The ability to solve elementary logic tasks in mice with the knockout of sodium-calcium exchanger gene 2 (NCX2).

Mice with a knockout of the sodium-calcium exchanger 2 (NCX2) gene were statistically significantly more successful than wild-type controls in the solution of two cognitive tasks, the test for the capacity to extrapolate the direction of the stimulus movement and the "puzzle-box" test for the capacity to find a hidden route to safe environment, which were based on food and aversive motivations, respectively. In both tests, the success of task solution was based on the animal's ability to use the object's "permanence" rule (according to J. Piaget). The data confirm that the knockout of this gene, which is accompanied by modulation of the temporal pattern of calcium membrane flux, also induces changes in mouse CNS plasticity.

Testing cognitive navigation in unknown territories: homing pigeons choose different targets.

Homing pigeons (Columba livia) are believed to adopt a map-and-compass strategy to find their way home. Surprisingly, to date a clear demonstration of the use of a cognitive map in free-flight experiments is missing. In this study, we investigated whether homing pigeons use a mental map in which - at an unknown release site - their own position, the home loft and a food loft are represented simultaneously. In order to test this, homing pigeons were trained to fly to a 25-30 km distant food loft. A total of 131 hungry and satiated pigeons were then released from an unfamiliar site equidistant from the food loft and the home loft. Their vanishing bearings and homing times were assessed conventionally at four sites, and also their flight tracks from one release site by means of GPS loggers. The vanishing bearings of fed and hungry birds differed significantly at all release sites and a highly significant proportion of hungry birds flew to the food loft, while the fed birds headed home. The GPS experiment revealed a number of pigeons flying very precisely to the food loft, others correcting their flight direction after topography-induced detours. This implies that the pigeons knew their geographical position in relation to the targets, and chose a flight direction according to their locally manipulated needs - clearly the essence of a cognitive navigational map.

[Vaccines against coronavirus disease 2019 (COVID-19) : Efficacy comparison, safety aspects, and current challenges]. / Impfstoffe gegen "coronavirus disease 2019" (COVID-19) : Wirksamkeitsvergleich, Sicherheitsaspekte und aktuelle Herausforderungen.

Several RNA-, vector-, and protein-based coronavirus disease 2019 (COVID-19) vaccines are currently available in order to achieve high titers of neutralizing antibodies against the spike protein as well as strongly activated CD4+- and CD+ T­cells. However, there are formulation-specific advantages and disadvantages with regard to physicochemical stability, spectrum of adverse effects, need for adjuvants or adaptability to potentially novel viral variants. Whereas children and pregnant women now have access to COVID-19 vaccines, it often remains difficult to achieve sufficient cellular and humoral immunity in heavily immunocompromised patients. As a consequence, innovative vaccines need to be developed for these patients. Undoubtedly, reports addressing, e.g. vaccine-associated myocarditis or thrombotic thrombocytopenia have led to uncertainties; however, vaccination remains the most important cornerstone in containing the pandemic.

[Pharmaceutical residues in aquatic compartments : Status quo and perspectives]. / Arzneimittelrückstände in Gewässern : Status quo und Perspektiven.

Meanwhile, more than 600 different pharmaceuticals have been detected in surface water, with diclofenac, ethinylestradiol and cotrimoxazole as the frequently dominating substances. The highest concentrations of parent compounds, metabolites and transformation products were measured particularly in urban wastewater discharges, in liquid manure from animal husbandries and aquaculture facilities; however, the levels of certain psychopharmaceuticals and estrogen effective substances in surface water have been associated with behavioral changes and reproduction toxicity in fish species. As a consequence, in the near future measures must be implemented that noticeably reduce the discharge of pharmaceuticals into the environment. With respect to drinking water, the currently detected concentrations of active agents have so far not been found to reach toxicologically relevant concentrations for human beings. In contrast, swimming and bathing in receiving waters can be critical.

Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion.

