungen der Gesamtnetze. Basierend auf den vorliegenden Erfahrungen vereinbarten die Berliner Wissenschaftseinrichtungen, ein technisch neues Verbundnetz in Gigabit-Ethernet-Technik mit einheitlichen Geräten und einem zentralen Netzwerkmana-gement aufzubauen und zu betreiben. Seit November 2003 betreibt BRAIN auf dem landeseignen Glasfasernetz ein auf MPLS-Technik basie-rendes Gigabit-Ethernet-Netz, das „BRAIN-Verbundnetz“, mit den Diensten LAN-to-LAN-Kopplung der Einrichtungen, regionaler IP-Verkehr, Übergang zum Verwaltungsnetz und WiN-Backup. Das BRAIN-Verbundnetz löste die dezentral betreuten Vorläufernetze komplett ab. Von den derzeit 27 BRAIN-Teilnehmern nutzen 24 Einrichtungen an 53 in der Stadt verteilten Standorten die Dienste des BRAIN-Verbundnetzes, 18 Standorte sind mit 1000 Mbit/s und 35 Standorte mit 100 Mbit/s angeschlossen. Für verteilte Standorte einer Einrichtung besteht zudem die Möglichkeit, diese über dedizierte Fasern oder Bandbreiten miteinander zu vernetzen. Seit dem 2. Quartal 2007 wird im Rahmen eines Pilotprojekts der Nutzen eines zentral gemanagten Fibre Channel-Netzwerks "BRAIN-SAN" ermittelt, um Möglichkeiten einer verteilten Datenhaltung der Berliner Hochschulen und wissenschaftlichen Einrichtungen zu schaf-fen. Zusätzlich zu den vorgenannten Diensten nutzt der DFN-Verein die BRAIN-Struktur für die Verbindun-gen der X-WiN-Kernnetzknoten in Berlin und Potsdam untereinander und für Zugangsleitungen zu den Anwendern. Mit Stand 2007 nutzt das Berliner Wissenschaftsnetz BRAIN vom landeigenen Glasfasernetz 2100 km Einzelfasern und verbindet insgesamt 43 Einrichtungen (BRAIN-Teilnehmer und DFN-Anwender) aus Wissenschaft, Bildung und Kultur mit 129 Standorten. Der Betrieb von BRAIN wird im wesentlichen durch seine Nutzer finanziert. Das Land Berlin trägt aller-dings pauschal die überwiegenden Kosten für die Wartung des Glasfasernetzes, soweit es vom ITDZ be-reit gestellt wird. Zentrales Planungs- und Steuerungsorgan für BRAIN ist die von der Senatsverwaltung für Bildung, Wis-senschaft und Forschung eingerichtete BRAIN-Planungsgruppe. Sie besteht aus Mitarbeitern der Rechen-zentren der drei Berliner Universitäten und des ZIB. Nach außen wird BRAIN in rechtlicher und wirtschaftlicher Hinsicht treuhänderisch vom ZIB vertreten, die BRAIN-Geschäftsstelle befindet sich ebenfalls im ZIB.
    Description: Berlin as a city state is both local authority and federal state of the Federal Republic, as well as a location of many renowned institutions of research and culture. In close cooperation of the institutions of research with the IT service centre Berlin (ITDZ, the former Landesbetrieb für Informationstechnik) - which is the appropriate facility for the authorities of Berlin - a glass fibre network of a total extension of 856 kilome-tres of fibre optics (144 fibres each cable optic) for the common use of research and administration has been established and advanced since 1993. In 1994, when a resolution of the Senate of Berlin laid down the use of the appropriate fibre networks by the research facilities, this was the official beginning of the Berlin Research Area Information Network (BRAIN). The first seven interfaces in this fibre network in ATM technology (Classical BRAIN-ATM) were already established by the research facilities in 1995. In 1999, first systems run in Ethernet technology (Classical BRAIN-GE). These heterogeneous networks with different interfaces have been supported locally by the network administrators of the research facili-ties following global agreements. Management and advancement of the overall networks were encum-bered by these local administrations. Based on the existing experience, Berlin's research facilities agreed on the building and advancement of a technically new integrated network in gigabit Ethernet technology with standardised facilities and a centrally managed network. Since November 2003 the Berlin Research Area Information Network established a Gigabit Ethernet - called “BRAIN Integrated Network” - based on MPLS technology, including LAN to LAN linking of the facilities, local IP traffic, interface to the administration's network and WIN back-up. This BRAIN Inte-grated Network has completely replaced the locally administered predecessor networks. 24 of 27 BRAIN participants use the services of the BRAIN Integrated Network on 53 locations spread all over the city. 18 locations are connected with 1000 Mbit/s and 35 locations with 100 Mbit/s. Moreover, spread locations of a single facility have the possibililty to communicate by dedicated fibres or bandwidths. From the 2nd quarter 2007 within the scope of a pilot scheme, the advantage of a centrally administered fibre channel network "BRAIN-SAN" will be determined in order to accomplish possibilities of a spread data manage-ment of Berlin's universities and research facilities. In addition to the aforementioned services the DFN association makes use of BRAIN's structure for the connection of the X-WiN-core network nodes in Berlin and Potsdam und for access pathways to the us-ers. As from 2007, Berlin's research network BRAIN uses 2100 kilometres of single fibres from the country's fibre glass network and connects a total of 43 facilities (BRAIN participants and DFN users) from re-search, education and culture with 129 locations. The operations of BRAIN are funded basically by its users. However, the country of Berlin bears most of the costs for the maintenance of the glass fibre network, as far as it is provided by ITDZ. Central planning and steering body for BRAIN is the BRAIN planning group, which has been arranged by the administration of the Senatsverwaltung für Bildung, Wissenschaft und Forschung. It consists of staff from the computing centres of Berlin's three universities and of ZIB. BRAIN is represented legally and economically on a trust basis by the ZIB, where the BRAIN office is located also.
    Keywords: ddc:004
    Language: German
    Type: reportzib , doc-type:preprint
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  • 18
    Publication Date: 2022-07-19
    Description: For medical diagnosis, visualization, and model-based therapy planning three-dimensional geometric reconstructions of individual anatomical structures are often indispensable. Computer-assisted, model-based planning procedures typically cover specific modifications of “virtual anatomy” as well as numeric simulations of associated phenomena, like e.g. mechanical loads, fluid dynamics, or diffusion processes, in order to evaluate a potential therapeutic outcome. Since internal anatomical structures cannot be measured optically or mechanically in vivo, three-dimensional reconstruction of tomographic image data remains the method of choice. In this work the process chain of individual anatomy reconstruction is described which consists of segmentation of medical image data, geometrical reconstruction of all relevant tissue interfaces, up to the generation of geometric approximations (boundary surfaces and volumetric meshes) of three-dimensional anatomy being suited for finite element analysis. All results presented herein are generated with amira ® – a highly interactive software system for 3D data analysis, visualization and geometry reconstruction.
    Keywords: ddc:004
    Language: English
    Type: reportzib , doc-type:preprint
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  • 19
    Publication Date: 2022-07-19
    Description: This work introduces novel internal and external memory algorithms for computing voxel skeletons of massive voxel objects with complex network-like architecture and for converting these voxel skeletons to piecewise linear geometry, that is triangle meshes and piecewise straight lines. The presented techniques help to tackle the challenge of visualizing and analyzing 3d images of increasing size and complexity, which are becoming more and more important in, for example, biological and medical research. Section 2.3.1 contributes to the theoretical foundations of thinning algorithms with a discussion of homotopic thinning in the grid cell model. The grid cell model explicitly represents a cell complex built of faces, edges, and vertices shared between voxels. A characterization of pairs of cells to be deleted is much simpler than characterizations of simple voxels were before. The grid cell model resolves topologically unclear voxel configurations at junctions and locked voxel configurations causing, for example, interior voxels in sets of non-simple voxels. A general conclusion is that the grid cell model is superior to indecomposable voxels for algorithms that need detailed control of topology. Section 2.3.2 introduces a noise-insensitive measure based on the geodesic distance along the boundary to compute two-dimensional skeletons. The measure is able to retain thin object structures if they are geometrically important while ignoring noise on the object's boundary. This combination of properties is not known of other measures. The measure is also used to guide erosion in a thinning process from the boundary towards lines centered within plate-like structures. Geodesic distance based quantities seem to be well suited to robustly identify one- and two-dimensional skeletons. Chapter 6 applies the method to visualization of bone micro-architecture. Chapter 3 describes a novel geometry generation scheme for representing voxel skeletons, which retracts voxel skeletons to piecewise linear geometry per dual cube. The generated triangle meshes and graphs provide a link to geometry processing and efficient rendering of voxel skeletons. The scheme creates non-closed surfaces with boundaries, which contain fewer triangles than a representation of voxel skeletons using closed surfaces like small cubes or iso-surfaces. A conclusion is that thinking specifically about voxel skeleton configurations instead of generic voxel configurations helps to deal with the topological implications. The geometry generation is one foundation of the applications presented in Chapter 6. Chapter 5 presents a novel external memory algorithm for distance ordered homotopic thinning. The presented method extends known algorithms for computing chamfer distance transformations and thinning to execute I/O-efficiently when input is larger than the available main memory. The applied block-wise decomposition schemes are quite simple. Yet it was necessary to carefully analyze effects of block boundaries to devise globally correct external memory variants of known algorithms. In general, doing so is superior to naive block-wise processing ignoring boundary effects. Chapter 6 applies the algorithms in a novel method based on confocal microscopy for quantitative study of micro-vascular networks in the field of microcirculation.
    Description: Die vorliegende Arbeit führt I/O-effiziente Algorithmen und Standard-Algorithmen zur Berechnung von Voxel-Skeletten aus großen Voxel-Objekten mit komplexer, netzwerkartiger Struktur und zur Umwandlung solcher Voxel-Skelette in stückweise-lineare Geometrie ein. Die vorgestellten Techniken werden zur Visualisierung und Analyse komplexer drei-dimensionaler Bilddaten, beispielsweise aus Biologie und Medizin, eingesetzt. Abschnitt 2.3.1 leistet mit der Diskussion von topologischem Thinning im Grid-Cell-Modell einen Beitrag zu den theoretischen Grundlagen von Thinning-Algorithmen. Im Grid-Cell-Modell wird ein Voxel-Objekt als Zellkomplex dargestellt, der aus den Ecken, Kanten, Flächen und den eingeschlossenen Volumina der Voxel gebildet wird. Topologisch unklare Situationen an Verzweigungen und blockierte Voxel-Kombinationen werden aufgelöst. Die Charakterisierung von Zellpaaren, die im Thinning-Prozess entfernt werden dürfen, ist einfacher als bekannte Charakterisierungen von so genannten "Simple Voxels". Eine wesentliche Schlussfolgerung ist, dass das Grid-Cell-Modell atomaren Voxeln überlegen ist, wenn Algorithmen detaillierte Kontrolle über Topologie benötigen. Abschnitt 2.3.2 präsentiert ein rauschunempfindliches Maß, das den geodätischen Abstand entlang der Oberfläche verwendet, um zweidimensionale Skelette zu berechnen, welche dünne, aber geometrisch bedeutsame, Strukturen des Objekts rauschunempfindlich abbilden. Das Maß wird im weiteren mit Thinning kombiniert, um die Erosion von Voxeln auf Linien zuzusteuern, die zentriert in plattenförmigen Strukturen liegen. Maße, die auf dem geodätischen Abstand aufbauen, scheinen sehr geeignet zu sein, um ein- und zwei-dimensionale Skelette bei vorhandenem Rauschen zu identifizieren. Eine theoretische Begründung für diese Beobachtung steht noch aus. In Abschnitt 6 werden die diskutierten Methoden zur Visualisierung von Knochenfeinstruktur eingesetzt. Abschnitt 3 beschreibt eine Methode, um Voxel-Skelette durch kontrollierte Retraktion in eine stückweise-lineare geometrische Darstellung umzuwandeln, die als Eingabe für Geometrieverarbeitung und effizientes Rendering von Voxel-Skeletten dient. Es zeigt sich, dass eine detaillierte Betrachtung der topologischen Eigenschaften eines Voxel-Skeletts einer Betrachtung von allgemeinen Voxel-Konfigurationen für die Umwandlung zu einer geometrischen Darstellung überlegen ist. Die diskutierte Methode bildet die Grundlage für die Anwendungen, die in Abschnitt 6 diskutiert werden. Abschnitt 5 führt einen I/O-effizienten Algorithmus für Thinning ein. Die vorgestellte Methode erweitert bekannte Algorithmen zur Berechung von Chamfer-Distanztransformationen und Thinning so, dass diese effizient ausführbar sind, wenn die Eingabedaten den verfügbaren Hauptspeicher übersteigen. Der Einfluss der Blockgrenzen auf die Algorithmen wurde analysiert, um global korrekte Ergebnisse sicherzustellen. Eine detaillierte Analyse ist einer naiven Zerlegung, die die Einflüsse von Blockgrenzen vernachlässigt, überlegen. In Abschnitt 6 wird, aufbauend auf den I/O-effizienten Algorithmen, ein Verfahren zur quantitativen Analyse von Mikrogefäßnetzwerken diskutiert.
    Keywords: ddc:004
    Language: English
    Type: doctoralthesis , doc-type:doctoralThesis
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  • 20
    Publication Date: 2022-07-19
    Description: One crucial step in virtual drug design is the identification of new lead structures with respect to a pharmacological target molecule. The search for new lead structures is often done with the help of a pharmacophore, which carries the essential structural as well as physico-chemical properties that a molecule needs to have in order to bind to the target molecule. In the absence of the target molecule, such a pharmacophore can be established by comparison of a set of active compounds. In order to identify their common features,a multiple alignment of all or most of the active compounds is necessary. Moreover, since the “outer shape” of the molecules plays a major role in the interaction between drug and target, an alignment algorithm aiming at the identification of common binding properties needs to consider the molecule’s “outer shape”, which can be approximated by the solvent excluded surface. In this thesis, we present a new approach to molecular surface alignment based on a discrete representation of shape as well as physico-chemical properties by points distributed on the solvent excluded surface. We propose a new method to distribute points regularly on a surface w.r.t. a smoothly varying point density given on that surface. Since the point distribution algorithm is not restricted to molecular surfaces, it might also be of interest for other applications. For the computation of pairwise surface alignments, we extend an existing point matching scheme to surface points, and we develop an efficient data structure speeding up the computation by a factor of three. Moreover, we present an approach to compute multiple alignments from pairwise alignments, which is able to handle a large number of surface points. All algorithms are evaluated on two sets of molecules: eight thermolysin inhibitors and seven HIV-1 protease inhibitors. Finally, we compare the results obtained from surface alignment with the results obtained by applying an atom alignment approach.
    Description: Die Identifizierung neuer Leitstrukturen (lead structures) zur Entwicklung optimierter Wirkstoffe ist ein äußerst wichtiger Schritt in der virtuellen Wirkstoffentwicklung (virtual drug design). Die Suche nach neuen Leitstrukturen wird oft mit Hilfe eines Pharmakophor-Modells durchgeführt, welches die wichtigsten strukturellen wie auch physiko-chemischen Eigenschaften eines bindenden Moleküls in sich vereint. Ist das Zielmolekül (target) nicht bekannt, kann das Pharmakophor-Modell mit Hilfe des Vergleiches aktiver Moleküle erstellt werden. Hier ist insbesondere die gleichzeitige Überlagerung (multiple alignment) aller oder nahezu aller Moleküle notwendig. Da bei der Interaktion zweier Moleküle die "äußere Form" der Moleküle eine besondere Rolle spielt, sollte diese von jedem Überlagerungsalgorithmus, der sich mit der Identifizierung von Bindungseigenschaften befasst, berücksichtigt werden. Dabei kann die "äußere Form" durch eine bestimmte Art von molekularer Oberfläche approximiert werden, die man als solvent excluded surface bezeichnet. In dieser Arbeit stellen wir einen neuen Ansatz zur Überlagerung molekularer Oberflächen dar, der auf einer diskreten Repräsentation sowohl der Form als auch der molekularen Eigenschaften mittels Punkten beruht. Um die Punkte auf der molekularen Oberfläche möglichst regulär entsprechend einer gegebenen Punktdichte zu verteilen, entwickeln wir eine neue Methode. Diese Methode ist nicht auf Moleküloberflächen beschränkt und könnte daher auch für andere Anwendungen von Interesse sein. Basierend auf einem bekannten Point-Matching Verfahren entwickeln wir einen Point-Matching Algorithmus für Oberflächenpunkte. Dazu erarbeiten wir u.a. eine effiziente Datenstruktur, die den Algorithmus um einen Faktor von drei beschleunigt. Darüberhinaus stellen wir einen Ansatz vor, der Mehrfachüberlagerungen (multiple alignments) aus paarweisen Überlagerungen berechnet. Die Herausforderung besteht hierbei vor allem in der großen Anzahl von Punkten, die berücksichtigt werden muss. Die vorgestellten Algorithmen werden an zwei Gruppen von Molekülen evaluiert, wobei die erste Gruppe aus acht Thermolysin Inhibitoren besteht, die zweite aus sieben HIV-1 Protease Inhibitoren. Darüberhinaus vergleichen wir die Ergebnisse der Oberflächenüberlagerung mit denen einer Atommittelpunktüberlagerung.
    Keywords: ddc:004
    Language: English
    Type: doctoralthesis , doc-type:doctoralThesis
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  • 21
    Book
    Book
    Boston :Birkhäuser,
    Title: Sampling, wavelets, and tomography /
    Contributer: Benedetto, John , Zayed, Ahmed I.
