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Pulmonale Komplikationen treten bei hämatologischen Patienten häufig auf. In einer Übersichtsarbeit wird das Ergebnis einer Diskussion zusammengefasst, die während eines Expertentreffens zum Thema Lungeninfiltrate stattfand. Die häufigsten Ursachen von Lungeninfiltraten bei hämatologischen Patienten sind bakterielle Infektionen, aber auch Virusinfektionen verursachen, zum Teil mit relevanter saisonaler Schwankung, einen wichtigen Anteil pulmonaler Infiltrate. Für beide Erregergruppen stellt die mikrobiologische Untersuchung von Materialien des Respirationstrakts (möglichst bronchoalveoläre Lavage, BAL) die wichtigste Diagnostik dar. Insbesondere bei länger anhaltender (> 7 Tage) Neutropenie steigt die Wahrscheinlichkeit, dass Infiltrate durch Pilzinfektionen bedingt sind. Nichtinfektiöse Ursachen, z. B. durch Medikamente bedingte Infiltrate, sind differentialdiagnostisch grundsätzlich zu berücksichtigen, dürfen jedoch eine schnelle Diagnostik und adäquate antimikrobielle Therapie nicht verzögern. Pulmonary complications are frequent in haematologic patients. This review article summarizes the outcome of a discussion that took place during an expert meeting on the subject of pulmonary infiltrates. The most common causes of pulmonary infiltrates in haematologic patients are bacterial infections. Viral infections are subject to relevant seasonal variations, but they may also cause an important proportion of pulmonary infiltrates. Microbiological examination of respiratory tract material (if possible, bronchoalveolar lavage, BAL) is the most important diagnostic procedure. Particularly in the case of prolonged (> 7 days) neutropenia, the likelihood of infiltrates being caused by fungal infections increases. For a differential diagnosis, however, also non-infectious causes, e.g. drug-induced infiltrates, have to be taken into consideration. The diagnostic workup, however, should not delay a timely start of an adequate antimicrobial therapy.

In den letzten Jahren hat die zielgerichtete Arzneimitteltherapie in der klinischen Onkologie erheblich an Bedeutung zugenommen. Neben den intravenös zu applizierenden monoklonalen Antikörpern stehen immer mehr oral anwendbare „small molecules“ zur Verfügung (z. B. Tyrosinkinase- und mTOR-Inhibitoren). Diese Substanzen hemmen die Signaltransduktionswege an verschiedenen Stellen und bieten durch ihre orale Verabreichung die Option einer kontinuierlichen Wirkstoffexposition über die gesamte Behandlungsdauer.

In the present study, we used a new training paradigm in the intelliCage automatic behavioral assessment system to investigate cognitive functions of the transgenic mice harboring London mutation of the human amyloid precursor protein (APP.V717I). Three groups of animals: 5-, 12- and 18-24-month old were subjected to both Water Maze training and the IntelliCage-based appetitive conditioning. The spatial memory deficit was observed in all three groups of transgenic mice in both behavioral paradigms. However, the APP mice were capable to learn normally when co-housed with the wild-type (WT) littermates, in contrast to clearly impaired learning observed when the transgenic mice were housed alone. Furthermore, in the transgenic mice kept in the Intellicage alone, the cognitive deficit of the young animals was modulated by the circadian rhythm, namely was prominent only during the active phase of the day. The novel approach to study the transgenic mice cognitive abilities presented in this paper offers new insight into cognitive dysfunctions of the Alzheimers disease mouse model.

The role of adult brain neurogenesis (generating new neurons) in learning and memory appears to be quite firmly established in spite of some criticism and lack of understanding of what the new neurons serve the brain for. Also, the few experiments showing that blocking adult neurogenesis causes learning deficits used irradiation and various drugs known for their side effects and the results obtained vary greatly. We used a novel approach, cyclin D2 knockout mice (D2 KO mice), specifically lacking adult brain neurogenesis to verify its importance in learning and memory. D2 KO mice and their wild-type siblings were tested in several behavioral paradigms, including those in which the role of adult neurogenesis has been postulated. D2 KO mice showed no impairment in sensorimotor tests, with only sensory impairment in an olfaction-dependent task. However, D2 KO mice showed proper procedural learning as well as learning in context (including remote memory), cue, and trace fear conditioning, Morris water maze, novel object recognition test, and in a multifunctional behavioral system—IntelliCages. D2 KO mice also demonstrated correct reversal learning. Our results suggest that adult brain neurogenesis is not obligatory in learning, including the kinds of learning where the role of adult neurogenesis has previously been strongly suggested.

Tyrosine kinase inhibitors (TKI) are effective in the targeted treatment of various malignancies. Imatinib was the first to be introduced into clinical oncology, and it was followed by drugs such as gefitinib, erlotinib, sorafenib, sunitinib, and dasatinib. Although they share the same mechanism of action, namely competitive ATP inhibition at the catalytic binding site of tyrosine kinase, they differ from each other in the spectrum of targeted kinases, their pharmacokinetics as well as substance-specific adverse effects. With variations from drug to drug, tyrosine kinase inhibitors cause skin toxicity, including folliculitis, in more than 50% of patients. Among the tyrosine kinase inhibitors that are commercially available as yet, the agents that target EGFR, erlotinib and gefitinib, display the broadest spectrum of adverse effects on skin and hair, including folliculitis, paronychia, facial hair growth, facial erythema, and varying forms of frontal alopecia. In contrast, folliculitis is not common during administration of sorafenib and sunitinib, which target VEGFR, PDGFR, FLT3, and others, whereas both agents have been associated with subungual splinter hemorrhages. Periorbital edema is a common adverse effect of imatinib. Besides the haematological side effects of most of TKIs like anemia, thrombopenia and neutropenia, the most common extraheamatologic adverse effects are edema, nausea, hypothyroidism, vomiting and diarrhea. Regarding possible long term effects, recently cardiac toxicity with congestive heart failure is under debate in patients receiving imatinib and sunitinib therapy; however, this observation was probably relate to patients selection, although, TKIs overall appear to be a very well tolerated drug class.