BACKGROUND: Anti-epidermal growth factor receptor treatment strategies, i.e. monoclonal antibodies such as cetuximab and panitumumab, or epidermal growth factor receptor (EGFR) small molecule tyrosine kinase inhibitors, such as erlotinib and gefitinib, have expanded the treatment options for different tumor types. Dermatologic toxic effects are the most common side-effects of EGFR inhibitor therapy. They can profoundly affect the patient's quality of life. PURPOSE: The aim of this study was to provide interdisciplinary expert recommendations on how to treat patients with skin reactions undergoing anti-EGFR treatment. MATERIAL AND METHODS: An expert panel from Germany with expertise in medical oncology, dermatology or clinical pharmacology was convened to develop expert recommendations based on published peer-reviewed literature. RESULTS: The expert recommendations for the state-of-the-art treatment of skin reactions induced by EGFR inhibitor therapy include recommendations for diagnostics and grading as well as grade-specific and stage-adapted treatment approaches and preventive measures. It was concluded that EGFR-inhibitor-related dermatologic reactions should always be treated combining basic care of the skin and a specific therapy adapted to stage and grade of skin reaction. For grade 2 and above, specific treatment recommendations for early- and later-stage skin reactions induced by EGFR-inhibitor therapy were proposed. CONCLUSION: This paper presents a German national expert opinion for the treatment of skin reactions in patients receiving EGFR inhibitor therapy.

Short restraint time does not influence markers of serum oxidative stress in homing pigeons (Columba livia).

Restraint in a confined space, such as a cage or a box, may be perceived by birds as a stressful condition. Some concern has been expressed about restraining homing pigeons (Columba livia) in transport crates for sport or for scientific research. Therefore, this study sought to test whether short restraint time in a transport crate for 1, 2 or 18 (overnight) h causes oxidative stress in homing pigeons and whether it is more stressful than flying. To isolate the effect of crowding from that of transport per se, the pigeons were kept in an immobile crate, that is, without any movement. To quantify oxidative stress, we measured serum levels of oxidative damage (ROMs) and of antioxidant capacity (OXY). We found that pigeons restrained in transport crates showed no significant variation for both markers of oxidative stress, regardless of the duration of restraint. Conversely, pigeons which had flown around 200 km had increased levels of oxidative damage and decreased levels of serum OXY, both clear manifestations of oxidative stress. These results suggest that maintaining homing pigeons in transport crates for a short time (i.e. 1-18 h) does not cause oxidative stress.

Postnatal modification of hippocampal circuitry alters avoidance learning in adult rats.

In rats and mice, the genetically mediated extent of the mossy fiber projection that synapses on the basal dendrites of hippocampal pyramidal cells is inversely correlated with rate of two-way avoidance (shuttle-box) learning. Postnatal hyperthyroidism, induced in 51 rat pups, resulted in marked variations of this infrapyramidal mossy fiber projection. The number of trials required for criterion performance of these rats in adulthood remained correlated with the neuroanatomical trait (r = 0.74, P less than 0.0001).

Individual hippocampal mossy fiber distribution in mice correlates with two-way avoidance performance.

Mice systematically bred for randomization of their genotype show large individual differences when performing a two-way avoidance task (shuttle-box learning). Their behavioral scores correlate strongly (r = -0.80, P less than .01) with the number of mossy fibers synapsing on basal dendrites of hippocampal pyramidal neurons, poor avoiders having relatively more such terminals. This confirms previous findings showing that rat and mouse strains known for genetically dependent poor avoidance learning have extended intra- and infrapyramidal mossy fiber projections.

Bisphosphonate-induced osteonecrosis of the jaw (ONJ): Incidence and risk factors in patients with breast cancer and gynecological malignancies.

OBJECTIVE: Since 2003, multiple cases of bisphosphonate-induced osteonecrosis of the jaw (ONJ) were reported. The aim of this study was to describe the incidence and risk factors of ONJ in patients with breast cancer or gynecological malignancies receiving bisphosphonates (BP). METHODS: ONJ was recorded for all patients with breast cancer or gynecological malignancies treated with intravenous bisphosphonates at the Department of Gynecology and Obstetrics, University Hospital Tuebingen during April, 1999 and May, 2006. RESULTS: 10 of 345 (2.9%) patients with breast cancer or gynecological malignancies developed ONJ while receiving bisphosphonate therapy. Six patients with ONJ had a history of recent dental procedures. All patients had received zoledronic acid as part of their bisphosphonate regimen. Time of exposure to bisphosphonates and the number of treatment cycles were significant risk factors for the development of ONJ (p<0.001). In patients diagnosed with ONJ the mean number of treatment cycles was 27+/-18 cycles. However, the mean number of treatment cycles in patients without manifestation of ONJ was 12+/-12 cycles. CONCLUSION: Length of exposure to BPs and the cumulative dose of given BPs seem to be the most important risk factors for the development of ONJ followed by dental procedures.

Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity.

During development, Eph receptors mediate the repulsive axon guidance function of ephrins, a family of membrane attached ligands with their own receptor-like signaling potential. In cultured glutamatergic neurons, EphB2 receptors were recently shown to associate with NMDA receptors at synaptic sites and were suggested to play a role in synaptogenesis. Here we show that Eph receptor stimulation in cultured neurons modulates signaling pathways implicated in synaptic plasticity, suggesting cross-talk with NMDA receptor-activated pathways. Mice lacking EphB2 have normal hippocampal synapse morphology, but display defects in synaptic plasticity. In EphB2(-/-) hippocampal slices, protein synthesis-dependent long-term potentiation (LTP) was impaired, and two forms of synaptic depression were completely extinguished. Interestingly, targeted expression of a carboxy-terminally truncated form of EphB2 rescued the EphB2 null phenotype, indicating that EphB2 kinase signaling is not required for these EphB2-mediated functions.

Essential role for TrkB receptors in hippocampus-mediated learning.

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB regulate both short-term synaptic functions and long-term potentiation (LTP) of brain synapses, raising the possibility that BDNF/TrkB may be involved in cognitive functions. We have generated conditionally gene targeted mice in which the knockout of the trkB gene is restricted to the forebrain and occurs only during postnatal development. Adult mutant mice show increasingly impaired learning behavior or inappropriate coping responses when facing complex and/or stressful learning paradigms but succeed in simple passive avoidance learning. Homozygous mutants show impaired LTP at CA1 hippocampal synapses. Interestingly, heterozygotes show a partial but substantial reduction of LTP but appear behaviorally normal. Thus, CA1 LTP may need to be reduced below a certain threshold before behavioral defects become apparent.

Impaired attentional modulation of auditory evoked potentials in N-methyl-D-aspartate NR1 hypomorphic mice.

In human neurophysiology, auditory event-related potentials (AEPs) are used to investigate cognitive processes such as selective attention. Selective attention to specific tones causes a negative enhancement of AEPs known as processing negativity (PN), which is reduced in patients with schizophrenia. The evidence suggests that impaired selective attention in these patients may partially depend on deficient N-methyl-D-aspartate receptor (NMDAR)-mediated signaling. The goal of this study was to corroborate the involvement of the NMDAR in selective attention using a mouse model. To this end, we first investigated the presence of PN-like activity in C57BL/6J mice by recording AEPs during a fear-conditioning paradigm. Two alternating trains of tones, differing in stimulus duration, were presented on 7 subsequent days. One group received a mild foot shock delivered within the presentation of one train (conditioning train) on days 3-5 (conditioning days), while controls were never shocked. The fear-conditioned group (n= 9) indeed showed a PN-like activity during conditioning days manifested as a significant positive enhancement in the AEPs to the stimuli in the conditioning train that was not observed in the controls. The same paradigm was then applied to mice with reduced expression of the NMDAR1 (NR1) subunit and to a wild-type control group (each group n= 6). The NR1 mutants showed an associative AEP enhancement, but its magnitude was significantly reduced as compared with the magnitude in wild-type mice. We conclude that electrophysiological manifestations of selective attention are observable yet of different polarity in mice and that they require intact NMDAR-mediated signaling. Thus, deficient NMDAR functioning may contribute to abnormal selective attention in schizophrenia.

Genetically modified mice and cognition.

Cognition in transgenic and knockout mice is preferentially assessed by spatial learning in the Morris water maze. Awareness is growing, however, that the putative cognitive deficits observed using such a paradigm may be biased by the genetic background and behavioral peculiarities of the specific animals used. Recent progress in cognitive research includes new behavioral tests and refined analysis of performance impairments. Advances in our understanding of memory and learning are being made possible through use of transgenic rescue of disrupted genes, inducible and reversible gene targeting in selected brain regions, and single-cell recordings of hippocampal place cells in mutant mice.

[Treatment of metastatic castration-resistant prostate cancer : Drug interaction potentials of abiraterone acetate and enzalutamide]. / Therapie des metastasierten kastrationsresistenten Prostatakarzinoms : Arzneimittelinteraktionspotenziale von Abirateronacetat und Enzalutamid.