    Publisher: Boston :Birkhäuser,
    Year of publication: 2003
    Pages: p. cm
    Series Statement: Applied and computational harmonic analysis
    ISBN: 0-8176-4304-4 , 3-7643-4304-4
    Type of Medium: Book
    Language: English
    Keywords: Hamonic analysis ; Wavelets (Mathematics) ; Fourier analysis ; Sampling (Statistics) ; Tomography
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  • 22
    ISSN: 1432-2277
    Keywords: Key words Implantation model ; Aortic valves ; Valve dysfunction ; Rejection ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Structural failure of heart valve allografts may be related to technical factors or immunological reactions. To circumvent nonimmunological factors a new rat implantation model was developed to study whether alloreactivity results in histopathological changes and valve dysfunction. Syngeneic (WAG-WAG, DA-DA) and allogeneic (WAG-BN, WAG-DA) transplantation was carried out using this new technique, and the function of explanted valves was assessed 21 days later by retrograde comptence testing. Additionally, grafts were examined using standard histological and immunohistochemical techniques. There was no leakage during retrograde injection in nine of tem syngeneic and two of ten allogeneic grafts. Microscopically, syngeneic valves appeared normal without fibrosis or intimal thickening, although CD8+ lymphocytes and macrophages were found in necrotic myocardial rim and adventitia. In contrast, allogeneic valves were deformed and noncellular, with extensive infiltration of CD4+, CD8+ and CD68+ cells in adventitia and media. Absence of fibrosis and intimal thickening in syngeneic transplanted valves indicated circumvention of nonimmunological factors. Allogeneic valve transplantation induces cellular infiltration in the graft with subsequent graft failure.
    Type of Medium: Electronic Resource
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  • 23
    ISSN: 1432-2277
    Keywords: Key words Hypoxia-reoxygenation ; JNK1/SAPK1 ; Rat ; Hepatocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Organ injury after ischemia and reperfusion (I/R) remains one of the most important limiting factors in liver surgery and transplantation. Oxygen-free radical (OFR) generation is considered a major cause of this damage. JNK1/SAPK1, a member of MAPK family, regulates cell adaptation to stressful conditions. The aim of this study was to determine if hypoxia-reoxygenation (H/R) can activate JNK1/SAPK1 and if OFR are involved in this activation. Primary cultured rat hepatocytes isolated from other liver cells and blood flow were submitted to warm and cold H/R phases mimicking surgical and transplant conditions. JNK1/SAPK1 was activated by both warm and cold H/R. Deferoxamine (1 mM), di-phenyleneiodonium (50 μM) and N-acetylcysteine (10 mM) significantly inhibited this kinase activation.
    Type of Medium: Electronic Resource
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  • 24
    ISSN: 1432-2277
    Keywords: Key words Small bowel transplantation ; Split tolerance ; FK 506 ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Functional long-term allograft survival after experimental small bowel transplantation (SBT) is limited by chronic rejection. Initial application of high-dose FK 506 has been shown to induce stable long-term graft function. In order to examine whether this long-term function is associated with donor-specific tolerance, we analyzed the functional status of recipient T cells in vivo and in vitro. One-step orthotopic SBT was performed in the allogeneic Brown Norway (BN)-to-Lewis rat strain combination. FK 506 was given daily at a dose of 2 mg/kg from days 0–5 in the rejection model and from days 0–9 in the long-term functional model. Mean survival time in the rejection model was 98 ± 2.8 days. Histological examination of these small bowel allografts disclosed signs of chronic rejection. In contrast, all animals of the long-term functional model survived long term ( 〉 250 days) without clinical signs of chronic rejection. The latter model, furthermore, produced evidence of donor-specific tolerance. Whereas heterotopic Dark Agouti (DA) hearts were rejected regularly within 7 days, BN hearts survived indefinitely ( 〉 70 days). In vitro, mixed leukocyte reactivity of CD4 + T cells was similarly strong against donor (BN) antigens as against third-party (DA) antigens. The split tolerance revealed by our in vivo and in vitro results enabled acceptance of both the small bowel allograft without signs of chronic rejection and of donor-specific heart allografts.
    Type of Medium: Electronic Resource
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  • 25
    ISSN: 1432-2307
    Keywords: Key words T-type calcium channel blockade ; Mibefradil ; Myocardial infarction ; Cardiac remodeling ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Fibrillar collagen accumulates within the interstitium and around coronary arteries following cardiac failure and is responsible for abnormal myocardial stiffness and reduced coronary performance associated with impaired cardiac function. The aim of the study was to determine the effects of long-term treatment with the T-type calcium channel antagonist mibefradil on myocardial remodeling and cardiac function after chronic myocardial infarction (MI). MI was induced by permanent ligation of the left coronary artery in male Wistar rats. Animals were assigned to sham-operated, placebo-treated or mibefradil-treated (10 mg/kg per day p.o.) MI groups. Treatment with mibefradil was started either 7 days before, 24 h after, or 7 days after ligation and continued for 6 weeks after MI. At this time point, mean arterial blood pressure (MAP), heart rate (HR), left ventricular end-diastolic pressure (LVEDP) and cardiac contractility (dP/dtmax) were measured in conscious rats. Morphometric parameters were determined in picrosirius red-stained hearts: total heart weight (THW), interstitial and perivascular collagen volume fraction (ICVF, PCVF), myocardial infarct size (IS), vascular perimeter (VP), inner vascular diameter (IVD) and media thickness (MT). Six weeks after MI, MAP and dP/dtmax were decreased, and LVEDP was increased in placebo-treated animals. In mibefradil-treated animals whose treatment started 7 days before or 24 h after MI, MAP and dP/dtmax were higher, and LVEDP was lower than in placebo-treated controls. THW, ICVF, PCVF and MT were higher in placebo-treated animals. Mibefradil treatment resulted in higher ICVF and IS, higher VP and IVD (when started 7 days before MI) and lower PCVF and MT (when started 7 days before or 24 h after MI) than were observed in placebo-treated controls. Chronic treatment with mibefradil reduced interstitial and perivascular fibrosis and improved cardiac function in MI-induced heart failure in rats. Cardiac remodeling was best prevented when treatment was begun before the ischemic event.
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  • 26
    ISSN: 1432-2307
    Keywords: Keywords 7 ; 12-dimethylbenz(a)anthracene ; Rat ; Submandibular gland ; Adenocarcinoma Myoepithelial cell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  In an attempt to induce adenocarcinoma containing myoepithelial cells (MECs) in the rat submandibular gland, we injected 7,12-dimethylbenz(a)anthracene (DMBA) dissolved in acetone into the glands of rat pups at the age of 10 days. In both male and female pups, the glands, including their developing terminal secretory units, contained far greater numbers of cells positive for proliferating cell nuclear antigen (PCNA) than did adult glands. A single administration of 1% DMBA (0.05 ml/130 g b.w.) did not produce adenocarcinoma, but did induce occasional sarcomas, such as rhabdomyosarcoma and fibrosarcoma, in 2 months. Most glands regenerated with minimal scar formation. Microscopically, these glands were atypical in that they contained increased numbers of PCNA-positive cells, underdeveloped granular ducts, and striated ducts surrounded by MECs positive for alpha smooth muscle actin (αSMA). Though these features were also observed in the regenerated glands after acetone injection, the number of PCNA-positive cells was relatively high in the glands of DMBA-treated females, especially in the terminal secretory unit. The second DMBA injection at 10 weeks of age produced adenocarcinoma made up of αSMA-positive MECs and keratin 19-positive duct cells. Such MEC-associated adenocarcinoma was induced in the glands of more than half the female but not the male animals. Replacement of either of the double DMBA treatments with acetone, or DMBA treatment, single or double, of adult glands did not produce adenocarcinoma, but did produce sarcoma and squamous cell carcinoma. These results suggest that (1) at least two genetic mutations are necessary for induction of adenocarcinoma with MECs in the rat submandibular gland, (2) the mutation is efficiently introduced to pup glands whose terminal secretory units exhibit extreme proliferative activity, and (3) the second mutation is difficult to introduce in male glands, whose proliferative activity is relatively low, and/or transformed cells need some female hormone after the mutation to propagate.
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  • 27
    ISSN: 1432-2277
    Keywords: Key words Small bowel transplantation ; Monoclonal antibody ; Rat ; Rejection ; Flow cytometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study assessed the effect of an anti-rat CD4 monoclonal antibody (OX38) on heterotopic small bowel allograft rejection. Fully allogeneic small bowel transplants were performed in the PVG-to-DA-rat strain combination. Animals received either i) short course (days –1, 0 and 1) of 1 mg/kg per day OX38, ii) short course of 5 mg/kg per day or iii) extended course (days –2, –1, 0, 1, 2 and twice weekly thereafter) of 1 mg/kg per day. Both the high dose (13 days) and extended low-dose (12 days) courses prolonged graft survival compared to untreated control animals (7 days). The low-dose, short-course treatment had no effect. Similar regimens were given to animals that did not receive transplants and in which peripheral blood CD4+ cell counts fell to between 20 and 55 % of pretreatment levels and 20–30 % of binding sites were blocked. In summary, anti-CD4 monoclonal antibody therapy delayed rejection of rat small bowel allografts; however, long-term survival was not achieved.
    Type of Medium: Electronic Resource
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  • 28
    ISSN: 1432-198X
    Keywords: Key words Metabolic acidosis ; Growth ; Growth hormone ; Insulin-like growth factor-I ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Growth impairment induced by chronic metabolic acidosis is associated with an abnormal growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. To examine the potentially beneficial effects of IGF-I on acidosis-induced growth impairment and the influence of GH and IGF-I treatment on the GH/IGF-I axis, three groups of acidotic young rats (untreated, AC, n=12; treated with recombinant human GH, GH, n=8; treated with recombinant human IGF-I, IGF-I, n=8) were studied, and compared with nonacidotic rats fed ad libitum (C, n=9)) or pair-fed with the AC group (PF, n=12). After 14 days of acidosis and 7 days of treatment, growth rate, hepatic abundance of 4.7-kilobase (kb) and 1.2-kb GH receptor transcripts and 7.5-kb and 1.8- to 0.8-kb IGF-I transcripts, serum GH-binding protein (GHBP), and IGF-I concentrations (mean±SEM) were analyzed. Significant decreases of 4.7-kb GH receptor [26±2 vs. 49±6 arbitrary densitometry units (ADU)] and 7.5 kb IGF-I (41±3 vs. 104±10 ADU) transcripts and low serum GHBP (25±1 vs. 32±1 ng/ml) and IGF-I (279±50 vs. 366±6 nmol/l) levels were found in the AC compared with the C rats. The majority of these alterations were also observed in PF rats. Compared with acidotic untreated rats, GH and IGF-I therapy produced no improvement in growth rate. GH treatment normalized the levels of IGF-I mRNA, aggravated the acidosis-related inhibition of the GH receptor gene, and did not modify the serum levels of GHBP and IGF-I. In contrast, IGF-I administration depressed the hepatic expression of all GH and IGF-I transcripts and normalized serum IGF-I concentrations. Our results confirm that sustained metabolic acidosis alters the GH/IGF-I axis, in part because of associated malnutrition, and induced growth retardation that is resistant to GH therapy. Our study also shows that administration of IGF-I does not accelerate the growth of acidotic rats, suggesting a peripheral mechanism, at the level of target tissues, is responsible for the resistance to the growth-promoting actions of GH and IGF-I.
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  • 29
    ISSN: 1432-198X
    Keywords: Key words Apoptosis ; Ceramide ; Development ; Kidney ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Ceramide is emerging as an important hydrophobic sphingolipid involved in cell differentiation and apoptosis. Since apoptosis plays a significant role in cellular remodeling during renal morphogenesis, we measured ceramide content and apoptosis in the fetal (18 days gestation), neonatal (3, 7, and 14 days postnatal), and adult rat kidney. In addition, to determine whether developmental changes in ceramide content are tissue-specific, we compared renal ceramide content with that in lung and liver. Ceramide was measured by the diacylglycerol kinase assay, and apoptosis was determined by the TUNEL technique. Renal ceramide content fell over 100-fold from the fetus to the 7th postnatal day. Renal apoptosis paralleled ceramide content, with a greater than 300-fold decrease in apoptosis from fetal to adult life. Ceramide content of the lung and liver was significantly less than that of the kidney, and changed less with maturation. We conclude that maturational changes in ceramide content are tissue-specific, and that the high rate of apoptosis in the developing kidney may be related to the elevated ceramide content.
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  • 30
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    Journal of cancer research and clinical oncology 126 (2000), S. 27-32 
    ISSN: 1432-1335
    Keywords: Key words Heart irradiation ; Plasma enzyme levels ; Myocardial enzyme levels ; Rat ; AbbreviationsCK creatine kinase ; LDH lactate de-hydrogenase ; AST aspartate aminotransferase ; ALT alanine aminotransferase ; α-HBDHα-hydroxybutyrate dehydrogenase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Plasma levels of myocardial enzymes present after local heart irradiation were studied in a rat model. The purpose was to investigate whether, within days after irradiation, these enzyme levels change to such an extent that they may be helpful in assessing the severity of cardiac damage after radiotherapy. Therefore, activities of creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and α-hydroxybutyrate dehydrogenase (α-HBDH) were determined in the plasma and left ventricular myocardium of rats following local heart irradiation with a single dose of 20 Gy. A dose of 20 Gy is known to cause irreversible cardiac damage and to reduce survival times of the animals. Cardiac enzyme assays were performed directly after and twice daily for up to 2 weeks after radiation. Plasma CK, LDH, AST and α-HBDH levels were increased between 2 h and 24 h after irradiation. Plasma ALT levels remained unchanged. Myocardial enzyme levels, measured between 24 h and 16 days after radiation, did not differ between irradiated and control animals, although acute (first 12 h) reductions were observed in the irradiated group. The elevated enzyme levels in plasma appeared to correlate with the acutely reduced myocardial enzyme levels. Although irradiation with a dose of 20 Gy induced acute rises of cardiac enzyme levels in plasma, it is doubtful that fractionated radiation, as applied clinically for treatment of solid tumors, will induce plasma enzyme elevations that are large enough to indicate the extent of cardiac damage occurring acutely or chronically.
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  • 31
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    Child's nervous system 16 (2000), S. 451-456 
    ISSN: 1433-0350
    Keywords: Keywords Intracranial pressure ; CSF dynamics ; Infusion test ; Rat ; H-Tx rat ; Outflow resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Although the hydrocephalic H-Tx rat is a widely used model, data on the cerebrospinal fluid (CSF) dynamics in hydrocephalic rats are rare or – as the pressure volume index (PVI) – not available. We used hydrocephalic and nonhydrocephalic H-Tx rats, a stock with a high percentage of inherited hydrocephalus, for the evaluation of such data. In addition, a new, simple mathematical algorithm (”dynamic infusion test”), which has not formerly been used in animal experiments, was used as a pathophysiological model of CSF dynamics. Compared with classical methods for evaluation of these data, the dynamic infusion test gives a deeper insight into the relation between ICP and CSF dynamics. It was found that the resistance to outflow (ROF) in hydrocephalic rats was at least twice that in nonhydrocephalic rats. The PVI measured was similar in hydrocephalic and nonhydrocephalic animals, but clearly higher than the values reported in the literature. This may be attributable to the fact that the classically used bolus test, in contrast to the ”dynamic infusion test”, is representative only for the CSF compartment which is directly exposed to the bolus application.
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  • 32
    ISSN: 1432-0843
    Keywords: Key words 7-Hydroxymethotrexate ; Methotrexate ; Maximum tolerated dose ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: After more than 50 years of methotrexate (MTX) treatment of acute lymphoblastic leukaemia (ALL), it is currently believed that as long as dose escalations are followed by adequate leucovorin rescue guided by monitoring MTX serum concentrations, hydration and urinary alkalinization, high-dose MTX (HD-MTX) can be tolerated without life-threatening toxicity. However, our recent experimental animal studies of the major metabolite of MTX, 7-OH-MTX, indicate that this concept may have some limitations. Animals with levels of 7-OH-MTX of 1 mM, which is below the levels routinely found in patients on HD-MTX, demonstrate intolerable toxicity and some animals die within 8 h. Electron microscopy indicates that endothelial cell and platelet functions are perturbed. Since animal data are lacking, and interspecies differences not known, we wanted to investigate the maximum tolerated doses of MTX and 7-OH-MTX in a rat model of short-term effects. The maximum tolerated dose was chosen instead of LD50 for reasons of animal welfare. Methods: We infused MTX and 7-OH-MTX into anaesthetized male Wistar rats and monitored the animals for 8 h. The drugs were given as a bolus plus continuous infusion. The dose-finding ranges were 1.8–11.3 g/kg MTX and 0.1–1.2 g/kg 7-OH-MTX. Results: The maximum tolerated dose was between 3 and 5 g/kg for MTX and lower than 0.1 g/kg for 7-OH-MTX. The mean serum concentrations of MTX and 7-OH-MTX in animals that did not survive the 8-h period were 21.9 and 1.6 mM, respectively. The animals that received the highest MTX or 7-OH-MTX doses and concentrations died after sudden reductions in heart rate and blood pressure. Conclusions: We demonstrated a lower maximum tolerated dose of 7-OH-MTX than of MTX in rats after 8 h. The 7-OH-MTX concentrations were in the therapeutic range after HD-MTX. If the rat/human interspecies differences are not large, our data may indicate that HD-MTX regimens should not be further dose intensified, due not so much to the effects of MTX as to those of 7-OH-MTX.