Tyrosine kinase inhibitors (TKI) are effective in the targeted treatment of various malignancies. Imatinib was the first to be introduced into clinical oncology, and it was followed by drugs such as gefitinib, erlotinib, sorafenib, sunitinib, and dasatinib. Although they share the same mechanism of action, namely competitive ATP inhibition at the catalytic binding site of tyrosine kinase, they differ from each other in the spectrum of targeted kinases, their pharmacokinetics as well as substance-specific adverse effects. With variations from drug to drug, tyrosine kinase inhibitors cause skin toxicity, including folliculitis, in more than 50 of patients. Among the tyrosine kinase inhibitors that are commercially available as yet, the agents that target EGFR, erlotinib and gefitinib, display the broadest spectrum of adverse effects on skin and hair, including folliculitis, paronychia, facial hair growth, facial erythema, and varying forms of frontal alopecia. In contrast, folliculitis is not common during administration of sorafenib and sunitinib, which target VEGFR, PDGFR, FLT3, and others, whereas both agents have been associated with subungual splinter hemorrhages. Periorbital edema is a common adverse effect of imatinib. Besides the haematological side effects of most of TKIs like anemia, thrombopenia and neutropenia, the most common extraheamatologic adverse effects are edema, nausea, hypothyroidism, vomiting and diarrhea. Regarding possible long term effects, recently cardiac toxicity with congestive heart failure is under debate in patients receiving imatinib and sunitinib therapy; however, this observation was probably relate to patients selection, although, TKIs overall appear to be a very well tolerated drug class.

Background: Cytotoxic agents have a narrow therapeutic window. A high percentage of some of them is renally excreted in unchanged form. Accurate assessment of an individual's glomerular filtration rate (GFR) helps to predict the pharmacokinetic behavior of those drugs more precisely. GFR calculations, however, have their limitations.Objective: To establish a more accurate calculation of renal function over a broad range of constitutive GFR values.Methods: Patients with cancer were included in the analysis. Serum levels of cystatin C, creatinine, urea, albumin, and β-trace protein were measured, and GFR was calculated by 8 mathematical formulas. The results were compared with creatinine clearance (CrCI) calculated from timed urine specimens.Results: One hundred two patients were evaluated: median age, 57.5 years (range 20–91); females, 52; males, 50; and mean urinary CrCI, 77.0 mL/min. The bias (mean percentage error) was -2% and the precision (mean absolute percentage error) was 23% for the Modification of Diet in Renal Disease (MDRD) estimation of GFR. All equations significantly overestimated CrCI in patients with measured clearance less than 50 mL/min (p <0.05), with the exception of the modified Salazar-Corcoran formula. All equations underestimated CrCI in patients with measured clearance greater than 100 mL/min. The Wright formula was the least biased and most precise (–5%, 16%, respectively). In patients with measured CrCI 50–100 mL/min, the MDRD calculation had a bias of -4% and a precision of 17%. The Jelliffe and Larsson equations were associated with significant sex bias (p <0.05).Conclusions: These observations suggest that individual GFR values over a broad range cannot be calculated accurately enough with only one selected formula. It may be useful to classify renal function of patients with cancer according to the novel algorithm by using MDRD first and then to subsequently calculate GFR in higher and lower ranges with the Wright and modified Salazar-Corcoran formulas, respectively. This algorithm should be validated using larger numbers of patients.

Understanding the function of the distinct amygdaloid nuclei in learning comprises a major challenge. In the two studies described herein, we used c-Fos immunolabeling to compare the engagement of various nuclei of the amygdala in appetitive and aversive instrumental training procedures. In the first experiment, rats that had already acquired a bar-pressing response to a partial food reinforcement were further trained to learn that an acoustic stimulus signaled either continuous food reinforcement (appetitive training) or a footshock (aversive training). The first training session of the presentation of the acoustic stimulus resulted in significant increases of c-Fos immunolabeling throughout the amygdala; however, the pattern of activation of the nuclei of the amygdala differed according to the valence of motivation. The medial part of the central amygdala (CE) responded, surprisingly, to the appetitive conditioning selectively. The second experiment was designed to extend the aversive versus appetitive conditioning to mice, trained either for place preference or place avoidance in an automated learning system (INTELLICAGE). Again, much more intense c-Fos expression was observed in the medial part of the CE after the appetitive training as compared to the aversive training. These data, obtained in two species and by means of novel experimental approaches balancing appetitive versus aversive conditioning, support the hypothesis that the central nucleus of the amygdala is particularly involved in appetitively motivated learning processes.