With an ageing population and associated increasing multimorbidity and polypharmacy, the potential for drug-drug interactions (DDIs) becomes increasingly important. In general, DDIs are more likely to be clinically significant for drugs with a narrow therapeutic index, necessitating dosage adjustments or replacement of co-administered drugs. Many DDIs are a result of pharmacokinetic interactions of the cytochrome P450 enzymes. In particular, the CYP3A4 isoenzyme is involved in the metabolism of about 50 % of currently used drugs. Accordingly, many commonly used drugs in patients with prostate cancer are substrates of Cyp3A4. Hence enzalutamide, a strong Cyp3A4 inductor, has the potential to substantially decrease plasma concentrations and the effects of many co-medications in this patient population, whereas abiraterone acetate, a strong Cyp2D6 inhibitor, is less of a concern with respect to Cyp450 inhibition, since the Cyp2D6-mediated metabolism is much smaller and Cyp2D6 substrates are prescribed to a lesser extent in patients with prostate cancer.

Impairment of mossy fiber long-term potentiation and associative learning in pituitary adenylate cyclase activating polypeptide type I receptor-deficient mice.

The pituitary adenylate cyclase activating polypeptide (PACAP) type I receptor (PAC1) is a G-protein-coupled receptor binding the strongly conserved neuropeptide PACAP with 1000-fold higher affinity than the related peptide vasoactive intestinal peptide. PAC1-mediated signaling has been implicated in neuronal differentiation and synaptic plasticity. To gain further insight into the biological significance of PAC1-mediated signaling in vivo, we generated two different mutant mouse strains, harboring either a complete or a forebrain-specific inactivation of PAC1. Mutants from both strains show a deficit in contextual fear conditioning, a hippocampus-dependent associative learning paradigm. In sharp contrast, amygdala-dependent cued fear conditioning remains intact. Interestingly, no deficits in other hippocampus-dependent tasks modeling declarative learning such as the Morris water maze or the social transmission of food preference are observed. At the cellular level, the deficit in hippocampus-dependent associative learning is accompanied by an impairment of mossy fiber long-term potentiation (LTP). Because the hippocampal expression of PAC1 is restricted to mossy fiber terminals, we conclude that presynaptic PAC1-mediated signaling at the mossy fiber synapse is involved in both LTP and hippocampus-dependent associative learning.

Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members.

The amyloid precursor protein (APP) involved in Alzheimer's disease is a member of a larger gene family including amyloid precursor-like proteins APLP1 and APLP2. We generated and examined the phenotypes of mice lacking individual or all possible combinations of APP family members to assess potential functional redundancies within the gene family. Mice deficient for the nervous system-specific APLP1 protein showed a postnatal growth deficit as the only obvious abnormality. In contrast to this minor phenotype, APLP2(-/-)/APLP1(-/-) and APLP2(-/-)/APP(-/-) mice proved lethal early postnatally. Surprisingly, APLP1(-/-)/APP(-/-) mice were viable, apparently normal, and showed no compensatory upregulation of APLP2 expression. These data indicate redundancy between APLP2 and both other family members and corroborate a key physiological role for APLP2. This view gains further support by the observation that APLP1(-/-)/APP(-/-)/APLP2(+/-) mice display postnatal lethality. In addition, they provide genetic evidence for at least some distinct physiological roles of APP and APLP2 by demonstrating that combinations of single knock-outs with the APLP1 mutation resulted in double mutants of clearly different phenotypes, being either lethal, or viable. None of the lethal double mutants displayed, however, obvious histopathological abnormalities in the brain or any other organ examined. Moreover, cortical neurons from single or combined mutant mice showed unaltered survival rates under basal culture conditions and unaltered susceptibility to glutamate excitotoxicity in vitro.

Orientation in the wandering albatross: interfering with magnetic perception does not affect orientation performance.

After making foraging flights of several thousands of kilometers, wandering albatrosses (Diomedea exulans) are able to pinpoint a specific remote island where their nests are located. This impressive navigation ability is highly precise but its nature is mysterious. Here we examined whether albatrosses rely on the perception of the Earth's magnetic field to accomplish this task. We disturbed the perception of the magnetic field using mobile magnets glued to the head of nine albatrosses and compared their performances with those of 11 control birds. We then used satellite telemetry to monitor their behavior. We found that the ability of birds to home specific nest sites was unimpaired by this manipulation. In particular, experimental and control birds did not show significant differences with respect to either foraging trip duration, or length, or with respect to homing straightness index. Our data suggest that wandering albatrosses do not require magnetic cues to navigate back to their nesting birds.