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  • 33
    ISSN: 1432-0738
    Keywords: Key wordsα2u-Globulin ; Diethylstilbestrol ; Endocrine disrupter ; Rat ; Screening
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract α2u-Globulin (AUG) is a major rat urinary protein, which has a molecular weight of 16 kDa (kidney type) or 19 kDa (native type). The biosynthesis of this protein is under multi-hormonal regulation. In this study, we investigated changes in serum AUG level and their association with changes in the reproductive organs of male rats after the administration of the estrogenic chemical, diethylstilbestrol (DES) at doses ranging from 0.01 mg/kg per day to 100 mg/kg per day by gavage for 14 days. Our aim was to establish basic data for the development of a new screening method for endocrine disrupting chemicals based on serum AUG levels. DES treatment decreased the weight of testes in a dose-dependent manner; and was accompanied by atrophic histopathological changes in testes. Testis weights were significantly decreased by the group given 1 mg/kg per day DES; however, histopathological abnormalities were found in the group given 0.1 mg/kg per day DES. In four of five animals in the group given 1 mg/kg per day there was no significant decrease in testis weight and only a slight or moderate degeneration of the pachytene spermatocytes. Despite these findings, serum AUG levels in this group decreased markedly, while the serum AUG level markedly decreased even in the animals with no histopathological change in the 1 mg/kg per day or 0.1 mg/kg per day groups with no histopathological change also showed decreased serum AUG level. These results suggest that the serum AUG level may be a sensitive parameter for detecting the activity of estrogenic chemicals in intact male rats. Although a uterotropic assay has been proposed for immature female or ovariectomized female rats and is currently undergoing validation studies internationally, there is no screening method for estrogenic chemicals in intact male animals. More data on AUG changes by treatment with other estrogenic chemicals are needed in order to determine the sensitivity and specificity of this response to estrogens. Nonetheless, an AUG-based screening test for estrogenic chemicals may be useful owing to its applicability to conventional toxicity studies and an apparently higher sensitivity of this parameter compared to organ weight change or histology of testis in intact male rats and applicability to conventional toxicity studies.
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  • 34
    ISSN: 1432-0738
    Keywords: Key words Flutamide ; Androgen antagonist ; Rat ; Enhanced OECD Test Guideline 407 ; Endocrine disrupters
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In association with the international validation project to establish a test protocol for the `Enhanced OECD Test Guideline 407', we performed a preliminary 28-day, repeated-dose toxicity study of flutamide, a non-steroidal androgen antagonist, and assessed the sensitivity of a list of parameters for detecting endocrine-related effects of endocrine-disrupting chemicals (EDCs). Seven-week-old CD(SD)IGS rats were divided into four groups, each consisting of 10 males and 10 females, and administered flutamide once daily by oral gavage at doses of 0 (control), 0.25, 1 and 4 mg/kg body weight/day. Male rats were killed 1 day after the 28th administration. Female rats were killed on the day they entered the diestrus stage in the estrous cycle following the last treatment. Male rats receiving flutamide at dose levels of 1 and 4 mg/kg showed lobular atrophy of the mammary gland and a decrease in epididymal weight. In addition, 4 mg/kg flutamide-treated males exhibited raised serum testosterone and estradiol levels and decreased weight of the accessory sex glands. In females, a slight prolongation of the estrous cycle was also observed in the 4 mg/kg flutamide-treated group. No dose-related changes could be detected by haematology, serum biochemistry and sperm analysis. Thus, among the parameters tested in the present experimental system, the weight of endocrine-linked organs and their histopathological assessment, serum hormone levels, and estrous cycle stage allowed the detection of endocrine-related effects of flutamide.
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  • 35
    ISSN: 1432-119X
    Keywords: Endothelin-A receptor ; Endothelin-B receptor ; Rat ; Pulmonary fibrosis ; Immunohistochemistry ; Quantitative PCR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: AbstractPulmonary fibrosis is characterized by excessive extracellular matrix deposition with concomitant loss of gas exchange units, and endothelin-1 (ET-1) has been implicated in its pathogenesis. Increased levels of ET-1 from tissues and bronchoalveolar lavage have been reported in patients with pulmonary fibrosis and in animal models after intratracheal bleomycin. We characterized the cellular distribution of alveolar ET receptors by immunohistochemistry in bleomycin-induced pulmonary fibrosis in the rat and determined the regulation by bleomycin of ET receptor mRNA expression in isolated alveolar macrophages and rat lung fibroblasts. We found significant increases in the numbers of fibroblasts and macrophages at day 7 compared to day 28 and control animals. ETB receptor immunoreactivity was observed on fibroblasts and invading monocytes. Isolated fibroblasts expressed both ETA and ETB receptor mRNA, and ETA receptor mRNA was upregulated by bleomycin. Isolated resident alveolar macrophages expressed neither ETA nor ETB receptor mRNA which were also not induced by bleomycin. We conclude that, while ETB receptor stimulation of fibroblasts and monocytes recruited during bleomycin-induced lung injury exerts antagonistic effects on fibroblast collagen synthesis, the observed increase in the number of fibroblasts in vivo and upregulation of fibroblast ETA receptor mRNA by bleomycin in vitro point to a predominance of the profibrotic effects of ET receptor engagement.
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  • 36
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    Experimental brain research 130 (2000), S. 100-104 
    ISSN: 1432-1106
    Keywords: Key words NF-κB ; p65 ; Hippocampal neurons ; Glia ; Astrocytes ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  NF-κB is found in many neuronal cell types in different states of activity. This study aimed to define which conditions induce constitutive NF-κB activity in cultured hippocampal neurons using activity-specific antibody staining. In co-culture with astroglia, hippocampal neurons were devoid of activated NF-κB. In these co-cultures, NF-κB could not be activated via kainate or glutamate. In contrast, separating neurons from the glial compartment resulted in a time-dependent increase of activated neuronal NF-κB. In this line, activation of NF-κB by kainate or glutamate is very effective in freshly separated cultures, but inhibited when the cultures are reassembled after stimulation. These findings suggests that a neuronal-glial interaction may regulate gene expression via NF-κB.
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  • 37
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    Acta neuropathologica 100 (2000), S. 75-81 
    ISSN: 1432-0533
    Keywords: Key words Fas ; Fas ligand ; Rat ; Spinal cord ; Trauma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This immunohistochemical study evaluated Fas and Fas ligand (FasL) in the rat nervous system and their changes in the spinal cord subjected to compression. Normal spinal cord showed a low level of Fas and FasL immunoreactivity in the white matter except in the corticospinal tracts. Fas and FasL immunoreactivity seemed to be located in axons and their myelin sheaths. Other regions of the nervous system did not show immunoreactivity to Fas and FasL. Moderate and severe compression injury of the spinal cord resulted in a reduction of Fas and FasL immunoreactivity in the white matter of injured T8–9 segments at 4 h and a complete loss at 1 day after trauma. This was seen even in the remaining white matter. In contrast, increased immunoreactivity to Fas and FasL was present in the cranial T7, caudal T10 (moderate injury) and T12 (severe injury) segments at day 4 with most intense staining were seen at day 9 after trauma. Increased Fas and FasL immunoreactivity may have pathophysiological implications for the development of secondary injuries after trauma to the spinal cord. Fas-FasL interactions may for instance be involved in apoptosis of oligodendrocytes which occurs as a delayed phenomenon after trauma to the spinal cord. The integrity of myelin sheaths may in this way be jeopardized by apoptosis of oligodendrocytes.
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  • 38
    ISSN: 1432-0533
    Keywords: Key words Hypothermia ; Immunohistochemistry ; Microtubule-associated protein 2 (MAP2) ; Rat ; Spinal cord injury
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Systemic hypothermia has been shown to exert neuroprotective effects in experimental ischemic CNS models caused by vascular occlusions. The present study addresses the question as to whether systemic hypothermia has similar neuroprotective qualities following severe spinal cord compression trauma using microtubule-associated protein 2 (MAP2) immunohistochemistry combined with the avidin-biotin-peroxidase complex method as marker to identify neuronal and dendritic lesions. Fifteen rats were randomized into three equally sized groups. One group sustained thoracic laminectomy, the others severe spinal cord compression trauma of the T8-9 segment. The control group contained laminectomized animals submitted to a hypothermic procedure in which the esophageal temperature was reduced from 38 °C to 30 °C. The two trauma groups were either submitted to the same hypothermic procedure or kept normothermic during the corresponding time. All animals were sacrificed 24 h following the surgical procedure. The MAP2 immunostaining in the normothermic trauma group indicated marked reductions in MAP2 antigen in the cranial and caudal peri-injury zones (T7 and T10, respectively). This reduction was much less pronounced in the hypothermic trauma group. In fact, the MAP2 antigen was present in almost equally sized areas in both the hypothermic groups independent of previous laminectomy alone or the addition of trauma. Our study thus indicates that hypothermia has a neuroprotective effect on dendrites of rat spinal cords subjected to compression trauma.
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  • 39
    ISSN: 1432-2277
    Keywords: Key words Kidney transplantation ; Rat ; Chronic rejection ; Cytomegalovirus ; Adhesion molecules
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Previous studies have demonstrated that both cytomegalovirus (CMV) infection and prolonged cold ischemia of the allograft (CI) are associated with chronic rejection of renal transplants. The purpose of this study is to investigate the effect of CMV infection, of CI and of the combination of both, on the progression of chronic rejection, and to obtain a more detailed insight in their effects on the expression of adhesion molecules. Therefore, a rat transplantation model was used. Lewis recipients of renal allografts (with and without CI) from MHC-incompatible Brown Norway rats were inoculated with rat CMV or left uninfected. CMV infection alone resulted in an increased influx of CD4+ cells and macrophages early after infection, and in an increase in glomerular sclerosis and intima proliferation. CI caused an increase in infiltrating NK cells and an effect on intimal proliferation, glomerular sclerosis, and tubular atrophy. When CMV infection and CI were combined, an additive effect could be measured. This was however not the case for the function of the kidney. The creatinin showed a synergistic effect of the two influencing factors. Due to the CMV infection, an increase in CD49 d cells was detected. CI resulted in an increase in CD18 cells and an increase in the expression of CD62P on vessels, and CD54 and CD44 on tubules. When CMV infection and CI were combined, all the effects caused by CMV and CI alone were present in an additional way.¶The results of the present study suggest that special attention should be paid to the recipient of an ischemically injured graft when either the donor or the recipient is CMV-infected. The patterns seen in histology, the infiltration of leukocytes and the expression of adhesion molecules, suggest that CI and CMV infection both have an effect on rejection, but act by different mechanisms.
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  • 40
    ISSN: 1432-2072
    Keywords: Keywords Novelty ; Context ; Environment ; Stress ; 6-OHDA ; Rotational behavior ; Striatum ; Nucleus accumbens shell ; Caudate ; Amphetamine ; Dopamine ; Glutamate ; Aspartate ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: We have previously shown that environmental novelty enhances the behavioral activating effects of amphetamine and amphetamine-induced expression of the immediate early gene c-fos in the striatal complex, particularly in the most caudal portion of the caudate. In contrast, we found no effect of novelty on the ability of amphetamine to induce dopamine (DA) overflow in the rostral caudate or in the core of the nucleus accumbens. Objectives: The twofold aim of the present study was to determine the effect of environmental novelty on (1) amphetamine-induced DA overflow in the shell of the nucleus accumbens and in the caudal portions of the caudate, and (2) glutamate and aspartate overflow in the caudal portions of the caudate. Methods: Two groups of rats with a unilateral 6-hydroxydopamine lesion of the mesostriatal dopaminergic system received amphetamine (0.5 mg/kg, i.v.) in physically identical cages. For one group, the cages were also the home environment, whereas, for the other group, they were a completely novel environment. In vivo microdialysis was used to estimate DA, glutamate, and aspartate concentrations. Results: Environmental novelty enhanced amphetamine-induced rotational behavior (experiments 1–3) but did not alter amphetamine-induced DA overflow in either the shell of the nucleus accumbens (experiment 1) or the caudate (experiment 2). In addition, the ability of environmental novelty to enhance amphetamine-induced behavioral activation was not associated with changes in glutamate or aspartate efflux in the caudate (experiment 3). Conclusions: The present data indicate that the psychomotor activating effects of amphetamine can be modulated by environmental context independent of its primary neuropharmacological actions in the striatal complex.
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  • 41
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    Psychopharmacology 151 (2000), S. 219-225 
    ISSN: 1432-2072
    Keywords: Keywords Amphetamine ; Wheel running ; Behavioral sensitization ; Pharmacological sensitization ; Novelty ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: This study explored whether repeated injections of amphetamine (AMP), which increase general locomotion, also increase acute wheel running, a highly structured, rewarding, motor behavior not correlated with other locomotor activities. Objectives: The experiments determine how 1–5 mg/kg d-AMP affects wheel running and see if, over repeated injections, the AMP effects show context specific sensitization. Methods: In experiment 1, 2 mg/kg AMP or saline (SAL) was injected on days 1, 3, 6, 8, and 10 to male Sprague-Dawley rats with either limited or no wheel experience. 20 min after the injection animals were tested in an open field for 5 min and then in a running wheel for 1 h. Rats were injected with SAL or AMP on the days following testing. On days 13 and 15, animals were tested for conditioning (following SAL) and sensitization (following AMP). In experiment 2, the effects on wheel running of repeated 1, 2, or 5 mg/kg AMP were tested. Results: In experiment 1, AMP (2 mg/kg) elevated open field ambulation but suppressed wheel running. Limited wheel experience potentiated the AMP-induced suppression. At test, the suppression of running was found to be context specific. In experiment 2, 1 mg/kg did not affect running, while 2 and 5 mg/kg resulted in dose-dependent running suppression. Acquisition and test AMP dose both influenced the running suppression at test; context had a marginal influence. Conclusions: The degree of running suppression induced by repeated AMP is determined by both psychological (the injection context) and pharmacological (the acquisition dose) factors. This AMP-induced running suppression is consistent with the sensitization of stereotyped behavior.
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  • 42
    ISSN: 1432-2072
    Keywords: Key words Nicotine ; Drug discrimination ; Self-administration ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The cellular effects of nicotine underlying its addictive liability are thought to be mediated by neuronal nicotinic receptors (nACHRs) in the central nervous system. It is believed that densely expressed β2-containing nACHRs in the central nervous system are responsible for these actions, but few data are available that can directly assess subtype mediation of nicotine’s acute subjective and reinforcing effects. Objective: The present study compared the effects of the competitive nACHR antagonist erysodine and the noncompetitive antagonist mecamylamine in rats trained to discriminate or self-administer nicotine. Methods: Adult male rats were trained to disciminate 0.4-mg/kg injections of nicotine from vehicle in a two-lever procedure of food-maintained behavior, or to self-administer 0.03-mg/kg injections of nicotine under fixed-ratio 5 or progressive-ratio schedules of reinforcement. Additional rats were trained under a food-maintained procedure of lever pressing. Results: Erysodine (0.3–10 mg/kg) and mecamylamine (0.1–1.0 mg/kg) blocked nicotine discrimination, although only erysodine produced the rightward shift that would be predicted of a competitive antagonist. Erysodine (0.32–32 mg/kg) and mecamylamine (0.32–3.2 mg/kg) also selectively reduced nicotine self-administration on a fixed-ratio schedule and lowered break points on a progressive-ratio schedule. Conclusions: Based on the known affinity of erysodine for α4β2 nACHRs and its selectivity relative to α7 and α1β1γδ receptors, the present data support a critical role of β2-containing nACHR constructs in the discriminative and reinforcing actions of nicotine.
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  • 43
    ISSN: 1432-2072
    Keywords: Key words Drug discrimination ; Olanzapine ; Clozapine ; Chlorpromazine ; Haloperidol ; Thioridazine ; Raclopride ; Risperidone ; Scopolamine ; Ritanserin ; Atypical antipsychotic ; Neuroleptic ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Analysis of the preclinical behavioral effects of atypical antipsychotic agents will provide a better understanding of how they differ from typical antipsychotics and aid in the development of future atypical antipsychotic drugs. Objectives: The present study was designed to provide information about the discriminative stimulus properties of the atypical antipsychotic olanzapine. Methods: Rats were trained to discriminate the atypical antipsychotic olanzapine (either 0.5 mg/kg OLZ or 0.25 mg/kg OLZ, i.p.) from vehicle in a two- lever drug discrimination procedure. The atypical antipsychotic clozapine fully substituted for olanzapine in both the 0.5-mg/kg OLZ group (99.3% drug lever responding [DLR]) and the 0.25-mg/kg OLZ group (99.9% DLR). The typical antipsychotic chlorpromazine also substituted for olanzapine in both the 0.5-mg/kg OLZ group (87.5% DLR) and in the 0.25-mg/kg OLZ group (98.9% DLR); whereas, haloperidol displayed partial substitution for olanzapine in the 0.5-mg/kg OLZ group (56.1% DLR) and in the 0.25-mg/kg OLZ group (76.4% DLR). The 5.0-mg/kg dose of thioridazine produced olanzapine-appropriate responding in the 0.5-mg/kg OLZ group (99.6% DLR), but only partial substitution was seen with the 0.25-mg/kg OLZ training dose (64.0% DLR). The atypical antipsychotics raclopride (53.9% DLR) and risperidone (60.1% DLR) displayed only partial substitution in the 0.5-mg/kg OLZ group. Both the muscarinic cholinergic antagonist scopolamine (90.0% DLR) and the 5-HT2A/2C serotonergic antagonist ritanserin (86.0% DLR) fully substituted for olanzapine in the 0.5-mg/kg OLZ group. Conclusions: In contrast to previous discrimination studies with clozapine-trained rats, the typical antipsychotic agents chlorpromazine and thioridazine and the serotonin antagonist ritanserin substituted for olanzapine. These results demonstrate that there are differences in the mechanisms underlying the discriminative stimulus properties of clozapine and olanzapine. Specifically, olanzapine’s discriminative stimulus properties appear to be meditated in part by both cholinergic and serotonergic mechanisms.