Die Taxane Paclitaxel und Docetaxel haben inzwischen einen festen Stellenwert in der Behandlung des Ovarial-, Bronchial-, Mamma- und Prostatakarzinoms eingenommen, wobei sich – je nach Studienlage – die zugelassenen Indikationen voneinander unterscheiden.Bei der Behandlung des Ovarialkarzinoms gilt die Kombination aus Paclitaxel und Carboplatin als Mittel der ersten Wahl, auch wenn der Einsatz von Doctaxel anstelle von Paclitaxel nach bisherigen Untersuchungen zu keiner verminderten Wirksamkeit führt. Vorteilhaft erscheint beim Docetaxel die Möglichkeit der rascheren Applizierbarkeit über eine Stunde und die einfachere Art der Prämedikation, da nur auf das Glucocorticoid Dexamethason zurückgegriffen wird. Hinsichtlich des Toxizitätsprofils ist zu beobachten, dass der Einsatz von Docetaxel mit ausgeprägteren Neutropenien verbunden ist. Allerdings steht mit G-CSF diesbezüglich eine wirksame supportive Maßnahme zur Verfügung. Hingegen führt der Einsatz von Docetaxel gegenüber Paclitaxel seltener und weniger ausgeprägt zu peripher neurotoxischen Begleiterscheinungen. Somit könnte die Kombination Docetaxel/ Carboplatin vor allem dann bei der Behandlung des Ovarialkarzinoms von Interesse sein, wenn periphere Neuropathien den Einsatz einer Paclitaxel/Carboplatin-Therapie begrenzen. Einzelfallberichten zufolge bilden sich beispielsweise Paclitaxel/Carboplatin-assoziierte Grad-II-III-Neuropathien wieder zurück, wenn auf Docetaxel/Carboplatin gewechselt wurde. Allerdings nehmen auch beim Docetaxel nach kumulativen Gesamtdosen über 600 mg/m2i.v. die peripheren Neuropathien in Ausmaß und Schwere deutlich zu.Für beide Taxane liegen inzwischen Studienergebnisse für die palliative, adjuvante und neoadjuvante Behandlung des Mammakarzinoms vor. Allerdings liegen bisher nur für das Docetaxel Ergebnisse vor, die sowohl in der Monotherapie als auch in der Kombinationstherapie eine Überlegenheit gegenüber einer konventionellen Anthrazyklin-Therapie bei der Behandlung des fortgeschrittenen Mammakarzinoms zeigen konnten. Auch in einer direkten Vergleichsstudie mit Docetaxel und Paclitaxel zeichneten sich Wirksamkeitsvorteile für das Docetaxel in der genannten Indikation ab, jedoch stehen bisher nur vorläufige Studienergebnisse zur Verfügung, so dass noch keine umfassende Interpretation der Ergebnisse möglich ist. Beide Taxane führen in der Kombination mit anderen definierten Wirkstoffen zu einer signifikanten Wirksamkeitssteigerung in der adjuvanten Therapie.Ursprünglich sahen die Chemotherapie-Protokolle vor, dass beide Taxane grundsätzlich alle drei Wochen verabreicht werden. Inzwischen mehren sich allerdings Hinweise, dass auch wöchentliche Gaben in modifizierter Dosierung möglich sind und insbesondere Vorteile in der Verträglichkeit mit sich bringen können. Darüber hinaus eröffnen sie teilweise die Möglichkeit der höheren Dosisintensität und damit vielleicht auch ein höheres Tumoransprechen. Allerdings kann sich durch die wöchentliche Gabe auch das Toxizitätsprofil des Taxans signifikant ändern, wie dies für Docetaxel im Rahmen einer direkten Vergleichsstudie deutlich wurde. So war das Ausmaß der Grad-III/IV-Neutropenie im Rahmen der wöchentlichen Gabe signifikant geringer, während es im Rahmen der wöchentlichen Gabe häufiger zu starkem Tränenfluss und Epistaxis (Nasenbluten) kam.Was die bisherigen Optionen der Supportivtherapie betrifft, so lässt sich zweifelsohne die Neutropenie unter Docetaxel durch den Einsatz von G-CSF gut beherrschen, während sich bisher noch kein Durchbruch zur Prophylaxe oder Therapie peripherer Neuropathien abzeichnet. Zwar bestehen erfolgversprechende Ansätze mit Wirkstoffen, die die NGF-Expression beeinflussen können, wie z.B. Acetyl-L-Carnitin, jedoch sind noch eine Reihe von Studien notwendig, bis hierzu klare Empfehlungen ausgesprochen werden können. Dasselbe gilt für den symptomatischen Einsatz von Venlafaxin bei manifesten Neuropathien.Zusammenfassend sollte in der klinischen Praxis zur Monotherapie oder Kombinations-Chemotherapie dasjenige Taxan ausgewählt werden, das angesichts pharmakokinetischer und pharmakodynamischer Gesichtspunkte (z.B. bezüglich interaktiver Risiken), bisheriger Studienergebnisse und Zulassungskriterien, aber auch möglicher Vorteile in der Anwendung am besten auf die Bedürfnisse des Patienten und potentiell bestehenden Risikofaktoren zugeschnitten ist.