Deviance-related electrophysiological activity in mice: is there mismatch negativity in mice?

OBJECTIVE: Mismatch negativity (MMN) is an auditory event-related potential (ERP) that provides an index of auditory sensory memory and has become an important tool to investigate auditory sensory memory in cognitive neuroscience and disorders such as schizophrenia and dyslexia. The development of a mouse model of human MMN would permit to investigate the molecular biology of normal and dysfunctional MMN generation. However, the presence of MMN-like electrophysiological activity in mice has not been demonstrated. METHODS: Deviance-related ERPs were recorded in awake mice using 3 frequency deviance paradigms and one duration deviance paradigm. These paradigms were modelled after paradigms used in human studies to characterize MMN. RESULTS: Significant deviance-related activity was observed in all paradigms. However, in all frequency deviance paradigms this activity manifested as an enhancement of similar activity to the standard due to differences in stimulation rate between deviant and standard stimuli rather than qualitatively different MMN-like activity. In the duration deviance paradigm negative deflections were observed that showed characteristics typical of human MMN. CONCLUSIONS: MMN-like activity can be observed in mice in duration deviance paradigms. In frequency deviance paradigms effects of different stimulation rates of deviant and standard stimuli seem to be the main determinants of deviance-related activity. SIGNIFICANCE: Investigations of MMN-like ERPs in mice may permit to investigate the molecular basis for normal and abnormal MMN generation in neuropsychiatric disorders and dyslexia.

[Features of the c-Fos gene expression along the hippocampal rostro-caudal axis in common voles after rapid spatial learning].

The levels of the Fos protein expression in neurons was used as an index of transcription activation in the hippocampus of common voles (Microtus arvalis Pall.) after their rapid spatial learning. Fos-positive cells were stained and calculated in 20 brain sections along hippocampal rostro-caudal axis. Voles (learning group) were trained in a modified 8-arm radial maze to find the entry to the home cage through a target arm (6 trials per session, 2-hour session). The animals were pretrained to enter the home cage through an arm isolated from the maze. Animals of active control group continued entering the home cage through the isolated arm, and animals of the passive control group were taken for the Fos immunohistochemistry from the home cage. Both in the learning group and active control group, a significant increase in c-Fos expression was shown in all the examined areas (CA1, CA3 and the dentate gyrus) as compared to the passive control. A significant increase in the number of c-Fos positive neurons was observed in the caudal hippocampus of the learning animals as compared to the active control, however, no differences were found in the rostral part. The maximum effects were observed in the dentate gyrus and the CA3 field. The results suggest a functional rostro-caudal inhomogeneity of the vole's hippocampus in the spatial learning task.

[Original preparations versus generics--latanoprost: how similar is different?]. / Originalpräparat versus Generika--Latanoprost : Wie gleich ist unterschiedlich?

BACKGROUND: To test the interchangeability of the commercially available (in Germany) latanoprost drugs and their generics respectively, the concentration of the active substance was tested. Guidelines of the European Medicines Agency postulate a sufficient bioequivalence, if the range of the agent is within 80-125% of the original drug. METHODS: All compounds of latanoprost were procured registered. The concentration of latanoprost and benzalkoniumchloride was measured by high-performance liquid chromatography (HPLC) in a validated reference labroratory for 23 generics. In addition, the mean volume of drops and the pH of the formulation were measured. The packaging label and the readability of the enclosed information leaflet were checked. RESULTS: All products contained less than 50 µg/ml latanoprost. The deviating reduction of the active substance (mean: - 7.39%, ± 2.8%) was accompanied by fluctions of the eyedrops' mass (mean: 0.03 g, ± 0.002 g). The concentration of benzalkonium chloride was mostly increased (median: 5.45%, min: - 2.5%, max: 11.5%). The pH of the original drug and the generics (median 6.78, min: 6.62, max: 6.81) was similar to the original drug, but was significantly different from an unpreserved formulation (pH 7.18). Due to type size, the packaging leaflet was illegible for humans with impaired vision. CONCLUSIONS: Before prescribing generics in ophthalmology, different factors have to be considered, which might influence the amount of IOP lowering in effect. In the absence of healthcare research it is still unclear, how different bottle forms of eyedrops--such as appearance (e.g. Cyrillic characters) or pressure point (administration)--reduce the adherence of glaucoma patients.