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  • 44
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    Psychopharmacology 148 (2000), S. 243-250 
    ISSN: 1432-2072
    Keywords: Key words Attention ; Scopolamine ; Mecamylamine ; Oxotremorine ; Physostigmine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: This study tried to determine the relative roles of muscarinic and nicotinic cholinergic receptors in attentional processing. Methods: The effects of cholinoceptor agonists and antagonists, and of an anticholinesterase, were studied on performance of rats in a five-choice serial reaction time task. Results: Scopolamine (0.1 mg/kg) and mecamylamine (5.0 mg/kg) produced deficits in accuracy and reaction time, respectively. This may suggest a differential role for the two types of cholinoceptors in information processing. Combinations of sub-threshold doses of scopolamine (0.01–0.03 mg/kg) and mecamylamine (0.5–1.6 mg/kg), which alone did not affect accuracy or reaction time, did not produce significant deficits in attention. However, the pattern of effects after combined treatment suggested that the differential deficits seen with these drugs alone remained. The anticholinesterase physostigmine (0.1 mg/kg) and the non- selective muscarinic agonist oxotremorine (0.03 mg/kg) induced severe behavioural disruption at doses that appeared to be relatively well tolerated in previous studies; this precluded the derivation of accuracy and response time data at these doses. At lower doses, neither physostigmine (0.05 mg/kg) nor oxotremorine (0.003 mg/kg) significantly affected any performance measure; this may reflect the ability of both drugs to indirectly or directly activate presynaptic muscarinic receptors that inhibit acetylcholine release, respectively. Conclusions: Both muscarinic and nicotinic cholinoceptors may be important in attention but they may serve different roles in information processing; this hypothesis could be tested using tasks that place different emphasis on different stages of information processing.
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  • 45
    ISSN: 1432-2072
    Keywords: Key words ACTH ; Corticosterone ; GABA ; Noradrenaline ; Adrenaline ; Stress ; Rat ; Diazepam
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Gabolysat PC60 is a fish protein hydrolysate with anxiolytic properties commonly used as a nutritional supplement. Objective: The diazepam-like effects of PC60 on stress responsiveness of the rat pituitary-adrenal system and on sympathoadrenal activity were studied. Methods: The activity of the pituitary-adrenal axis, measured by plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone (B) of the sympathoadrenal complex, measured by circulating levels of noradrenaline (NA) and adrenaline (A), and the gamma aminobutyric acid (GABA) content in the hippocampus and the hypothalamus were investigated in male rats which received daily, by an intragastric feeding tube, for 5 days running either diazepam (1 mg/kg) or PC60 (300 or 1200 mg/kg). Controls received only solvent (carboxymethylcellulose 1%). Six hours after the last force-feeding, the rats were subjected to 3 min ether inhalation or 30 min restraint and killed by decapitation 30 min after ether stress or at the end of restraint. Results: Baseline plasma levels of ACTH, B, NA and A were not affected by either diazepam or PC60. Both ether- and restraint-induced release of ACTH, but not B, were similarly and drastically reduced by diazepam and PC60 (1200 mg/kg). Both diazepam and PC60 (1200 mg/kg) deleted restraint-induced NA and A increases. Both treatments also reduced the ether-induced rise of A. Basal levels of GABA were significantly increased in both the hippocampus and the hypothalamus in PC60-treated rats and only in the hippocampus in diazepam-treated ones. In controls, ether inhalation as well as restraint increased GABA content of these two brain structures. In contrast, such stress procedures performed in PC60-treated rats reduced GABA content slightly in the hippocampus but significantly in the hypothalamus. In diazepam-treated rats, GABA content of the hypothalamus was unaffected by stresses but that of the hippocampus was slightly decreased. Conclusions: Present data suggest diazepam-like effects of PC60 on stress responsiveness of the rat pituitary adrenal axis and the sympathoadrenal activity as well as GABA content of the hippocampus and the hypothalamus under resting and stress conditions. These effects of PC60 agree with anxiolytic properties of this nutritional supplement, previously reported in both rats and humans.
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  • 46
    ISSN: 1432-2072
    Keywords: Key words Morphine ; Opioid receptor ; NMDA ; Tolerance ; Rat ; Tail flick
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Pairings of a sweet taste and injection of morphine result in a learned avoidance of that taste and learned analgesic tolerance. This avoidance is mediated by the drug’s peripheral effect, while learned tolerance involves activation of N-methyl-d-aspartate (NMDA) receptors. Exposure to a sweet taste also reduces morphine analgesia. We studied whether this taste-mediated reduction was reversed by an NMDA or peripheral opioid receptor antagonist. Objectives: To determine whether an intraoral infusion of saccharin would modulate morphine analgesia in rats, and to study the contribution of NMDA as well as peripheral opioid receptors to this modulation. Methods: Six experiments used the rat’s tail-flick response to study the effect of an intraoral infusion of a sodium saccharin solution on morphine analgesia, and the effects of the quaternary opioid receptor antagonist methylnaltrexone as well as the non-competitive NMDA receptor antagonist MK-801 on this modulation of analgesia. Results: An intraoral infusion of saccharin reduced the analgesic effects of an intraperitoneal (i.p.) injection of morphine across a range of doses (experiment 1a), which was not attributable to an influence on tail-skin temperature (experiment 1b). This reduction was mediated by opioid receptors in the periphery and activation of NMDA receptors because morphine analgesia was reinstated by an i.p. injection of either methylnaltrexone (experiment 2a) or MK-801 (experiment 3a), which was not due to the effect of methylnaltrexone (experiment 2b) or MK-801 (experiment 3b) on morphine analgesia in the absence of saccharin. Conclusions: These results document evidence for an antagonism of morphine analgesia by actions of the drug at peripheral opioid receptors and excitatory amino-acid activity at NMDA receptors. They are discussed with reference to the aversive motivational effects of peripheral opioid receptors and pain facilitatory circuits.
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  • 47
    ISSN: 1432-2072
    Keywords: Key words  m-Chlorophenylpiperazine ; Drug discrimination ; Ethanol withdrawal ; Anxiety ; 17β-estradiol ; Sex difference ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The serotonergic system plays a role in regulation of anxiety and ethanol withdrawal (EW). Nevertheless, few studies have assessed sex differences in serotonergic effects on EW. Objectives: This study examined sex differences in the anxiogenic stimu-li induced by a serotonin (5-HT)1b/2 agonist, meta- chlorophenylpiperazine (mCPP), prior to ethanol and during EW. Methods: Gonadectomized or sham-operated adult male and female rats and 17β-estradiol (2.5 mg, 21-day release, s.c.) -replaced ovariectomized (OVX) rats were trained to discriminate mCPP (1.2 mg/kg, i.p.) from saline in a two-lever choice task for food. Latency to the first lever press and mCPP lever selection were measured following mCPP (0–1.2 mg/kg). Rats then received chronic ethanol-containing liquid diet (6.5%) for 10 days and were tested for mCPP lever selection 12 h and 36 h after removal of ethanol. Results: Fewer sham female and β-estradiol-replaced OVX rats selected the mCPP lever than male or OVX rats, and showed an increased initiation latency after mCPP injection. During EW (12 h and 36 h), fewer sham female and β-estradiol-replaced OVX rats responded on the mCPP-lever after saline injection as well as after mCPP challenge than male or OVX rats. Castration did not alter any response of male rats to mCPP. Conclusions: (1) mCPP discrimination is a useful measure of EW in male and female rats; and (2) sham female and β-estradiol-replaced OVX rats are less sensitive to the discriminative stimulus prior to and during EW, but more sensitive to impaired behavioral initiation induced by mCPP than male or OVX rats.
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  • 48
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    Psychopharmacology 149 (2000), S. 181-188 
    ISSN: 1432-2072
    Keywords: Key words Acoustic startle response ; Prepulse inhibition ; Sensorimotor gating ; Schizophrenia ; Dopamine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Prepulse inhibition of acoustic startle is the reduction in startle response to an intense auditory stimulus when this stimulus is immediately preceded by a weaker prestimulus. Prepulse inhibition occurs normally in humans and experimental animals, but schizophrenic persons often exhibit a marked impairment in this measure. Previous studies have shown that dopamine (DA)-dependent neuronal mechanisms are involved in the modulation of prepulse inhibition. Objective: Experiments were conducted in rats to elucidate further the involvement of DA-ergic mechanisms in prepulse inhibition. Results: In line with previous studies, the indirect DA agonist, amphetamine, was shown to decrease prepulse inhibition. A close reverse relationship over time between DA overflow in the nucleus accumbens and prepulse inhibition was obtained using a technique allowing concomitant measurement of these parameters in awake, freely moving rats. This effect was more pronounced in amphetamine-treated rats compared to rats treated with equimolar doses of cocaine, which increased DA overflow without affecting prepulse inhibition. In other experiments, the combined treatment with subthreshold doses of the selective DA D1 agonist, SKF 38393, and the selective DA D2 agonist, quinpirole, was also shown to decrease prepulse inhibition. Finally, the selective DA D2 antagonist, raclopride, was shown to enhance prepulse inhibition. Conclusions: In line with previous studies, it is concluded that DA neurotransmission is involved in the modulation of prepulse inhibition and that the ventral part of the mesostriatal DA system may serve an important role in this modulation. Furthermore, the possibility is discussed that the discrepant results on prepulse inhibition obtained with amphetamine and cocaine may disclose functionally relevant differences in their mechanisms of action, and that the enhancement of prepulse inhibition induced by some antipsychotics in rats may reflect their propensity to induce adverse mental effects in humans.
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  • 49
    ISSN: 1432-2072
    Keywords: Key words 8-OH-DPAT ; WAY 100635 ; 5 ; 7-Dihydroxytryptamine ; Attention ; Impulsivity ; Pre- and postsynaptic 5-HT1A receptor ; Dorsal raphe ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Whilst several studies have investigated the role of serotonergic receptor subtypes in learning and memory, relatively few studies have examined their role in attentional processes. Objective: The present study investigated the role of pre- and postsynaptic 5-HT1A receptors on rats’ attentional performance in the five-choice serial reaction time task (5-CSRT). Methods: Hungry rats were trained in the 5-CSRT task to detect brief (0.5 s) flashes of light presented randomly in one of five locations with a fixed intertrial interval of 5 s paced by the rat. We studied the effects of 8-OH-DPAT, a 5-HT1A receptor agonist, at various subcutaneous (SC) doses (10–100 µg/kg) on measures of rats’ discriminative accuracy (the index of attentional functioning) and various behavioural indices of response control and motivation. Manipulations of basic task parameters, intracerebroventricular (ICV) injections of 5,7-dihydroxytryptamine (5,7-DHT) to deplete forebrain 5-HT and treatments with a selective 5-HT1A receptor antagonist WAY 100635 were made in order to determine the behavioural and neural specificity of the effects of 8-OH-DPAT. Results: A dose of 100 µg/kg, but not lower doses, significantly reduced choice accuracy and increased errors of omission, latencies to respond correctly and to collect food reward and premature responses. All these effects were completely blocked by WAY 100635, injected SC 5 min before 8-OH-DPAT at doses from 10–100 µg/kg. WAY 100635 by itself had no effect in the task. Dimming the visual stimuli to one-third of the usual brightness did not modify the effect of 8-OH-DPAT on choice accuracy. Prolonging the stimuli from 0.5 to 1.0 s reversed 8-OH-DPAT’s effect on choice accuracy but did not modify the other effects on rats’ performance. An ICV injection of 150 µg 5,7-DHT, which depleted forebrain serotonin by 90%, reversed 8-OH-DPAT’s effect on choice accuracy but did not modify the effects on errors of omission and latency to make correct responses. Similar effects were found by infusing 1.0 µg/0.5 µl WAY 100635 in the dorsal raphe 5 min before 8-OH-DPAT. 8-OH-DPAT increased the latency to collect the reinforcement; this effect was attenuated by ICV 5,7-DHT and completely antagonized by WAY 100635 in the dorsal raphe. Rats treated with 5,7-DHT or 8-OH-DPAT showed more premature responses and these effects were markedly reduced by the combined treatment. Conclusions: The results suggest that stimulation of presynaptic 5-HT1A receptors is involved in the ability of 8-OH-DPAT to cause attentional dysfunction and enhance impulsivity while slowing of responding and increase in errors of omission mainly depend on stimulation of postsynaptic 5-HT1A receptors.
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  • 50
    ISSN: 1432-2072
    Keywords: Key words Prefrontal cortex ; Dopamine ; Anxiety ; Drug discrimination ; Pentylenetetrazol ; Chlordiazepoxide ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The prefrontal cortical (PFC) dopamine (DA) system has been implicated in anxiety-related behavioral changes, but direct, unequivocal support for this idea is sparse. Objectives: The present aim was to study the functional significance of prefrontal DA using the pentylenetetrazol (PTZ) discrimination model of anxiety. A comparison was made with its role in the cue of the anxiolytic drug chlordiazepoxide (CDP). Methods: Two groups of rats were trained to discriminate either PTZ (20 mg/kg, s.c.) or CDP (10 mg/kg, i.p.) from saline using an operant drug discrimination procedure. After prolonged training, half of each group was used to assess biochemical changes induced by both drugs in different sub areas of the PFC. For the remaining rats, discrimination training continued and generalization tests with PTZ and CDP were performed. Rats were then provided with bilateral guide cannulae aimed at the ventromedial (vm) PFC, and the effects of local infusions of DAergic drugs on discriminative performance were evaluated. Results: CDP did not affect PFC DA activity, but PTZ increased the DOPAC/DA ratio in the vmPFC selectively. Generalization tests showed that the cues of PTZ and CDP were dose dependent. In PTZ-trained rats, infusions of the DA receptor antagonist cis-flupenthixol into the vmPFC blocked the PTZ cue dose dependently, whereas the agonist apomorphine partially generalized to this cue. In CDP-trained rats, neither drug antagonized or generalized to the CDP cue, showing that PFC DA is not critically involved in the CDP cue and that local pharmacological manipulations of PFC DA do not affect discriminative abilities per se. Conclusions: The DAergic innervation of the PFC is directly involved in the behavioral effects of PTZ, suggesting a role for it in anxiety.
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  • 51
    ISSN: 1432-2072
    Keywords: Key words 5-HT1A agonist ; Intrinsic activity ; Efficacy ; Irreversible antagonism ; Lower-lip retraction ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Maximal responses are often used as a measure of intrinsic activity or efficacy, but cannot be directly equated to efficacy. Using irreversible antagonists, estimates of efficacy can be obtained that may be less dependent on specific conditions. Objectives: To characterize the intrinsic activity of serotonin (5-HT)1A agonists by examining the effects of an irreversible antagonist on their ability to produce 5-HT1A receptor-mediated responses. Methods: The effects of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on the ability of 5-HT1A agonists to produce lower-lip retraction (LLR) in rats were studied. Results: In the absence of EEDQ, each 5-HT1A agonist produced full effects, the rank order of potency being: S 14506 〉 8-OH-DPAT 〉 buspirone 〉 ipsapirone. EEDQ decreased the number of 5-HT1A binding sites and shifted the dose–response curves (DRCs) of each agonist either to the right or, at higher EEDQ doses, to the right and downward. The manner in which these shifts occurred, however, differed among the compounds. For each agonist, all DRCs obtained after different doses of EEDQ were fitted to models proposed by Furchgott and Black and Leff, and the results indicated the following rank order of efficacy: ipsapirone 〈 buspirone ≈ 8-OH-DPAT 〈 S 14506. 5-HT1A agonist-induced LLR appears to be mediated by 5-HT1A receptors, because the 5-HT1A antagonist, WAY 100635, shifted the agonist DRCs to the right in a parallel and dose-related manner, with pA2 values ranging from 7.8 to 8.1. Moreover, pretreatment with WAY 100635 protected against the antagonist activity of EEDQ. Conclusions: The results suggest that the effects of EEDQ on the ability of 5-HT1A agonists to produce LLR in rats may be useful to obtain estimates of their apparent efficacy at 5-HT1A receptors.
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  • 52
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    Psychopharmacology 148 (2000), S. 106-110 
    ISSN: 1432-2072
    Keywords: Key words Interferon ; Depression ; Forced swimming test ; Locomotor activity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Objectives: We examined the immobility of the forced swimming test induced in an animal model by human interferon (IFN), which has often been reported to induce depression in clinical use. Methods: In the present study, we examined the effects of human IFNs on results of the forced swimming test in rats. Results: Single intravenous (IV) administration of human IFN-α (6×104 IU/kg), but not of human IFN-β or -γ, significantly increased immobility time in the forced swimming test in rats. Repeated administration of human IFN-α (6×103 IU/kg) also significantly increased the immobility time. On the other hand, none of the rat IFNs (rat IFN-α, -β and -γ, 6×104 IU/kg, IV) changed the immobility time. Neither human IFNs nor rat IFNs changed the locomotor activity of rats. Conclusions: These findings suggest that human IFN-α has a greater potential for inducing increase of the immobility in the rat forced swimming test than human IFN-β and -γ, and that the effect of human IFN-α might not be mediated through IFN-α/β receptors.
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  • 53
    ISSN: 1432-2072
    Keywords: Key words Opiate receptor ; Antinociception ; Habituation ; Novelty ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: There is now extensive evidence demonstrating that exposure to novel stimuli induces hypoalgesia and that this effect habituates over repeated exposure to the stimuli. Moreover, it has been shown that administration of the nonselective opiate receptor antagonist naloxone can attenuate the rate of habituation of novelty-induced hypoalgesia. Objectives: The present experiments were conducted to determine the relative influence of different opiate receptor subtypes in the attenuation of the habituation of novelty-induced hypoalgesia. Methods: In experiments 1–3, different groups of male, Wistar rats (275–300 g) were administered vehicle, 0.5, 1.0 or 2.0-nmol doses of the µ-selective antagonist Cys2-Tyr3-Orn5-Pen7-amide (CTOP), the δ-receptor selective antagonist naltrindole, or the κ-selective antagonist nor-binaltorphimine (nor-BNI). In experiment 4, animals were administered vehicle, 5, 25 or 75-nmol doses of nor-BNI. All injections were delivered to the right lateral ventricle 30 min prior to exposure to a novel hot-plate apparatus (48.5°C), once a day for eight consecutive days. Results: Paw-lick latencies in vehicle-treated animals were long during the initial exposures and declined over repeated tests, suggesting the habituation of novelty-induced hypoalgesia. The rate of habituation was significantly attenuated by administration of 1.0-nmol and 2.0-nmol doses of CTOP, by a 2.0-nmol dose of naltrindole, but was unaffected by all doses of nor-BNI. Conclusions: These results support the involvement of the µ and δ, but not the κ, opiate receptor subtypes in the habituation of novelty-induced hypoalgesia.