Wie bei vielen anderen Arzneimittelgruppen stellt sich auch bei den Antikoagulanzien immer wieder die Frage, welche Auswahlkriterien bei der Entscheidung für ein bestimmtes Präparat unter mehreren verfügbaren zu berücksichtigen sind. Unter mediko-legalen Aspekten ist es wichtig, den nationalen und internationalen Zulassungsstatus des Präparats zu kennen, da eine Anwendung im off-label-use grundsätzlich eine weitergehende Beratungspflicht gegenüber dem Patienten erforderlich werden lässt. Bei speziellen Indikationen, wie z.B. Anwendung in der Schwangerschaft, ist es ratsam, auf Präparate zurückzugreifen, bei denen möglichst viele dokumentierte Fälle vorliegen. Ergeben sich diesbezüglich keine Unterschiede, so entscheiden häufig Praktikabilitätsgründe (z.B. Möglichkeit der Einmalgabe pro Tag, Möglichkeit der Fixdosierung, Verfügbarkeit von Multidose, Pen oder Fertigspritzen) vor Ort die Auswahl. Während in den letzten 15 Jahren die niedermolekularen Heparine (NMH) aufgrund der Fülle der Studienergebnisse das unfraktionierte Heparin (UFH) zunehmend aus verschiedenen Indikationen verdrängten, ist bereits jetzt absehbar, dass mit dem selektiven Faktor-Xa-Inhibitor Fondaparinux und dem oralen direkten Thrombininhibitor (ODTI) Ximelagatran neue Diskussionen in Gang kommen, wie z.B. die ausschließliche Fixdosierung in der Thromboseprophylaxe und -therapie, der Verzicht auf Thrombozytenbestimmungen, die erleichterte Anwendung in Verbindung mit einer rückenmarksnahen Punktion oder Anbringen eines Katheters und — im Fall des ODTI — die Möglichkeit der oralen Thromboseprophylaxe ohne das Risiko von Cytochrom-P450-abhängigen Arzneimittelinteraktionen oder die Notwendigkeit eines INR—Monitorings [25]. Die Arbeitsgruppe um R. Janknegt hat in den 90er Jahren mit der SOJA-Methode ein System vorgeschlagen, das über ein definiertes Punktesystem eine ständig aktualisierbare, transparente und objektive Beurteilung von Arzneimitteln unter Berücksichtigung verschiedener, klinisch relevanter Parameter (Tab. 1) erlaubt [1]. Ein entsprechendes System ist derzeit in Deutschland nicht etabliert, wäre aber aus klinischpharmakologischen, pharmakoökonomischen und medikolegalen Aspekten wünschenswert, insbesondere auch unter dem Aspekt, dass neue Entwicklungen zeitnah diesem Rating unterzogen werden könnten.

Since the introduction of platinum-based combination chemotherapy, particularly cisplatin, the outcome of the treatment of many solid tumours has changed. The leading platinum compounds in cancer chemotherapy are cisplatin, carboplatin and oxaliplatin. They share some structural similarities; however, there are marked differences between them in therapeutic use, pharmacokinetics and adverse effects profiles [1-4]. Compared to cisplatin, carboplatin has inferior efficacy in germ-cell tumour, head and neck cancer and bladder and oesophageal carcinoma, whereas both drugs seem to have comparable efficacy in advanced non-small cell and small cell lung cancer as well as ovarian cancer [5-7]. Oxaliplatin belongs to the group of diaminocyclohexane platinum compounds. It is the first platinum-based drug that has marked efficacy in colorectal cancer when given in combination with 5-fluorouracil and folinic acid [8,9]. Other platinum compounds such as oral JM216, ZD0473, BBR3464 and SPI-77, which is a pegylated liposomal formulation of cisplatin, are still under investigation [10-13], whereas nedaplatin has been approved in Japan for the treatment of non-small cell lung cancer and other solid tumours. This review focuses on cisplatin, carboplatin and oxaliplatin.