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  • 54
    ISSN: 1432-2072
    Keywords: Key words Fentanyl ; mu opioids ; Drug discrimination ; Training dose ; pA2 analysis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Discriminative stimulus effects of mu opioids vary systematically as a function of training dose. Differences among training doses may arise from multiple mechanisms. Objectives: In vivo apparent pA2 analyses were used to examine the contributions of opioid mechanisms to stimulus control by low and high training doses of the mu opioid fentanyl. Methods: Saline and one of two doses of fentanyl, administered s.c., were established as discriminative stimuli in two groups of rats (low training dose group: 0.01 mg/kg; high training dose group: 0.04 mg/kg). Generalization tests and in vivo apparent pA2 analyses were used to evaluate receptor mechanisms of stimulus control. Results: Fentanyl, etonitazene, methadone, and morphine evoked full fentanyl generalization in both groups but were more potent in the low-dose group. Spiradoline and d-amphetamine did not evoke generalization in either group. Naltrexone antagonized stimulus and rate-altering effects of fentanyl in both groups, with apparent pA2 values of 7.6 in the low-dose group and 7.5 in the high-dose group. Nalbuphine and nalorphine evoked full generalization in the low-dose group but less than 40% generalization in the high-dose group. In the high-dose group, nalbuphine and nalorphine antagonized the stimulus and rate-altering effects of fentanyl with apparent pA2 values of 5.3 and 6.1, respectively, demonstrating lower efficacy mu actions. Conclusions: Changes in fentanyl training dose preserved the mu opioid selectivity of stimulus control but altered the intensity of the transduced mu opioid stimulus required for generalization. These differences in intensity of the fentanyl stimulus determined whether low efficacy mu opioids would evoke or antagonize fentanyl generalization.
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  • 55
    ISSN: 1432-2072
    Keywords: Key words Benzodiazepine ; Operant ; Force ; Tolerance ; Chronic ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Several benzodiazepines (BZs) have been shown to increase the peak force of operant responses at doses that increased, decreased, or had no effect on response rate, suggesting that operant response force may be a sensitive index of BZs’ effects rather than solely a correlate of rate-dependent effects. In addition, contingent tolerance to the rate-dependent effects of BZs has been reported, but the degree of contingent tolerance that develops when the critical variable of the task is force of the response has not been explored. Objectives: These experiments examined the effects of acute and repeated oral administration of diazepam (DZ) and midazolam (MZ) on a force-differentiation task to explore the importance of task requirements on the development of contingent tolerance. Methods: Two groups of rats were trained to press a force-sensing operandum, and responses having peak forces falling within fixed lower and upper limits [low force (8–10 g) or high force (40–50 g)] were reinforced with water. Acute effects of the oral administration of DZ (0.3, 1.0, 3.0, 10.0, 30.0 mg/kg) and MZ (same doses) were determined for the discriminated-force task before and after a repeated-administration procedure. Results: When administered acutely, both drugs increased the peak force of responses in a dose-related manner and concomitantly reduced the proportion of reinforced responses, with MZ exhibiting greater potency. For the next 36 days, one group received drug before experimental sessions and the other group received drug after the experimental session. A second dose–effect determination demonstrated that rats chronically dosed with DZ or MZ pre-session displayed more contingent tolerance to alterations in peak force than rats that had received 36 drug injections post- session, where there was no opportunity to practice the force-discrimination response while under the drug state. Conclusions: These results suggest that perceptual motor difficulty of the task rather than effort may be an important variable in predicting the degree of contingent tolerance that develops. Additionally, these results suggest that both behavioral and pharmacological mechanisms are involved in the development of drug tolerance to the BZs.
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  • 56
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    Psychopharmacology 148 (2000), S. 146-152 
    ISSN: 1432-2072
    Keywords: Key words Alprazolam ; Drug discrimination ; Benzodiazepines ; Antidepressant ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The triazolobenzodiazepine alprazolam has a unique clinical profile compared to most other benzodiazepines (e.g. diazepam, chlordiazepoxide), in that it is used to treat panic disorder and is effective in depression, two disorders that are usually treated with anti-depressants. Previous drug discrimination studies suggested that alprazolam has stimulus properties in common with antidepressants. Objective: In the present study, the discriminative stimulus properties of alprazolam were investigated to test more conclusively the role of benzodiazepine receptors and whether alprazolam has stimulus properties in common with antidepressants. Methods: Male Wistar rats (n=12) were trained to discriminate between alprazolam (2.0 mg/kg, PO) and vehicle in an operant two-lever drug discrimination procedure under a tandem VI40”-FR10 schedule of reinforcement. Generalization and antagonism tests were carried out under 2 min extinction. Results: In generalization tests, a number of benzodiazepines (alprazolam, chlordiazepoxide, midazolam, lorazepam) and the barbiturate pentobarbital substituted completely, while zolpidem and abecarnil substituted partially for alprazolam. In contrast, no significant degree of generalization to the antidepressants imipramine and fluvoxamine and the putative antidepressants buspirone and flesinoxan was found. In antagonism studies alprazolam could be antagonized (almost) completely by flumazenil, partially by pentylenetetrazole, but not by methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), N-methyl-β-carboline-3-carboxamide (FG-7142) and picrotoxin. Conclusions: These results show that the discriminative stimulus properties of alprazolam are mediated by benzodiazepine receptors and that the finding that antidepressants share discriminative stimulus effects with alprazolam may have limited generality.
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  • 57
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    Psychopharmacology 148 (2000), S. 209-216 
    ISSN: 1432-2072
    Keywords: Key words Methamphetamine ; Drug-discrimination ; Dopamine ; Cocaine ; GBR-12909 ; Nomifensine ; Bupropion ; Chloro-PB ; Chloro-APB ; NPA ; 7-OH-DPAT ; SCH-23390 ; Spiperone ; cis-Flupenthixol ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Dopamine plays a major role in the behavioral effects of methamphetamine. Objective: In the present experiments, the effects of different dopaminergic agonists, antagonists, and uptake inhibitors were evaluated in rats discriminating methamphetamine from saline. Methods: In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine, i.p., from saline under a fixed-ratio schedule of food delivery, the ability of various dopaminergic agonists and uptake inhibitors to substitute for methamphetamine was evaluated. Subsequently, the ability of various dopaminergic antagonists to block the discriminative-stimulus effects of the training dose of methamphetamine was tested. Results: The dopamine-uptake inhibitors cocaine (10.0 mg/kg), nomifensine (3.0 mg/kg), GBR-12909 (18.0 mg/kg), and bupropion (30.0 mg/kg) fully substituted for the 1.0 mg/kg training dose of methamphetamine. Chloro-APB (SKF-82958), a full agonist at D1 dopamine receptors, produced about 85% methamphetamine-appropriate responding, but the dose required (0.18 mg/kg) markedly decreased rates of responding. Chloro-PB (SKF-81297), another agonist at D1 receptors with a lower intrinsic activity than Chloro-APB, produced only partial generalization (maximum about 55%) at a dose of 1.0 mg/kg. Full substitution for the training dose of methamphetamine was observed with 0.03 mg/kg of the D2 agonist NPA and 0.56 mg/kg of the D3/D2 agonist 7-OH-DPAT. Both NPA and 7-OH-DPAT markedly decreased rates of responding at these doses. The D1 antagonist SCH-23390 (0.056 mg/kg), the D2 antagonist spiperone (0.18 mg/kg), and the mixed D1,D2 antagonist cis-flupenthixol (0.56 mg/kg) all completely blocked the discriminative-stimulus actions of the training dose of methamphetamine. Conclusions: The present findings in rats support previous research findings in other species indicating a major role of dopamine in the discriminative-stimulus effects of methamphetamine. These findings further indicate involvement of dopamine uptake sites as well as D1 and D2 receptors.
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  • 58
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    Psychopharmacology 149 (2000), S. 115-120 
    ISSN: 1432-2072
    Keywords: Key words Opiate ; Withdrawal ; Place aversion ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Administration of low doses of opiate antagonists to morphine-dependent rats produces an aversive response as measured by a conditioned place aversion, but the time course of such a learned aversion is largely unknown. Objectives: The purpose of this experiment was to examine the time course for the expression of a place aversion to opiate withdrawal. Methods: Morphine-dependent rats were tested in a three-chamber place- aversion apparatus. The conditioning phase consisted of three pairings of either naloxone (15 µg/kg s.c.) or vehicle with two compartments, with the most similar time allotments during the preconditioning test. During the testing phase, rats were again allowed to explore the entire apparatus. Different groups were tested at 24 h, 1 week, 2 weeks, 4 weeks, 8 weeks, and 16 weeks post-conditioning (morphine-free tests). Results: A robust place aversion was recorded at every time point tested, including at 16 weeks. In previously published work, placebo-pelleted rats tested with naloxone at the same dose failed to show a place aversion and nondependent rats showed a stable lack of aversion at tests up to 56 days. Dependent animals without naloxone also failed to show a place aversion at any of those time points. Conclusions: In the absence of any active intervention, the place aversion produced by opiate withdrawal is very long lasting and provides a model for protracted abstinence that may be useful for delineating the neurobiological substrate for vulnerability to relapse.
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  • 59
    ISSN: 1438-8359
    Keywords: Key words: Halothane ; Dopamine release ; Dopamine uptake ; Microdialysis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose. In our previous microdialysis study, sevoflurane or isoflurane anesthesia significantly decreased the extracellular level of dopamine in rat striatum in vivo. On the other hand, other investigators demonstrated that halothane anesthesia either increased or did not affect the extracellular dopamine level. To explore the differences among these volatile anesthetics, the effects of halothane and nitrous oxide on the striatal dopamine level were reinvestigated. Methods. Halothane alone, nitrous oxide with or without halothane, or drugs known to affect the dopaminergic pathway were administered to rats. Microdialysates were collected every 20 min and directly applied to an on-line high-performance liquid chromatograph without any pretreatment. The effects of halothane on respiratory and cardiovascular variables were monitored. Results. General anesthesia with halothane alone de-creased the dialysate (extracellular) concentration of dopamine but increased that of dopamine metabolites. Nitrous oxide alone slightly increased dopamine metabolites in dialysates but did not affect the halothane-induced decrease in extracellular dopamine. Apomorphine and haloperidol reproduced reported results, confirming the adequacy of our methodology. Nomifensine- or methamphetamine-induced increase in extracellular dopamine was augmented by halothane. Conclusion. These results suggest that halothane po-tently enhances striatal dopamine release and activates the reuptake or metabolic process, which is consistent with our previous results for sevoflurane or isoflurane. Volatile anesthetics interfere with dopamine regulation, at least in the rat striatum.
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  • 60
    ISSN: 1436-2023
    Keywords: Key words Adriamycin ; Rat ; Embryo ; VATER association ; Synovial joint ; Bones ; Limbs ; Vertebra ; Sirenomelia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The adriamycin-induced rat model of the Vertebral, Anorectal, Tracheo-Esophageal, Radial and Renal (VATER) association produces a variety of vertebral, rib, and limb abnormalities. This study was designed to document accurately the nature of these abnormalities and to determine whether synovial joints are affected. Fetuses from pregnant Sprague Dawley rats that had received intraperitoneal injections of 1.75 mg/kg of adriamycin on days 6–9 or 10–13 of gestation were harvested. Double-stained skeletal preparations and histological sections were examined for vertebral, rib, and limb anomalies. The incidence of anomalies was high in the group treated on gestational days (GD) 6–9, while it was low in the GD 10–13 group. The length and thickness of the long bones were reduced, with bowing and reduction in their endochondral ossification. Sirenomelia occurred in the group treated on GD 6–9, and was often associated with a short tail and anal atresia. The joint cavities, and intra-articular structures such as menisci and the cruciate ligaments developed normally from the mesenchymal interzone. These data indicate that adriamycin inhibits skeletal growth and differentiation without any interference in the differentiation of the mesenchymal interzone, thus producing normal synovial joints.
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  • 61
    ISSN: 1530-0358
    Keywords: Pravastatin ; ras p21 isoprenylation ; Colon carcinogenesis ; Flat colon tumor ; Azoxymethane ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract PURPOSE: The effect of pravastatin, an inhibitor ofras p21 isoprenylation, on the gross type of colon tumors induced by azoxymethane was investigated in Wistar rats. METHODS: Rats received ten weekly subcutaneous injections of 7.4 mg/kg body weight of azoxymethane and intraperitoneal injections of 10 or 20 mg/kg body weight of pravastatin every other day until the end of the experiment at Week 45. RESULTS: Administration of pravastatin at both dosages had no significant effect on the incidence of colon tumors but significantly increased the incidence of rats with adenomas only. In contrast to the elevated adenomas in control rats, flat adenomas were significantly more prevalent in rats given pravastatin. Pravastatin at both doses significantly decreased the labeling index, but not the apoptotic index, of elevated adenomas, whereas it significantly decreased the labeling index but increased the apoptotic index of flat adenomas. Administration of pravastatin at both dosages also significantly decreased the amounts of membrane-associatedras p21 in colon tumors. CONCLUSIONS: These findings suggest that theras oncogene may be closely related to the development of adenocarcinomas from adenomas and the development of elevated or polypoid tumors of the colon.
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  • 62
    ISSN: 1432-1211
    Keywords: Key words Vβ13 ; CD4/CD8 ratio ; Rat ; Tcrb ; Polymorphism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract. Three rat BV13S1 alleles (T-cell receptor β-chain variable gene 13) were characterized by new BV13S1-allele specific monoclonal antibodies (18B1 and 17D5) and sequence analysis of expressed and genomic BV13S1. Two alleles were functional and designated BV13S1A1 present in strains LEW, BUF, PVG, and BV13S1A2 present in BN and WF. Their products differed by six amino acids, two of them in complementarity-determing region (CDR)1 and one in CDR2. A third nonfunctional allele, BV13S1A3P, was found in strains F344 and DA. Apart from a single nucleotide insertion, it was identical to BV13S1A2. All 12 rat strains tested showed association of TCRBC1 with BV8S2/4 alleles but not with the BV13S1 alleles, which may reflect a different gene order of the rat BV compared to mouse. BV13S1A1-encoded T-cell receptors (TCRs) which bind both monoclonal antibody (mAb) 18B1 and mAb 17D5 are over-represented in the CD4 lymphocyte subset. BV13S1A2-encoded TCRs which are stained by mAb 18B1 but not by mAb 17D5 show a slight CD8-biased expression. Preferential usage of BV13S1A1-positive TCRs by CD4 but not by CD8 cells in (LEW×WF)F1 hybrids and cosegregation of BV13SA1 and increased frequency of BV13S1 TCR-positive CD4 cells in a (LEW×BN)×BN backcross suggest structural differences of the two allelic products as the reason for their contrasting CD4/CD8 subset bias.
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  • 63
    ISSN: 1432-0568
    Keywords: Key words Nerve repair ; Nerve fiber regeneration ; Sciatic nerve ; Muscle-vein-combined graft ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Clinical data have shown that a vein segment filled with fresh skeletal muscle can be considered a good autologous grafting conduit for the repair of peripheral nerve lesions. In this study, the long-term morphological organization of rat sciatic nerve fibers regenerated along a muscle-vein-combined graft conduit is further analysed by light and electron microscopy. Regenerated nerve fibers were organized into fascicles of various sizes that were clearly delimited by perineurial-like shells made by long and thin cytoplasmic processes of perineurial-like bipolar cells and by densely packed collagen fibrils. Grafted skeletal muscle fibers were still detectable among nerve fiber fascicles. However, in spite of the persistence of skeletal muscle along the graft, regenerated nerve fibers showed a good morphological pattern of regeneration, providing further evidence that the muscle-vein-combined grafting technique represents an effective surgical alternative to the classical fresh nerve autograft for the repair of peripheral nerve defects.
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  • 64
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    Anatomy and embryology 202 (2000), S. 247-255 
    ISSN: 1432-0568
    Keywords: Key words Enteric neurons ; Interstitial cells of Cajal ; Smooth muscle cells ; Guinea-pig ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Tachykinin receptors NK1r, NK2r and NK3r bind tachykinins with different affinities and share pharmacological and molecular differences among animal species. NK1r, NK2r, NK3r and tachykinin (SP/NKA) distribution was studied by immunohistochemistry in the ileum of mouse since no data are available for this species. The results were then compared to those obtained in the rat and guinea pig either by us or by others to ascertain interspecies similarities and/or differences. NK1r- and NK3r-immunoreactivity (IR) were detected in neurons and NK1r-IR in the interstitial cells of Cajal at the deep muscular plexus. At variance with rat and guinea pig, NK1r-IR was also found in the myoid cells of the villi, while NK2r-IR was never detected in nerve varicosities. This latter datum suggests that the NK2r does not play a presynaptic role in the mouse. Unexpectedly, a high NK2r-IR and the presence of NK3r-IR were observed at the inner portion of the circular muscle layer in the mouse as well as in the rat and guinea pig, demonstrating a subregional distribution of these receptors. Tachykinin distribution did not show noticeable species-related differences. The present findings show species-related differences in the tachykinin receptor distribution that might be related to a different tachykinin controlof intestinal motility.
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  • 65
    ISSN: 1432-0568
    Keywords: Key words GABAB receptor ; CNS ; Dorsal root ganglia ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The anatomical distribution of the GABAB receptor (GBR) splice variants GBR1a and 1b in the CNS has not previously been studied. In the present study, distribution of the splice variants was mapped using immunohistochemistry. Polyclonal antibodies against splice variant unique epitopes were raised in rabbits. Affinity purified antibodies were used according to routine immunohistochemical procedures in sections from the rat CNS or dorsal root ganglia (DRG). The staining intensity was high in the cerebral cortex but lower in basal ganglia and the hippocampus. In the cerebellum, there was a marked difference in the distribution of GBR1a- and 1b-like immunoreactivity (LI). GBR1a-LI was preferentially localised in the granule cell layer whilst GBR1b-LI was mostly found in Purkinje cells and in the molecular layer. Cell bodies of the deep cerebellar nuclei stained for the GBR1a antibody while terminals surrounding the cell bodies were strongly labelled with the GBR1b antibody. A similar pre- vs postsynaptic pattern was seen in several nuclei ventral or caudal to the cerebellum (e.g. the cochlear nucleus, the facial nucleus, the spinal cord) but not in regions rostral to the cerebellum. In the spinal cord, strong labelling for both antibodies was seen in the dorsal horn. The GBR1b but not the GBR1a antibody stained tanycytes in the epithelium of the 3rd ventricle and in the central canal at the brain stem level. DRG neurons were positive for both the GBR1a and 1b antibody, but the former stained the cells much more intensely. Satellite cells were labelled with the GBR1b antibody. The most important aspect of these findings is that in some nuclei, GBR1b may mediate inhibition of transmitter release while in the same regions, GBR1a may mediate postsynaptic inhibition. Further, the observations support previous findings that GBR1b is the predominant splice variant in Purkinje cells.
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  • 66
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    Annals of biomedical engineering 28 (2000), S. 128-134 
    ISSN: 1573-9686
    Keywords: Hippocampus ; Vigilance states ; Paired-pulse ; Dentate gyrus ; Dentate granule cells ; Evoked response ; Rat ; In vivo studies ; Perforant path ; Maturation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Technology
    Notes: Abstract This study examined the effect of normal development and vigilance state on the modulation of dentate granule cell activity in the freely moving rat at 15, 30, and 90 days of age across three vigilance states: quiet waking, slow-wave sleep, and rapid eye movement sleep. Using paired-pulse stimulation, the paired-pulse index (PPI) was obtained for the dentate evoked field potentials elicited by the stimulation of the medial perforant path. Although significant differences in PPI values were observed during development, no significant vigilance state related changes were obtained. Preweaning infant rats, i.e., 15-day old, exhibited significantly less early (interpulse intervals, IPI= 20–50 ms) and late (IPI = 300–1000 ms) inhibition, and less facilitation (IPI = 50–150 ms) when compared to the 90-day old adult rats during all three vigilance states. PPI values obtained from the 30-day old group fell intermediate between the 15- and 90-day old animals. These changes in PPI values provide a quantitative measure of changes in the modulation of dentate granule cell excitability during normal maturation. They can now can be used to evaluate the impact of various insults, such as prenatal protein malnutrition or neonatal stress, on hippocampal development. © 2000 Biomedical Engineering Society. PAC00: 8717Nn, 8719La, 8719Nn
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  • 67
    ISSN: 1573-9686
    Keywords: Heart ; Left ventricle ; LV contractility ; ESPVR ; Pig ; Rat ; Magnetic resonance imaging
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Technology
    Notes: Abstract The end systolic pressure–volume relation (ESPVR) has been shown to be a relatively load independent measure of left ventricular (LV) contractility. Recently, several single-beat ESPVR computation methods have been developed, enabling the quantification of LV contractility without the need to alter vascular loading conditions on the heart. Using a single-beat ESPVR method, which has been validated previously in humans and assumes that normalized elastance is constant between individuals of a species, we studied the effects of myocardial infarction on LV contractility in two species, the rat and the pig. In our studies, LV pressure was acquired invasively and LV volume determined noninvasively with magnetic resonance imaging, at one week postinfarction in pigs and at 12 weeks postinfarction in rats. Normalized systolic elastance curves in both animal species were not statistically different from that of humans. Also, the slope of the ESPVR $$\left( {E_{es} } \right)$$ decreased significantly following infarction in both species, while the volume-axis intercept $$\left( {V_0 } \right)$$ was unaffected. These results indicate that a single-beat ESPVR method can be used to measure the inotropic response of the heart to myocardial infarction, and that the basis for this method (i.e., constant normalized elastance) is applicable to a variety of mammalian species. © 2000 Biomedical Engineering Society. PAC00: 8719Uv, 8761Lh, 8719Hh, 8719Rr, 8719Ff
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  • 68
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    Annals of biomedical engineering 28 (2000), S. 1101-1115 
    ISSN: 1573-9686
    Keywords: Time–frequency analysis ; Coherence ; Cross correlation ; Nonstationary persistent signals ; Central pattern generator ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Technology
    Notes: Abstract We present a novel time-varying phase spectrum (TVPS) method to quantify the dynamics of coevolution of two persistent nonstationary coupled signals. Based on the TVPS, an instantaneous intersignal phase shift is defined within the primary frequency range in which the two signals are highly correlated. The TVPS is estimated using a fixed-window method or an adaptive-window method. In the latter method, the window length changes dynamically and automatically as a function of change in frequency of the signals. The effects of altering window types and lengths on the accuracy of the estimation of the primary phase shift is assessed by analyzing synthesized linear chirp signals with decaying amplitude and constant relative phase shift or decaying amplitude and changing relative phase shifts. The methods developed are also used for determining the evolution of the primary phase shift among ventral root activities during fictive locomotion in an in vitro rat spinal cord preparation. The analyses indicate that the TVPS method in conjunction with the determination of the primary frequency range, allows determination of both the evolution of the coupling strength and the evolution of the phase shift between two persistent nonstationary rhythmic signals in the joint time–frequency domain. An adaptive window reduces the estimation bias and the estimation variability. © 2000 Biomedical Engineering Society. PAC00: 0230-f, 8780Tq
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  • 69
    ISSN: 0219-1032
    Keywords: c-Fos ; Dopamine ; D1 ; Hippocampus ; Rat ; Synaptic Plasticity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract While dopamine is likely to modulate hippocampal synaptic plasticity, there has been little information about how dopamine affects synaptic transmission in the hippocampus. The expression of IEGs including c-fos has been associated with late phase LTP in the CA1 region of the hippocampus. The induction of c-fos by dopaminergic receptor activation in the rat hippocampus was investigated by using semiquantitative RT-PCR and immuno-cytochemistry. The hippocampal slices which were not treated with dopamine showed little expression of c-fos mRNA. However, the induction of c-fos mRNA was detected as early as 5 min after dopamine treatment, peaked at 60 min, and remained elevated 5 h after treatment. Temporal profiles of increases in c-fos mRNA by R(+)-SKF-38393 (50 μM) and forskolin (50 μM) were similar to that of dopamine. An increase in [cAMP] was observed in dopamine-, SKF-, or forskolin-treated hippocampal slices. By immunocytochemical studies, control hippocampal cells showed little expression of c-Fos immunoreactivity. However, when cells were treated with dopamine, an increase in the expression of c-Fos immunoreactivity was observed after treatment for 2 h. The treatment of hippocampal neurons with R(+)-SKF38393 (50 μM) or forskolin (50 μM) also induced a significant increase in c-Fos expression. These results indicate that the dopamine D1 receptor-mediated cAMP dependant pathway is associated with the expression of c-Fos in the hippocampal neurons. These data are consistent with the possible role of endogenous dopamine on synaptic plasticity via the regulation of gene expression. Furthermore, these results imply that dopamine might control the process of memory storage in the hippocampus through gene expression.
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  • 70
    ISSN: 1434-0879
    Keywords: Key words Castration ; Epidermal growth factor ; Insulin-like growth factor I ; Prostate ; Testosterone ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) are strong inducers of proliferation to prostate cells cultured in serum-free medium. Accordingly we wanted to study the growth of the prostate gland in castrated rats after treatment with EGF, IGF-I and testosterone. Castrated Wistar rats were treated with growth factors (EGF 35 μg/rat per day; IGF-I 350 μg/rat per day) or testosterone (2 mg/rat per day) for 3 days either immediately after or 10 days after castration. Prostate tissue was examined by stereological and immunohistochemical techniques and by enzyme-linked immunosorbent assay (ELISA). Treatment with EGF inhibited the involution of the prostate (P 〈 0.05), whereas treatment with IGF-I did not affect the prostate involution as compared to castrated controls. EGF treatment significantly increased the endogenous rat EGF in the ventral prostate, but cellular proliferation was not affected. Testosterone treatment increased the weight of the prostate, by increase of all tissue components of the prostate, and significantly increased cellular proliferation. Systemic administration of EGF but not IGF-I decreased the involution of the rat prostate induced by castration. Compared with testosterone, the effects of EGF treatment on the prostate involution were moderate, and the effects of EGF were not related to cellular proliferation.
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  • 71
    ISSN: 1434-0879
    Keywords: Key words Bladder ; Rat ; Aging ; Obstruction ; Cystometrics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Bladder dysfunction in the aging population is a significant problem. However the concomitant presence of other diseases in many patients can make it difficult to distinguish between changes in bladder function and other influences. The present study was designed to study, in aging rats, bladder function and the effect of partial bladder outlet obstruction (BOO) on bladder function. Cystometrics were performed in awake, female Fischer 344 rats of four age groups (6, 12, 18 and 24 months) following subcutaneous implantation of a mediport catheter. Cystometric evaluations were carried out in control rats or those subject to three weeks of BOO. Bladder compliance significantly decreased with aging, which reflected an increase in threshold pressure without changes in bladder capacity. Partial BOO caused development of severe bladder instability. Following BOO, bladder capacity and compliance were significantly increased in all age groups. Threshold pressure was lower in obstructed animals, except for 6-month rats. Younger animals were able to generate a higher contraction pressure to compensate for the BOO, whereas older animals did not. Using an awake model of cystometric measurement, we have demonstrated that aging, by itself can affect bladder function. Furthermore, aged animals respond differently to BOO than younger animals. These results demonstrate that both aging and disease can contribute to bladder dysfunction, and suggest that treatment of bladder dysfunction may require a combination of therapies targeted to multiple etiologies.
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  • 72
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    Urological research 28 (2000), S. 141-146 
    ISSN: 1434-0879
    Keywords: Key words Kidney ; Nitric oxide ; Ischemia-reperfusion injury ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In this study we attempted to clarify the release of nitric oxide (NO) and its role in the ischemia-reperfusion rat kidney. After right nephrectomy, male Wistar rats were divided into four groups: one sham operated and three groups who underwent ischemia (30 min) and reperfusion of the left renal artery. Thirty minutes prior to ischemia-reperfusion, two groups were injected intraperitoneally with 10 and 30 mg/kg of NG-nitro-l-arginine methylester (L-NAME). Real-time monitoring of blood flow and NO release in the rat kidney was measured with a laser Doppler flowmeter and an NO-selective electrode, respectively. Serum creatinine and blood urea nitrogen (BUN) levels were measured 1 and 7 days after the induction of ischemia-reperfusion. Clamping of the renal artery decreased blood flow to 1–5% of the basal level measured before clamping. After removal of the clip, the blood flow of the 30 mg/kg L-NAME rats was significantly lower than that of the controls. Immediately following the clipping of the renal artery, NO release rapidly increased. After removing the clip, NO release immediately returned to three-quarters of the basal level. Serum creatinine and BUN levels of the ischemia-reperfusion rats were slightly but not significantly higher and those of 30 mg L-NAME rats were significantly higher than those of the control or ischemia-reperfusion rats 1 day and 7 days after ischemia-reperfusion. Our data suggest that NO acts as a cytoprotective agent in ischemia-reperfusion injury of the rat kidney.
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  • 73
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    European journal of applied physiology 83 (2000), S. 310-319 
    ISSN: 1439-6327
    Keywords: Key words Motor unit ; Mechanomyography ; Evoked contraction ; Medial gastrocnemius muscle ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Acoustic phenomena accompanying contractions of single motor units (MUs) have previously received little attention. Therefore, in the present study, the mechanomyographic (MMG) signals during evoked contractions of single MUs have been recorded from the medial gastrocnemius muscle of the rat. A piezoelectric transducer immersed in a paraffin-oil pool was used for the measurement of these signals. Muscle fibre action potentials, tension and MMG were recorded in parallel during twitch (the weakest) and fused tetanic (the strongest) MU contractions. It was observed that the onset of the MMG signals was coincident with the beginning of the increase in tension for both the twitch and tetanus. Weaker MMG signals than those accompanying the beginning of the first phase of the fused tetanus were seen during the beginning of the relaxation after tetanic contraction. During contraction and relaxation, MMG signals were characterised by the reverse-direction of the first extreme phase, positive and negative, respectively. No MMG signals were observed when the tension was constant during the fused tetanus. The amplitude of MMG signals was correlated with both the tension increase and the velocity of tension increase during both the twitch and the fused tetanus. The strongest MUs (fast fatiguable) generated MMG signals of the highest amplitude. MMG signals were not detected for some of the weakest slow MUs (with tension increases of ≤2 mN). These results indicate a strong correlation between the MMG and the change of tension. Therefore, we believe that MMG signals are generated by muscle deformation that occurs during the contraction of MU muscle fibres. We conclude that the number of active muscle fibres, their topography, and their localisation in relation to the muscle surface (which is variable for different types of MUs) influence these MMG phenomena.
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  • 74
    ISSN: 1615-3146
    Keywords: Key Words Spinal cord compression ; Autoradiography ; Blood flow ; ATP ; Glucose ; Lactate ; Bioluminescence ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Many data are available concerning spinal cord blood flow (SCBF) and metabolism on various models and timing after spinal cord injury, however, detailed information on their exact relationship in the same injury model is lacking. This relationship is a crucial factor in the understanding of the pathophysiology of spinal cord trauma. Rats were subjected to lumbar laminectomy or lumbar spinal cord compression trauma. 3 hours later, changes in SCBF were evaluated autoradiographically and changes in ATP, glucose and lactate levels were analyzed using substrate-specific bioluminescence techniques. Measurements were performed at the lesion site (segment L4), adjacent segments (L3 and L5) and at remote thoracic segments (Th8 to Th9). Laminectomy alone did not change SCBF, both in thoracic and lumbar segments. In contrast, ATP levels were significantly reduced and lactate levels were increased at the lesion site and in adjacent lumbar segments at 3 hours after laminectomy, whereas glucose levels were not significantly changed. In animal subjected to additional compression trauma, SCBF was significantly reduced in segments L3, L4 and L5 paralleled by a significant ATP reduction and lactate increase. Glucose levels did not differ significantly from controls 3 hours after compression injury. This metabolic profile was also reflected in the remote thoracic segments. In contrast, SCBF was not reduced in thoracic segments of traumatized animals. The observation that ATP was already significantly reduced and lactate increased in laminectomized segments and in remote thoracic regions after trauma signals that metabolic changes are sensitive indicators to spinal stress. The fact that posttraumatic metabolic profile differs from the pattern of hemodynamic and metabolic changes induced by ischemia, suggests posttraumatic mediators may be involved in the different regulation of the energy producing machinery.
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  • 75
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    Medical & biological engineering & computing 38 (2000), S. 42-48 
    ISSN: 1741-0444
    Keywords: Bowel sounds ; Rat ; Motility ; Body acoustics ; Signal detection ; Signal characterisation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract This study is aimed at detecting gastrointestinal sounds (GIS) and correlating their characteristics with gastrointestinal (GI) conditions. The central hypotheses are that GIS generation depends on the motility patterns and the mechanical properties of the gut, and that changes in those result in measurable differences in GIS. An animal model which included both healthy rats and those with small bowel obstruction (SBO) was developed. The acoustic bursts, of GIS were detected by amplitude thresholding the signal envelope. Three methods of envelope estimation were proposed and evaluated. Envelope estimation using a Hilbert transform was found to produce the best results in the current application. The duration and dominant frequency of each detected GIS event was estimated and clear differences between healthy and diseased rats were discovered. In the control state, GIS events were found to consistently be of relatively short duration (3–65ms). Although the majority of events in the SBO state had similar short duration, infrequent longer events were also detected and appeared to be pathognomonic. Long duration events (〉100 ms) occurred in each of seven obstructed, but in none of 14 non-obstructed, cases (p〈0.001). It is concluded that GIS analysis may prove useful in the non-invasive, rapid, and accurate diagnosis of SBO.
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  • 76
    ISSN: 1437-7799
    Keywords: Key words VEGF ; Glomeruli ; Ribonuclease protection assay ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background. Vascular endothelial growth factor (VEGF) is a selective endothelial growth factor which potently enhances microvascular permeability. In the kidney, VEGF mRNA is known to be highly expressed in visceral epithelial cells in glomeruli. However, the physiological role of VEGF in glomerular function and its involvement in the pathogenesis of proteinuria are not clear. The present studies were designed to determine whether altered expression of VEGF mRNA was observed in the course of puromycin aminonucleoside (PAN) nephrosis in rats (a model of human minimal change nephrosis). Methods. The message level of VEGF in isolated glomeruli of PAN nephrosis rats was measured using a ribonuclease protection assay. Results. VEGF expression began to decrease 4 days after PAN injection and could not be detected in the nephrotic stage of PAN nephrosis (on days 8 and 16). In the remission of stage of PAN nephrosis (on day 28), mRNA was restored to the control level. Conclusions. According to our results, a functional defect in the VEGF expression of visceral epithelial cells was observed in PAN nephrosis. VEGF could be a functional marker of visceral epithelial cells, and the loss of normal expression of VEGF after damage to visceral epithelial cells could affect glomerular endothelial cell function in PAN nephrosis.