letzten Jahren ist die Inzidenz an systemischen Pilzinfektionen weltweit gestiegen. Zu erklären ist dieses Phänomen nicht zuletzt auch mit der gestiegenen Anzahl an allogenen Transplantationen solider Organe oder peripheren Stammzellen, die den Patienten über eine gewisse Zeit in eine Phase erheblicher Immunsuppression und erhöhter Infektanfälligkeit versetzt. Lange Zeit war für die systemische Therapie von vermuteten und nachgewiesenen Pilzinfektionen, vor allem verursacht durch Candida spp. oder Aspergillus spp., konventionelles Amphotericin B (AmBd) Mittel der Wahl. Die inzwischen verfügbaren Lipid-Carrier des Amphotericin B, AmBisome®, Amphocil® und Abelcet®, haben inzwischen immer häufiger anstelle von AmBd ihren Platz in der klinischen Praxis gefunden, weil sie gegenüber AmBd besser verträglich sind und damit eine Dosiseskalation erlauben. Während beim AmBd aus Verträglichkeitsgründen üblicherweise eine Obergrenze von 1 mg/kg/Tag i.v. besteht, kann beim AmBisome® die tägliche Dosis bis auf 15 mg/kg i.v. gesteigert werden, ohne dass die Toxizität limitierend wirkt. Nach bisherigen Untersuchungen scheint AmBisome® am besten verträglich zu sein; die Stellung der beiden anderen Lipid-Carrier ABLC und ABCD in der klinischen Praxis muss zukünftig genauer herausgearbeitet werden. Dasselbe gilt auch für die Ad-hoc-Mischung aus AmBd mit einer handelsüblichen Fettemulsion wie z.B. Intralipid 20 %, die kurz vor Gebrauch angefertigt werden kann. Zwar waren erste klinische Ergebnisse mit dieser Mischung (AmB-IL) durchaus ermutigend, jedoch stehen zunehmend kritischere Fragen zur physikalisch-chemischen Stabilität von AmB-IL und kontroverse Ergebnisse zur Verträglichkeit gegenwärtig einer breiteren Anwendung dieser Ad-hoc-Mischung entgegen. Sofern keine akut lebensbedrohliche Infektion vorliegt, können bei Unverträglichkeit von AmBd die Triazolantimykotika Fluconazol und Itraconazol eingesetzt werden. Im Gegensatz zum Fluconazol wirkt Itraconazol gegen Aspergillus spp. Allerdings war es lange Zeit nur oral einsetzbar, da die schlechte Wasserlöslichkeit der schnellen Entwicklung einer parenteral applizierbaren Darreichungsform entgegenstand. Erst mit dem Einsatz des Hilfsstoffs Hydroxypropyl-β-Cyclodextrin gelang es erfolgreich, eine entsprechende Arzneiform anzubieten. Die beiden Beispiele, d.h. die Lipid-Carrier des Amphotericin B und der Einschluss des Itraconazol in Cyclodextrinderivate, zeigen eindrucksvoll, wie für die Therapie von Systemmykosen eine geeignete Darreichungsform entwickelt werden kann. Allerdings ist diese Entwicklung von systemisch anwendbaren Antimykotika nicht auf der Stufe des Polyenantibiotikums und der beiden Triazole stehen geblieben. Mit Voriconazol (Vfend®) und Caspofungin (z.B. Cancidas®) stehen nun zwei neue Verbindungen für die Behandlung von Systemmykosen zur Verfügung. Während Voriconazol sowohl intravenös als auch peroral gegeben werden kann, steht Caspofungin nur für die i.v.-Therapie zur Verfügung. Weitere Verbindungen, wie z.B. andere Echinocandin-Derivate, Triazolderivate, die Sordarine oder das Nikkomycin, werden klinisch getestet. Man darf gespannt sein, welche galenischen Herausforderungen sich mit diesen Verbindungen noch ergeben werden.

P revious behavioral studies (Minichiello et al., Neuron 1999;24:401–414) showed that mice deficient for the TrkB receptor in the forebrain were unable to learn a swimming navigation task with an invisible platform and were severely impaired in finding a visible platform in the same setup. Likewise, additional behavioral deficits suggested a malfunction of the hippocampus and proximally connected forebrain structures. In order to discriminate whether the behavioral impairment was caused either by deficits in spatial memory and learning, or alternatively by loss of behavioral flexibility, 8 trkBmutant, 13 wild‐type, and 22 heterozygous mice were implanted with transponders and released for 21 days into a large outdoor pen (10 × 10 m). The enclosure contained 2 shelters and 8 computer‐controlled feeder boxes, delivering food portions for every mouse only during their first visit. Every third day, mice received food ad libitum inside the shelters. All mice learned to patrol the boxes correctly within a few days. However, significant differences emerged during those days with free food available. Wild‐type mice remained inside the shelters, while all homozygous mutants continued to patrol the boxes in their habitual way, the heterozygous mutants showing intermediate scores. These and previous data suggest that one of the natural functions of the mouse hippocampus is to comediate behavioral flexibility, and that TrkB receptors might play an essential role in maintaining the neuronal short‐term plasticity necessary for this capacity. Hippocampus 2002;12:27–38. © 2002 Wiley‐Liss, Inc.

No abstract.

Abstract.: Several lines of mice with targeted deletion of the prion protein gene (Prnp) have been produced, some of them appearing phenotypically normal, others developing late-onset ataxia. This has been tentatively attributed to the size of the targeted deletion in the Prnp gene, but a masking role of genetic background could not be excluded. Thus, we have crossed an ataxic mutant line with large deletion of Prnp (Ngsk Prnp 0/0) with a knockout line showing only partial deletion of Prnp and no neurological deficits (Zrch1 Prnp 0/0). A F2 generation was then studied for up to 70 weeks for co-segregation of lesion size and behavioral phenotype, including cognitive and neurological anomalies. These mice were later crossed with a recently generated PrP-deficient line also having a large deletion and late-onset ataxia (Zrch2 Prnp 0/0). They underwent similar testing for up to 90 weeks. The ataxic phenotype always co-segregates with large homozygous deletions involving either the Ngsk or the Zrch2 allele, independent of genetic background or sex. Compound heterozygous Zrch1/Ngsk mice or Zrch1/Zrch2 mice showed intermediate neurological phenotypes, suggesting a gene-dosage effect of large deletions. At 12 weeks of age, large deletions were also associated with minor non-cognitive impairments in water maze learning, and hyperactivity in open field and elevated zero maze. These impairments were not predictive for the development of ataxia. Thus, the neurological deficits are closely associated with large deletions, which entail an upregulation of the recently discovered prion Doppel protein (Dpl), while genetic background factors seem to be responsible for shifting the onset of neurological symptoms.

Increasingly sophisticated and precise molecular genetic tools are applied to mice in order to study the cellular mechanisms underlying higher brain functions, including learning and memory. However, several studies have produced unclear or conflicting results. One reason for this is that performance in the behavioural tests used to assess learning and memory is influenced by various non-cognitive phenomena and can thus easily be affected by mutations through mechanisms unrelated to memory function. We conducted principal component analysis on data from 3003 mice tested using a standardized protocol to demonstrate this for the Morris swimming navigation test, one of the most widely used paradigms to assess memory and hippocampal function. In addition, we present a meta-analysis showing that genetic background and environment alone produce sufficient variation to span the range of most, if not all, behavioural variables and can thus easily mask or fake mutation effects if genetic studies are not designed properly. We suggest that the chance of obtaining useful results is maximized if behavioural deficits are differentiated by combining complementary behavioural protocols and by analysing multiple complementary parameters in each of them. Mutation effects must be contrasted statistically against the influences of genetic background and environment. In many situations, this is most efficiently achieved if (i) mutations are backcrossed to and maintained in one or (preferably) two well-characterized, commonly available inbred strains and (ii) if mutant and wild-type littermates are analysed on a hybrid or mixed genetic background, that is in F1 or F2 generations derived from the inbred stocks

Increasingly sophisticated and precise molecular genetic tools are applied to mice in order to study the cellular mechanisms underlying higher brain functions, including learning and memory. However, several studies have produced unclear or conflicting results. One reason for this is that performance in the behavioural tests used to assess learning and memory is influenced by various non‐cognitive phenomena and can thus easily be affected by mutations through mechanisms unrelated to memory function. We conducted principal component analysis on data from 3003 mice tested using a standardized protocol to demonstrate this for the Morris swimming navigation test, one of the most widely used paradigms to assess memory and hippocampal function. In addition, we present a meta‐analysis showing that genetic background and environment alone produce sufficient variation to span the range of most, if not all, behavioural variables and can thus easily mask or fake mutation effects if genetic studies are not designed properly. We suggest that the chance of obtaining useful results is maximized if behavioural deficits are differentiated by combining complementary behavioural protocols and by analysing multiple complementary parameters in each of them. Mutation effects must be contrasted statistically against the influences of genetic background and environment. In many situations, this is most efficiently achieved if (i) mutations are backcrossed to and maintained in one or (preferably) two well‐characterized, commonly available inbred strains and (ii) if mutant and wild‐type littermates are analysed on a hybrid or mixed genetic background, that is in F1 or F2 generations derived from the inbred stocks

We showed previously for mice that size differences of the infrapyramidal hippocampal mossy fiber projection (IIP-MF) correlate with spatial learning abilities. In order to clarify the role of the IIP-MF in a natural environment, we studied the bank vole (Clethrionomys glareolus), adapted to a wide range of different habitats, and the root vole (Microtus oeconomus), living in homogenous grassland habitats with small home ranges. Morphometry on Timm-stained horizontal brain sections of six C. glareolus and six M. oeconomus revealed that the size of the entire mossy fiber projection was 42% larger in C. glareolus than M. oeconomus. C. glareolus had also an IIP-MF projection about 230% larger than that of the root vole. A sample of captured animals was then transferred to the laboratory (C. glareolus, n = 23; M. oeconomus, n = 15) and underwent testing for swimming navigation according to a standardized protocol used to assess water maze learning in about 2,000 normal and transgenic mice. Both species learned faster than laboratory mice. Overall escape times showed no differences, but path length was significantly reduced in C. glareolus, which also showed superior performance in a variety of scores assessing spatial search patterns. On the other hand, M. oeconomus showed faster swimming speed, and strong thigmotaxis combined with circular swimming. M. oeconomus also scored at chance levels during the probe trial, about as poorly as mutant knockout mice considered to be deficient in spatial memory. These differences probably reflect differential styles of water maze learning rather than spatial memory deficits: C. glareolus appears to be superior in inhibiting behavior interfering with proper spatial search behavior, while M. oeconomus succeeds in escaping by using rapid circular swimming. We assume that size variations of the IIP-MF correspond to a mechanism stabilizing hippocampal processing during spatial learning or complex activities. This corresponds to the ecological lifestyle of the two species and is in line with previous observations on the role of the IIP-MF. Hippocampus 2000;10:17–30. © 2000 Wiley-Liss, Inc.

We showed previously for mice that size differences of the infrapyramidal hippocampal mossy fiber projection (IIP‐MF) correlate with spatial learning abilities. In order to clarify the role of the IIP‐MF in a natural environment, we studied the bank vole (Clethrionomys glareolus), adapted to a wide range of different habitats, and the root vole (Microtus oeconomus), living in homogenous grassland habitats with small home ranges.

Spatial learning of transgenic mice is often assessed in the Morris watermaze, where mice must use distant cues to locate a submerged platform. Such learning is confounded by species-specific noncognitive swimming strategies. Factor analysis permits cognitive and noncognitive strategies to be disentangled and their association with electrophysiological phenomena to be investigated.

Prenatally administered oxazepam (OX) impairs adult radial maze performance in mice, possibly by permanent hippocampal changes. CDI mice were tested in swimming navigation, a sensitive indicator for hippocampal damage. Ten males and ten females were exposed to OX on fetal days 12–16 by maternal administration PO of 30 mg/kg/day and fostered at birth to untreated dams, while control mice received vehicle solution. All mice were tested at 8–9 weeks for ability to find a submerged platform in a fixed location (acquisition: 18 trials, 6 trials per day) and for capacity to re-orient towards a new platform position (reversal: 12 trials, 6 trials per day). OX mice showed a slight but significant impairment of swimming navigation during the initial part of training, as indicated by longer swimming paths during the fourth and fifth trial (day 1), an impairment due both to delayed habituation to the novel stressfull condition and acquisition of platform climbing but unrelated to navigational abilities. No treatment-dependent differences were observed in the reversal phase. During reversal, both OX and control females spent significantly more time in swimming across the location of the old platform. Unrelated to navigational performance, females showed a slightly but significantly higher swimming speed than males. Due to the absence of any navigational impairment, data suggest that prenatal exposure to oxazepam exerts long-term influence on adult learning capacities primarily through interaction with brain systems located outside the hippocampus.