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  • 77
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    Pediatric surgery international 16 (2000), S. 285-292 
    ISSN: 1437-9813
    Keywords: Key words Major histocompatibility complex (MHC) ; Rat ; Immunohistochemistry ; Distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The present study systematically investigated the expression and distribution of the major histocompatibility complex (MHC) classes I and II in the rat. About 150 native tissue probes from eight adult Lewis rats were taken, representative for most organs, tissues, and the vascular system. MHC expression was analyzed by two monoclonal antibodies (mAb) generated against the non-polymorphic determinants of rat MHC class I (Ox-18) and class II (Ox-6). Immunoreactivities were compared to those of different endothelial (HIS52, TLD-3A12, Ox-43, REHA-1 antigen), histiocytic (ED1, ED2), B-cell (RLN-9D3), and T-cell (MRC Ox-52) markers. A nonspecific mAb (MR12/53) served as a negative control. Pretested concentrations on various tissues and the alkaline phosphatase-anti-alkaline phosphatase technique allowed semiquantitative evaluation of serial cryostat tissue sections. MHC class I expression was detected on most immunocompetent cells. Endothelial cells were stained heterogeneously along the vascular system and the organ-specific microcirculation. Furthermore, some organs showed staining of parenchymal cells. MHC class II was found on all immunocompetent cells positive for the B-cell marker and about 15% of cells positive for the histiocytic markers. Besides the well-known expression of MHC class II in the outer zone of the renal proximal tubule, further organ-specific cell forms were found positive. In conclusion, the present study outlines tissue-specific distribution of MHC I/II and implies that each organ carries a variable immunologic burden that needs to be considered for any transplantation model.
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  • 78
    ISSN: 1437-9813
    Keywords: Key words Fetal transplantation ; Proliferation ; Adrenal glands ; Addisonian crisis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The present study investigated the histologic maturation, proliferative capacity, and steroid production of fetal adrenal transplants (Tx) in adrenalectomized rats. A pair of fetal adrenal glands (18–20 days of gestation) was transplanted into the omentum of syngeneic Lewis rats (n=45). Four weeks later, in 5 animals the grafts were excised for morphologic evaluation. Proliferation was investigated by immunohistochemical staining for KI-67 protein and quantified by the proliferation index (PI = positive cells/100 counts). All other hosts (Tx; n = 40) underwent bilateral adrenalectomy (AE) to induce Addisonian crisis. Postoperatively, survival and concentrations of potassium, sodium, aldosterone, and corticosterone were recorded for 6 months. These data were compared to controls (C = only AE; n = 30) and a sham group (S; n = 10). At the end of the study period all surviving hosts were killed for histologic examination of grafts. At 4 weeks post-Tx the adrenal grafts demonstrated a distinct zona glomerulosa and frequent proliferation with a PI of 0.084, comparable to normal control (0.092). Following AE survival was significantly prolonged in Tx (86% vs 12% of C, P 〈 0.05). Control animals developed severe hyponatremia and hyperkalemia, whereas in Tx only transient signs of Addisonian crisis were recorded. Levels of aldosterone dropped within 7 days in the Tx and C groups, but returned to normal for Tx within 8 weeks. Corticosterone levels of Tx animals fell to 25% within week, but steadily increased to 70% by the end of the study. At 6 months, grafts revealed a mature adrenocortical structure with little proliferative activity, which was comparable to controls. In a syngeneic rat model fetal adrenal transplants thus mature and proliferate to provide sufficient steroid production for adrenalectomized hosts.
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  • 79
    ISSN: 1437-9813
    Keywords: Key words Congenital diaphragmatic hernia ; Hypoplastic lung ; Bromodeoxyuridine (BrdU) ; Antenatal glucocorticoids ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The aim of this study was to investigate the effect of antenatal glucocorticoid therapy on smooth-muscle-cell (SMC) DNA synthesis in the pulmonary arteries (PA) in a nitrofen-induced congenital diaphragmatic hernia (CDH) rat model following nitrofen administration on day 9.5 of gestation. Antenatal dexamethasone (DEX) was given intraperitoneally on days 18.5 and 19.5 of gestation. Bromodeoxyuridine (BrdU) was injected via a jugular vein into the dam 1 h before the fetuses were killed by cesarean section at term. The fetuses were divided into three groups: group I (n = 10): normal controls; group II (n = 10): nitrofen-induced CDH; group III (n = 10): nitrofen-induced CDH with antenatal DEX treatment. Immunostaining of the lungs with anti-BrdU antibody was obtained by a standard avidin-biotin complex method. The number of immunopositive cells in the PA media and adventitia were counted using an image analyzer and analyzed statistically. The number of BrdU-immunopositive cells in the media was significantly increased in group II (16.83 ± 3.01) compared to groups I (9.16 ± 2.20) and III (6.83 ± 1.70) (P 〈 0.01). There was no significant difference between groups I and III. The number of BrdU-immunopositive cells in the adventitia was not significantly different between the three groups. Antenatal DEX treatment inhibits SMC DNA synthesis in PA media in CDH lungs. This may be a possible mechanism by which antenatal DEX prevents structural PA changes in nitrofen-induced CDH in rats.
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  • 80
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    Pediatric surgery international 16 (2000), S. 485-487 
    ISSN: 1437-9813
    Keywords: Key words Duodenum ; Apoptosis ; Fetus ; Rat ; Duodenal atresia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Duodenum is thought to go through a solid-core stage followed by recanalization during its development. This study investigates the role of apoptosis in normal duodenal development, especially during widening of the lumen, and hence, the possible role of apoptosis in duodenal atresia (DA). Twenty-four time-mated Sprague-Dawley rats were killed from day 13 to day 20 of gestation. Duodenums of 3 fetuses were chosen randomly from each rat and processed. Apoptosis was determined by the terminal deoxytransferase-mediated biotin dUTP nick-end labeling (TUNEL) technique (ApopTag). Apoptosis count and cross-sectional areas were measured with an image analyzer (MetaMorph). The number of apoptotic cells per unit area duodenum peaked on day 15 for the mucosal/submucosal layer and on day 14 for the muscular/mesenchymal layer. The maximal number of apoptotic cells per cross-section of duodenum was between 7 and 8. The cross-sectional areas of the duodenal wall and lumen increased exponentially between day 17 and day 19 while duodenal-wall thickness remained relatively constant throughout duodenal development. The localization, timing, and intensity of apoptosis do not suggest that apoptosis is responsible for the widening of the duodenal lumen; enlargement of the lumen is related to the increase in duodenal circumference. Apoptosis thus may not be involved in the pathogenesis of DA.
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  • 81
    ISSN: 1432-2307
    Keywords: Key words Pyruvate kinase isoenzymes ; N-Nitrosomorpholine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The expression of the pyruvate kinase (PK) isoenzymes L and M2 was analysed in the livers of rats treated with the hepatocarcinogenic agent N-nitrosomorpholine (NNM) in the drinking water. In control animals L-PK expression was restricted to liver parenchymal cells, whereas M2-PK was detected in bile duct epithelial, blood vessel wall, endothelial and Kupffer cells. In rats treated with NNM proliferating oval cells were consistently L-PK negative and M2-PK positive, while the ductal cells of cholangiofibroses were clearly L-PK positive and coexpressed M2-PK. However, no morphological differentiation of ductal cells into hepatocyte-like cells was observed. In the clear and acidophilic cell foci storing glycogen in excess strong staining for L-PK was observed. In glycogen-poor foci induced by NNM a shift from L-PK to M2-PK expression takes place.
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  • 82
    ISSN: 1432-5233
    Keywords: Key words Cadmium ; Diabetes ; VEP ; TBARS ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Fifty-two healthy male Swiss albino rats, aged three months, were used in this study. They were divided into four groups: control (c), diabetic (D), cadmium (Cd), and diabetic + Cd (D+Cd). A diabetic condition was induced in D and D + Cd groups by administration of alloxane (5 mg/100 g). After this treatment, Cd and D + Cd groups were injected intraperitoneally with CdCl2 (2 mg/kg week). At the end of the 2-month experimental period, flash visual evoked potentials (FVEPs) of the four groups were recorded with disk electrodes attached with electrode paste 0.5 cm in front of and behind the bregma. The mean latencies off the P1, N1, P2, N2 and P3 components were significantly prolonged in the diabetic group compared with the control group. The mean latencies of P3 in the D + Cd group and of P1 and P3 in the Cd group were longer than those of the control group. P2N2 amplitude of Cd and D + Cd groups were significantly increased compared with the control group. On the other hand, thiobarbituric acid-reactive substances (TBARS) were determined as an indicator of lipid peroxidation. Our data showed that Cd treatment and diabetic condition caused a significant increase of lipid peroxidation in kidney, brain, retina and lens.
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  • 83
    ISSN: 1432-2307
    Keywords: Key words Medullary thyroid carcinoma ; Basement membrane ; Laminin ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Medullary thyroid carcinoma (MTC) originates from C cells, which secrete calcitonin (CT), their specific marker. C cells are located in contact with the basement membrane (BM) of the thyroid follicles, which is partly made up of the laminin-2 isoform synthesized by thyrocytes. During oncogenesis, proliferation of the C cells, invading the centre of the follicles, leads to a break in their normal contact with the BM. As specific interactions of cells with BM components, especially laminins, are important for proliferation and differentiation, we investigated the relationships of normal and neoplastic C cells with laminin in the Wag/Rij rat model of human MTC. Immunocytochemical studies showed a progressive loss of the laminin layer underlying the hyperplastic C cell nodules around the large dedifferentiated tumours. The α2, β1 and γ1 chains of the laminin-2 isoform were synthesized and secreted by rat MTC 6–23 cell cultures and the tumours induced by subcutaneous injection of these cells. In situ hybridization combined with anti-CT immunocytochemistry showed a low expression of α2 mRNA on differentiated C cells and thyrocytes, but an overexpression on immunonegative spontaneous MTC and induced intrathyroid tumours. The high level of α2 gene expression, together with tumour dedifferentiation, suggests a relationship with malignancy.
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  • 84
    ISSN: 1432-2277
    Keywords: Key words Xenotransplantation ; 15-deoxyspergualin ; Guinea pig ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study aimed to investigate the effects of 15-deoxyspergualin (DSG), tacrolimus (FK 506) and cyclosporin A (CyA), alone or in combination, on delayed xenograft rejection (DXR). We used the guinea-pig-to-C6-deficient (C6–)-PVG-rat heart transplantation model, since in this strain combination, hyperacute rejection is avoided. In C6- control rats, the guinea pig xenografts survived for 39.2 ± 6.3 h (mean ± SD). Splenectomy alone resulted in a xenograft survival of 71.8 ± 7.8 h, but the addition of CyA or FK 506 did not further improve graft survival (73.6 ± 3.0 h and 72.0 ± 17.6 h, respectively). In contrast, DSG treatment increased graft survival to a mean of 99.8 ± 9.2 h. When CyA or FK 506 was combined with DSG, no additional effects were observed (105 ± 24.3 h and 95.1 ± 5.6 h, respectively). DSG alone or in combination with FK 506 or CyA resulted in a significant reduction in the serum IgM levels and reduced the deposits of IgM and IgG in rejected grafts. However, all xenografts were still heavily infiltrated by ED1 + macrophages, regardless of the treatment used. Thus, DSG treatment resulted in moderate prolongation of xenograft survival in C6– rats. The effect seems to be related to suppression of xenoreactive antibody production. To prolong xenograft survival further, strategies that inhibit macrophage infiltration seem required.
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  • 85
    ISSN: 1432-1912
    Keywords: Key words Blood pressure ; Endothelium ; Human ; Mesenteric artery ; Rat ; Smooth muscle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The majority of the findings concerning arterial physiology and pathophysiology originate from studies with experimental animals, while only limited information exists about the functional characteristics of human arteries. Therefore, the aim of the present work was to compare the control of vascular tone in vitro in mesenteric arterial rings of corresponding size (outer diameter 0.75–1 mm) from humans and Wistar-Kyoto rats. The relaxations to acetylcholine (ACh) were clearly less marked in the mesenteric arteries of humans when compared with rats. How-ever, when calcium ionophore A23187 was used as the vasodilator, the endothelium-mediated relaxations did not significantly differ between these species. The NO synthase inhibitor N G-nitro-l-arginine methyl ester (l-NAME) attenuated the relaxations to ACh and A23187 in both groups. The endothelium-independent relaxations to the β-adrenoceptor agonist isoprenaline and the nitric oxide (NO)-donor nitroprusside were somewhat lower in human arteries, while vasodilation induced by the K+ channel opener cromakalim was similar between humans and rats. Arterial contractile sensitivity to noradrenaline and serotonin was slightly lower in human vessels, whereas contractile sensitivity to KCl was similar between these species. The contractions induced by cumulative addition of Ca2+ with noradrenaline as the agonist were effectively inhibited in both groups by the calcium channel blocker nifedipine, the effect of which was clearly more pronounced in human arteries. In conclusion, the control of vascular tone of isolated arteries of corresponding size from humans and rats appeared to be rather similar. The most marked differences between these species were the impaired endothelium-mediated dilation to ACh and the more pronounced effect of nifedipine on the Ca2+-induced contractions in human arteries.
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  • 86
    ISSN: 1432-198X
    Keywords: Key words Hypercalciuria ; Idiopathic hypercalciuria ; Bone mineral content ; 1 ; 25-Dihydroxyvitamin D ; Furosemide ; Ammonium chloride ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The relationship between bone mineral status and hypercalciuria is controversial. The effect on bone composition of different forms of hypercalciuria was studied in female rats made hypercalciuric by 7-week administration of oral furosemide (F, n=12), intraperitoneal 1,25-dihydroxy vitamin D (VD, n=11), or oral ammonium chloride (AC, n=12). Seven untreated rats served as controls (C). Hypercalciuria (mg/100 g per 24 h, mean ±SEM) of F (4.3±0.2), VD (4.1±0.4), and AC (3.9±0.3) groups was of similar intensity (C rats 1.3±0.1, P〈0.01). Weight and length gains and serum CO2, sodium, potassium, calcium, and phosphate were no different among the four groups. Bone was studied by dual-energy X-ray absorptiometry of left tibiae. AC rats had significantly less bone area (1.505±0.018 cm2) than VD and C (1.602±0.020 and 1.587±0.019 cm2). Bone mineral content was decreased in F (0.357±0.007 g) and AC (0.362±0.006 g) compared with VD (0.407±0.008 g) and C (0.389±0.009 g) groups. Bone mineral density was different between F (0.231±0.002 g/cm2) and VD and C rats (0.254±0.004 and 0.245±0.003 g/cm2), and also between AC (0.240±0.003 cm2) and VD rats. In these rat models, hypercalciuria of renal origin (F) and hypercalciuria caused by acid load (AC) adversely impaired bone mass.
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  • 87
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    Pediatric nephrology 13 (1999), S. 800-805 
    ISSN: 1432-198X
    Keywords: Key words In situ hybridization ; Kidney development ; Nephrogenesis ; Phosphatase activity ; Serine/threonine protein phosphatase 2A ; Protein phosphorylation ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Several lines of evidence suggest that the serine/threonine protein phosphatase (PP)2A is of vital importance for cell cycle regulation, cell differentiation, and signal transduction. This prompted us to study the expression of the mRNA for PP2A catalytic isoforms α and β in the developing rat kidney using in situ hybridization histochemistry. The expression patterns of the two isoforms were strikingly similar. Both were ubiquitously expressed in early metanephric kidneys. Later in gestation they were expressed in the nephrogenic zone. Strong expression was observed on postnatal day (PN) 10. This was followed by a downregulation at PN20, i.e., when nephrogenesis is completed. The expression in the adult kidney was very weak and mainly confined to the medulla. In a phosphatase activity assay, PP2A accounted for 78% of the total serine/threonine phosphatase activity in embryonic day 15 rat kidneys. PP1 was the main contributor to the remaining activity. In conclusion, PP2A is the major serine/threonine phosphatase in fetal kidneys. The age-dependent expression pattern supports the concept that this enzyme is of particular importance during renal morphogenesis and development.
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  • 88
    ISSN: 1432-198X
    Keywords: Key words Cystinosis ; Cysteamine ; Renal function ; Rat ; Prenatal
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The safety of cysteamine after renal transplantation and during pregnancy is an important issue, since girls with cystinosis are in better health on cysteamine therapy and thus more likely to become pregnant. In the first study, cysteamine was given to pregnant rats on days 6.5–18.5 post conception in oral doses of 0, 37.5, 75, 100, and 150 mg/kg per day. The dams were sacrificed on day 20.5, the fetal kidneys removed and prepared for histological examination. In the second study, cysteamine was given to dams on days 6.5–19.5 post conception in oral doses of 0, 37.5, 50, and 75 mg/kg per day. Dams were allowed to give birth naturally and pups were given cysteamine on days 4–21 to yield the same oral doses of cysteamine given to the dam. Renal function was evaluated on day 35. Histological examination of fetal kidneys revealed no changes even in kidneys from fetuses with growth retardation and malformations. Furthermore, there were no alterations in renal function in offspring on day 35. These findings demonstrate that cysteamine therapy does not affect renal development in the rat. Further investigations will be required to prove whether cysteamine therapy has the potential to affect renal development in the human.
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  • 89
    ISSN: 1432-1831
    Keywords: Key wordsToxoplasma gondii ; Toxoplasmosis ; Rat ; Animal model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract There is evidence that not only the immune status, but also the genetic predisposition of certain hosts influence the clinical outcome of Toxoplasma gondii infection. By far the majority of our knowledge on genetic and immunological mechanisms involved in control of T. gondii infection has been obtained by studying mouse models, which in terms of clinical outcome of infection differ considerably from humans. Rats which show a rather similar course of infection in comparison to humans have not so far been investigated for effects of genetic differences on course of the infection. In this study we show that, like mice, different strains of rats exhibit a remarkable variation in the number of brain cysts arising from chronic infection. LEW rats seem to be highly resistant to cyst formation, in contrast to F344 rats that are susceptible. In addition, F344 rats express high numbers of γδ T cells during the acute phase of infection, whereas LEW rats express elevated but comparably low numbers of γδ T cells. The RT1 (rat MHC) haplotypes of both strains are identical in the RT1A and RT1B/D regions, which encode the restriction elements for conventional peptide antigens. Consequently, rat strain-specific differences may be useful to define MHC-independent mechanisms of resistance against T. gondii, which may also act in humans.