This study was designed to test for a genetic association between the propensity to self-stimulate and the capacity for two-way avoidance learning and to search for hippocampal structural correlates of self-stimulation and avoidance. Forty-eight rats from four lines selectively bred for extremes in lateral hypothalamic self-stimulation were used, the parental stocks being designated LC1 and LC2, and the bidirectionally selected lines LC1-Hi and LC1-Lo and LC2-Hi and LC2-Lo (where Hi or Lo denotes high or low self-stimulation), respectively. Twelve animals per line (all females) were tested for the acquisition of two-way avoidance learning during 50 trials. A subsample (eight per line) of the same rats was subjected to hippocampal morphometry, the variables assessed being the proportions of synaptic fields (visualized by means of Timm's stain) in CA3/CA4 at the midseptotemporal portion of the hippocampus. High self-stimulatiors performed better in the shuttle box and showed a parallel selection effect, consisting of a relative enlargement of stratum oriens. The intra-infrapyramidal mossy fiber (IIP-MF) projection did not respond to selection for self-stimulation but was closely associated with differences in avoidance behavior, with poor performers having more IIP-MF.

Female mice from inbred strains carrying a Robertsonian translocation (nine CBARb and eight C57BL/6Rb) were compared with animals from their respective strains (seven CBA and nine C57BL/6) first in open-field activity (two exposures of 10-min duration), then during 5 days (with six trials each) in Morris' swimming navigation test, and finally, in their ability to extrapolate the future position of a food reward being moved slowly out of their reach. ANOVA (strain and translocation) revealed significant effects of Robertsonian translocations (Rb) in swimming navigation,Rb mice being impaired primarily in the initial phases of acquisition and during the first trials of platform reversal and the impairment being stronger in C57BL/6 mice. In the open field,Rb mice were as active as the normal strains but showed significantly increased path tortuosity and moved slightly faster. In the extrapolation task,Rb mice showed above-chance levels in moving to the target indicated by the disappearance of the stimulus, while normal mice chose at chance levels, but the translocation effects were not statistically significant. These data indicate that telocentric fusion of chromosomes may entail behavioral alterations, perhaps by subtle changes in neurotransmitters or limbic circuitry. The expression of such alterations, however, can be remarkably strain dependent.

The neurons of origin of the great cerebral commissures of the marmoset monkey were identified by horseradish peroxidase histochemistry and their distribution was studied. Six adult marmosets were used. Three were normal: the others were subjected to section of the corpus callosum (CC), sparing the anterior commissure (AC). All six were injected with horseradish peroxidase throughout one cerebral hemisphere. The three normals provide information on the origins of both the CC and AC, whereas the three callosotomized monkeys allow study of the origins of the AC alone. All CC and AC neurons in the marmoset are pyramidal cells. Except for layer I, all cortical layers possess commissural cells; their laminar organization varies according to cortical area. There exists a progression in predominance from supra- to infragranular commissural neurons proceeding from temporal through occipital to parietal and finally to frontal cortex. Major acallosal zones are found in the primary visual cortex and the fore- and hindlimb representations of the somatosensory cortex. Correlations between commissural neuron distribution and cytoarchitectonic areas are not always obvious. Commissural neurons were not organized in columnar fashion.

Dose-response curves of the induction of P4501A1-dependent 7-ethoxyresorufin O-deethylase (EROD) were analyzed in human hepatoma HepG2 cells treated with defined mixtures of polychlorinated dibenzop-dioxins (PCDDs) and their 2,3,7,8-substituted constituents, similar to previous studies with rat hepatocytes and H4IIE cells (Schrenk et al. 1991). PCDDs appear to act less potent in human HepG2 cells in comparison with rat cells. For example, EC50 values of 2,3,7,8-Cl4DD were 8-fold and 19-fold higher than in rat H4IIE cells and hepatocytes, respectively. EC50 values of PCDDs were compared with that of 2,3,7,8-Cl4DD and expressed as 2,3,7,8-Cl4DD equivalents (TEs). Although the rank order of PCDD potencies was similar, TEs for some PCDDs (1,2,3,7,8-Cl5 DD; TE=0.75 and 1,2,3,4,7,8-Cl6DD; TE=0.61) were found to be higher than in the rat system. In contrast to rat cells no significant induction of EROD could be detected with Cl8DD in HepG2 cells up to its limit of solubility. Experimentally determined TEs of PCDD mixtures containing 49 constituents were found to be largely due to additive effects of their 2,3,7,8-substituted constituents.

As a first step to assess biological activities of complex mixtures of polychlorinated dibenzo-p-dioxins (PCDDs), induction of 7-ethoxyresorufin O-deethylase (EROD) by defined mixtures and their constituents has been analysed in vitro. Two cell systems have been compared: primary hepatocyte cultures and hepatoma H4IIE cells. EC50 values of PCDDs were compared with that of the most potent compound, 2,3,7,8-Cl4DD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and expressed as 2,3,7,8-Cl4DD equivalents (TEs). TEs for three defined mixtures containing up to 49 PCDDs could be predicted from the sum of TEs for the 2,3,7,8-substituted congeners. Efficacies (maximal enzyme induction) of less potent PCDDs (1,2,3,4-Cl4DD, Cl8DD and of a mixture containing 86% Cl8DD and of benz(a)anthracene were lower in hepatocytes (by 33%) and in H4IIE cells (by 50%). The results suggest that biological activities of complex PCDD mixtures are largely due to additive effects of their 2,3,7,8-substituted consituents.

Abstract:  TAG-1/axonin-1 is a neuronal cell adhesion molecule of the immunoglobulin superfamily. It is predominantly expressed during neural development and has been reported to be involved in axonal growth and pathfinding. Here, the expression of TAG-1/axonin-1 was investigated anatomically in the adult mouse brain by in situ hybridization using digoxigenin-labeled cRNA probes. Low levels of TAG-1/axonin-1 could be detected in cerebellar granule cells, in tufted and mitral cells of the olfactory bulb, and in pyramidal cells of area CA1 and CA3 of the hippocampus. We suspect that the expression of TAG-1/axonin-1 in these structures of the adult brain may serve neural plasticity.

The size of the intra-/infrapyramidal mossy fiber projections (IIP-MF) and their left/right asymmetry were assessed in 86 mice of either sex, including 26 animals from two mouse lines bred for strong or weak paw preference, 38 mice of a randomly bred F3generation derived from an eight-way cross, and 22 mice with variably sized corpora callosa in which only the left hippocampus was measured. Prior to morphometry, all mice were tested for paw preference. In addition, we compared the strain means in paw preference as observed in nine inbred mouse strains with known differences in their IIP-MF distribution. Mice bred for strong paw preference had a 70% larger IIP-MF projection than weakly lateralized and dyscallosal mice; random-bred mice fell in-between the extremes. The individual scores of the strength of paw preference were positively correlated with the extent of the IIP-MF. Among the inbred strains, the extent of the IIP-MF was similarly correlated with the strength of paw preference. The acallosal mice showed a significant negative correlation between extent of the IIP-MF projection and test-retest reliability of paw use. The left-right asymmetry of the IIP-MF was significantly and positively correlated with the direction of paw preference in the entire sample. We conclude that size and asymmetry of the IIP-MF projection are some of the many factors influencing the direction of paw preference and its strength, albeit moderately. We hypothesize that mice with larger IIP-MF projections use a given paw more consistently, being perhaps more resistant to interferences, and that left-right asymmetries of the IIP-MF may bias and/or reinforce an initial choice of a paw. In addition, the data provide another example of correlations between IIP-MF variations and nonspatial behavior.

The brains of mice selectively bred for differential locomotor activity in an open field (DeFrieset al., Behav. Genet.8:3–13, 1978) were analyzed for selection-dependent changes in the size of synaptic fields at the midseptotemporal level of the hippocampus. Timm-stained areas of all hippocampal fields from both left and right hippocampi were measured on five horizontal sections from the midseptotemporal level. The sample included 25 mice from two replicate lines, each one consisting of a high (HI); a low (LO), and a control line (CTL). The main selection effect was an enlargement of the intrainfrapyramidal mossy fiber (IIP-MF) projection in both HI lines by about 70% compared to LO and CTL mice (p<.0001), while other mossy fiber fields did not show differences. These findings confirm that genetic variations of the IIP-MF projection influence hippocampal processes mediating exploratory activities.

The subject of this report are some connections between problem solving and recognition suggested by the consideration of a certain model. Both concepts - problem solving and recognition - at first will be used in the narrowly limited sense defined for representation in models: Problem solving refers to the interaction of two real or fictitious systems, where one system, the subject system, has the task of transforming the other system, called the object system, from a given initial state into a final or target state. The properties and structures of the object system are largely unknown to the subject system. the reason for this may be the lack of information or too complex a description (i.e. one not completely representable in the subject system). The target state can be defined either explicitly or implicitly in terms of a suitable control criterion. Under these circumstances, it is practical to distinguish up to four types of tasks for the subject system, each leading to a distinct form of behavior by that system. In order that problem-solving can be raised to a higher performance level than that of trial-and-error techniques, other recognition processes besides the identification of the target state have to be implemented in the subject-system. Here, recognition means the identification of certain input output patterns which occur in the course of the interaction between the two systems. Out of the set of informations stemming from this process, particular pieces of information are selected and ordered. This division of the whole set of information into specific subsets, or classes, may have various causes. Worthy of special attention is the case where classes are formed in ways which are especially helpful in problem solving, namely where each class of informations causes a specific course of action by the subject-system during interaction. In this connection the following proposition will be offered as a conjecture

A new battery-operated system based on microchips has been developed for detecting free-moving, wild small mammals. An electronic identification unit connected to a portable data-logger can simultaneously accommodate up to eight detector antennae, which are positioned in the habitat of the species under study. The system can operate even in extreme weather conditions and has the capacity to distinguish and record individual mammals entering burrows or visiting artificial feeding stations. Detection events are stored in a data-logger and subsequently can be edited and analysed by many common software packages. A pilot study tested the system by monitoring the visits of three species of small mammals to artificial feeding stations. Further possible applications are discussed. J. Exp. Zool. 280:97–99, 1998. © 1998 Wiley-Liss, Inc.

For Abstract see ChemInform Abstract in Full Text.