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  • 90
    ISSN: 1432-0738
    Keywords: Key words Benzene ; Benzene metabolites ; Diabetes ; Cytochrome P-450 ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Benzene is a ubiquitous environmental pollutant primarily metabolized by a cytochrome P-450 (CYP-450) isoenzyme, CYP-450 IIE1. A consistent induction of CYP450 IIE1 has been observed in both rat and human affected by diabetes mellitus. The aim of this study was to evaluate whether streptozotocin (STZ)-induced diabetes determines modifications in the metabolic pathways of benzene in rat. Benzene (100 mg/kg per day, dissolved in corn oil) was administered i.p. once a day for 5 days. Urine samples were collected every day in STZ-treated and normoglycaemic animals, treated and untreated with benzene (n = 10). Urinary levels of trans,trans-muconic acid and of phenol, catechol and hydroquinone (free and conjugated with sulphuryl and glucuronic group) were measured by high-performance liquid chromatography (HPLC). In normoglycaemic rats during the 5 days of treatment with benzene we observed a progressive and significant decrement in the urinary excretion of phenol, phenyl sulphate and glucuronide, catechol, catechol glucuronide, hydroquinone, hydroquinone glucuronide and t,t-muconic acid (P 〈 0.05). In the diabetic animals, conversely, the same metabolites showed progressively increasing urinary levels (P 〈 0.05). Catechol sulphate and hydroquinone sulphate levels were below the instrument's detection limit. In the comparison between diabetic and normoglycaemic benzene treated rats, the inter-group difference was significant (P 〈 0.05) from day 3 of treatment for t,t-muconic acid, and from day 1 for free and conjugated phenol, free and glucuronide catechol and free hydroquinone. In the normoglycaemic rat exposed to benzene the decreasing trend observed in urinary excretion of free and conjugated metabolites may be due to their capability to reduce cytochromial activity. Conversely, in the diabetic rat, urinary levels of benzene metabolites tended to increase progressively, probably due to the consistent induction of CYP-450 IIE1 observed in diabetes, which would overwhelm the inhibition of this isoenzyme caused by phenolic metabolites. Furthermore, the metabolic switch towards detoxification metabolites observed after administration of high doses of benzene is not allowed in the diabetic because of reduced glutathione-S-transferase activity. As a consequence, higher levels of hydroquinone, phenol and catechol, considered the actual metabolites responsibles for benzene toxicity, will accumulate in the diabetic rat. Extrapolating these data to human, we may thus suggest that occupational exposure to benzene of a diabetic subject poses a higher risk level, as his metabolism tends to produce and accumulate higher levels of reactive benzene catabolites.
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  • 91
    ISSN: 1432-0533
    Keywords: Key words Clomethiazole ; Rat ; Spinal cord-injury ; Neuroprotection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Clomethiazole (CMZ) has a neuroprotective effect in experimental focal and global forebrain ischemia. This neuroprotective effect may depend on its ability to enhance GABA receptor activity. We have studied the effect of pretreatment with CMZ on motor function recovery and nerve cell damage after spinal cord injury (SCI). Rats were randomized and 30 min before SCI they received a single intraperitoneal dose of CMZ (150 mg/kg) or saline. The spinal cord was injured with a 50 g (4.5 g/mm2) load, applied over the exposed dura, through a curved rectangular plate (2.2 × 5.0 mm) for 5 min at T8–9. The animals became paraplegic 1 day after injury. The rats were evaluated for recovery of hind limb motor function. All animals recovered to some extent over the observation period of 12 weeks. However, hind limb motor function was significantly better in the animals pretreated with CMZ. At 12 weeks the rats were killed and perfused/fixed for morphological investigations. Microtubule-associated protein 2 (MAP2) immunostaining was used to stain neurons and dendrites and Luxol-fast blue to stain myelinated tracts of the white matter. The injured segment of the spinal cord showed severe atrophy, distortion, cavitation and necrosis of grey and white matter. Compared to uninjured controls the transverse sectional area was reduced to 32.7 ± 4% in untreated animals but only to 38.5% ± 4.1 in CMZ-treated animals. MAP2 staining showed that, compared to uninjured controls, grey matter was reduced to 7.4 ± 2.7% in saline-treated injured animals and to 22.7 ± 5.4% in CMZ-treated rats. Our results thus show that in this model CMZ improves hind limb motor function and attenuates the morphological damage to the spinal cord.
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  • 92
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    Anatomy and embryology 200 (1999), S. 413-417 
    ISSN: 1432-0568
    Keywords: Key words Receptor cell ; Axon ; Vomeronasal organ ; Regeneration ; Rat ; HRP-WGA
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Chemosensory neurons in the vomeronasal epithelium (vomeronasal neurons) regenerate following experimentally induced degeneration. Transection of the vomeronasal nerves leads to retrograde degeneration of vomeronasal neurons followed by replacement of the cell population. The projection of the axons of regenerated vomeronasal neurons was examined by horseradish peroxidase(HRP) histochemistry and electron microscopy. HRP-wheat germ agglutinin (WGA) was placed on the surface of the vomeronasal organ of the rat. Dense distribution of HRP-labeled fibers was observed in the vomeronasal nerve and glomerular layers in the accessory olfactory bulb (AOB) of the intact rat. At one week after transection, HRP-labeled fibers were not found in the AOB, and no labeled fibers could be observed on the medial surface of the olfactory bulb where the vomeronasal nerve traversed. Three weeks after transection, labeled fiber bundles were observed on the medial surface of the olfactory bulb in all animals. No labeled fibers were detected in the AOB. From 12 to 32 weeks after transection, projection of HRP-labeled fibers was identified in the AOB in 8 out of 26 rats (the incidence of projection was 30%). But the number of projection fibers on the operated side was much smaller than on the control side. Electron microscopy confirmed that the HRP-labeled terminals make synaptic contacts with neurons in the AOB.
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  • 93
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    Anatomy and embryology 200 (1999), S. 521-531 
    ISSN: 1432-0568
    Keywords: Key words Development ; Internal capsule ; Nucleus basalis ; Rat ; Thalamus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  This study defines several features of the early connections of the developmentally transient perireticular thalamic nucleus of rats. The neocortex of developing rats was injected with either DiI, biotinylated dextran, WGA-HRP (wheatgerm agglutinin conjugated-horseradish peroxidase), fluorescent latex beads or cholera toxin subunit B (CTB) and their brains were processed for tracer detection with standard methods. In general, tracer injections into various regions of the developing neocortex revealed no labelled neurones within the perireticular nucleus, although some of these tracers (WGA-HRP, dextran) labelled many of the amoeboid microglial cells that are found within this nucleus. There were, however, many retrogradely labelled neurones in a region adjacent to the perireticular nucleus, within the nucleus basalis of the basal forebrain (medial edge of globus pallidus). Their identity was confirmed as neurones of the nucleus basalis since they were all were similar in morphology and somal size to neurones that were immunoreactive to NGFr (nerve growth factor receptor), an antigen found only among neurones of the nucleus basalis and basal forebrain. Moreover, double labelling experiments revealed that most, if not all, of the cortically labelled neurones were NGFr-immunoreactive also. Thus, in conclusion, our results suggest that the perireticular nucleus does not project to the neocortex; the only neurones in the general vicinity of the perireticular nucleus that have a cortical projection form part of the nucleus basalis.
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  • 94
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    Anatomy and embryology 200 (1999), S. 533-540 
    ISSN: 1432-0568
    Keywords: Key words Coronary vasculogenesis ; Angiogenesis ; Coronary artery ; Development ; Rat ; Embryonic heart
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The aim of this work was to address spatiotemporal and morphologic patterns of coronary artery development in rats, based on immunohistochemical and ultrastructural studies of hearts at different stages of prenatal development. Griffonia simplicifolia I lectin and α-smooth muscle antibody were used to demonstrate endothelial cells and/or their precursors and smooth muscle cells, respectively. Ultrastructural examination was performed on ED14–16 hearts to study the morphology of the developing coronary arteries in different regions of the truncus arteriosus and adjacent myocardium. On ED14 endothelial-like cells present within the mesenchyme surrounding the outflow tract penetrated the aortic wall and the truncoconal proximal myocardium. On ED15 these penetrating cells formed vascular clusters, which were the first signs of presumptive vascular channels. Development of the coronary artery proceeded by coalescence of discontinous vascular clusters, formation of the lumen (vascular channels) and establishing a connection of the proximal part with the aorta. The second layer of cells around vascular channels (embryonic media) consisted of mesenchymal cells that were attracted to the immature vessel and were first seen on ED15. At this time no lumenized connection of the coronary artery with the aorta has been seen. After the lumenized connection of the coronary artery with the aorta had been established perivascular cells of the media started to differentiate into vascular smooth muscle, as was shown by α-smooth muscle actin-staining. Further development and differentiation of the media and adventitia proceeded distally (towards the apex).
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  • 95
    ISSN: 1432-0568
    Keywords: Key words Morphogenesis ; Histochemistry ; Lectins ; Carbohydrates ; Salivary glands ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The developmental expression of salivary glycoconjugates was investigated in the rat submandibular and sublingual glands by conventional and lectin histochemistry. By the time of the first differentiation of secretory structures, in spite of similar morphological features, a different histochemical reactivity was detected, accounting for a relevant content of neutral glycoconjugates in the submandibular gland and the occurrence of both neutral and acidic glycoconjugates in the sublingual one. The use of lectins allowed the main changes of secretory components to be noted around gestational day 18. DBA and WGA lectins seemed to act as pre- and post-natal development markers while Con A lectin was indicative of post-natal differentiation. Taken together, data from lectin histochemistry indicated the transitional occurrence of glycoconjugates, probably involved in temporally restricted functions, as well as the co-existence of different secretory components that might also reflect maturational changes of single products.
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  • 96
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    Anatomy and embryology 199 (1999), S. 265-280 
    ISSN: 1432-0568
    Keywords: Key words Cat ; Rat ; Immunocytochemistry ; NADPH-diaphorase ; Thalamus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  To gain insight into the cellular organisation of the zona incerta, we have examined the chemoarchitectonic properties of this ”uncertain zone”. The brains of Sprague-Dawley rats and common cats were processed for immunocytochemistry or NADPH-diaphorase histochemistry using standard methods. For the immunocytochemistry, antibodies to γ-aminobutyric acid (GABA), glutamic acid decarboxylase (GAD), parvalbumin, calbindin, tyrosine hydroxylase, somatostatin, serotonin and glutamate were used. Two general patterns of distribution in the zona incerta were seen. First, labelled cells were restricted largely to one of the cytoarchitectonically defined sectors of the zona incerta. For instance, GABA, GAD and parvalbumin-immunoreactive cells were found principally within the ventral sector, NADPH-diaphorase and glutamate-immunoreactive cells within the dorsal sector and tyrosine hydroxylase- and somatostatin-immunoreactive cells within the rostral sector. Second, labelled cells were scattered somewhat across all incertal sectors, with no clear region of concentration. This pattern included the calbindin- and serotonin-immunoreactive cell groups. These results indicate that the zona incerta is made up of many neurochemically distinct cell groups, some of which respect the well-defined cytoarchitectonic boundaries of the nucleus, whilst others do not. This rich neurochemical diversity in the zona incerta suggests that this nucleus may have differential effects on the different structures that it projects to.
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  • 97
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    Zeitschrift für Lebensmittel-Untersuchung und -Forschung 208 (1999), S. 183-188 
    ISSN: 1431-4630
    Keywords: Key words Sulphadimidine ; Fermented sausage ; Carbon-14-labelling ; Rat ; Bound residues
    Source: Springer Online Journal Archives 1860-2000
    Topics: Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract  Sulphadimidine (SDM), a drug frequently administered to pigs, is partially converted into other compounds by processing meat to produce raw, fermented sausage. With the aid of 14C-labelled SDM, evidence was obtained that part of the radioactive matter was covalently bound to the matrix. Part of these bound residues could be released in vitro by 4 M HCl at 21  °C or by 0.024 M HCl at 37  °C. Female rats were also able to release bound SDM residues and to excrete these in their urine, in amounts approaching those obtained by treatment with 4 M HCl. Both the parent compound and its main metabolite, N 4-acetyl-SDM, were observed in the urine of rats.
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  • 98
    ISSN: 1432-0851
    Keywords: Key words Transgenic ; Rat ; EGP-2 ; GA733-2 ; Immunotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The human pancarcinoma-associated epithelial glycoprotein-2 (EGP-2), also known as 17-1A or Ep-CAM, is a 38-kDa transmembrane antigen, commonly used for targeted immunotherapy of carcinomas. Although strongly expressed by most carcinomas, EGP-2 is also expressed in most simple epithelia. To evaluate treatment-associated effects and side-effects on tumor and normal tissue respectively, we generated an EGP-2-expressing transgenic Wistar rat. To express the cDNA of the EGP-2 in an epithelium-specific manner, the 5′ and 3′ distal flanking regions of the human keratin 18 (K18) gene were used. EGP-2 protein expression was observed in the liver and pancreas, whereas EGP-2 mRNA could also be detected in lung, intestine, stomach and kidney tissues. In this rat, EGP-2-positive tumors can be induced by injecting a rat-derived carcinoma cell line transfected with the GA733-2 cDNA encoding EGP-2. Transgenic rats were used to study specific in vivo localization of an i.v. anti-EGP-2 monoclonal antibody, MOC31, applied i.v. Immunohistochemical analyses showed the specific localization of MOC31 in s.c. induced EGP-2-positive tumors, as well as in the liver. In contrast, in EGP-2-transgenic rats, MOC31 did not bind to EGP-2-negative tumors, the pancreas, or other normal tissues in vivo. In conclusion, an EGP-2-transgenic rat model has been generated that serves as a model to evaluate the efficacy and safety of a variety of anti-EGP-2-based immunotherapeutic modalities.
    Type of Medium: Electronic Resource
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  • 99
    ISSN: 1432-1106
    Keywords: Key words Coherence ; Entorhinal cortex ; Cortex ; Hippocampus ; Amygdala ; 192 IgG-saporin ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Changes in brain electrical activity in response to cholinergic agonists, antagonists, or excitotoxic lesions of the basal forebrain may not be reflective entirely of changes in cholinergic tone, in so far as these interventions also involve noncholinergic neurons. We examined electrocortical activity in rats following bilateral intracerebroventricular administration of 192 IgG-saporin (1.8 µg/ventricle), a selective cholinergic immunotoxin directed to the low-affinity nerve growth factor receptor p75. The immunotoxin resulted in extensive loss of choline acetyl transferase (ChAT) activity in neocortex (80%–84%) and hippocampus (93%), with relative sparing of entorhinal-piriform cortex (42%) and amygdala (28%). Electrocortical activity demonstrated modest increases in 1- to 4-Hz power, decreases in 20- to 44-Hz power, and decreases in 4- to 8-Hz intra- and interhemispheric coherence. Rhythmic slow activity (RSA) occurred robustly in toxin-treated animals during voluntary movement and in response to physostigmine, with no significant differences seen in power and peak frequency in comparison with controls. Physostigmine significantly increased intrahemispheric coherence in lesioned and intact animals, with minor increases seen in interhemispheric coherence. Our study suggests that: (1) electrocortical changes in response to selective cholinergic deafferentation are more modest than those previously reported following excitotoxic lesions; (2) changes in cholinergic tone affect primarily brain electrical transmission within, in contrast to between hemispheres; and (3) a substantial cholinergic reserve remains following administration of 192 IgG-saporin, despite dramatic losses of ChAT in cortex and hippocampus. Persistence of a cholinergically modulated RSA suggests that such activity may be mediated through cholinergic neurons which, because they lack the p75 receptor, remain unaffected by the immunotoxin.
    Type of Medium: Electronic Resource
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  • 100
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 126 (1999), S. 307-314 
    ISSN: 1432-1106
    Keywords: Key words Striatal dopamine depletion ; Rat ; Locomotion ; Ground reaction forces ; Gait ; Unilateral ; Kinetic ; Centre of mass
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Hemi-parkinsonian rats have preserved postural reflexes but are impaired in initiation of voluntary movements. Surprisingly, these rats can walk and run, suggesting that they can access some compensatory strategy to overcome the rigidity in their impaired limbs. The purpose of the present experiment was to investigate the locomotor compensations made by hemi-parkinsonian rats by measuring the forces exerted by the limbs on the ground throughout the stride during trotting. Rats with unilateral dopamine depletion produced by injection of 6-hydroxydopamine into the nigrostriatal bundle were trained to run back and forth in an alley for food reinforcement. Ground reaction forces were measured in three orthogonal directions using a force plate embedded in the runway. Rats were also videotaped so that limb movements were synchronized with force recordings. Although locomotion was obviously impaired, the affected limbs could support weight and provide some braking forces. In addition, the impaired hindlimb provided significant propulsive force, and a relatively large laterally directed force. Analysis of vertical movement of the centre of mass suggested that the impaired hindlimb was being used partly as a spring. The most significant abnormalities were seen during the diagonal couplet of the impaired forelimb and the unimpaired hindlimb, partly reflecting the important compensatory role of the unimpaired hindlimb. These results demonstrate that this method is useful in the analysis of hemi-parkinsonian gait and provide insights as to how rats can use an impaired limb to produce weight support and propulsion.
    Type of Medium: Electronic Resource
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