[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.

[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.

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.

[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.

[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.

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.

Synapse formation in adult barrel cortex following naturalistic environmental enrichment.

Environmental enrichment paradigms in adult laboratory animals, consisting of physical, perceptual, and social stimulation, have been shown to affect synapse and cell morphology in sensory cortex and enhance learning ability, whereas enrichment, which is in harmony with the animal's natural habitat may have even greater implications for plasticity. Previous studies in our laboratory have shown that whisker stimulation induced the formation of synapses and spines in the corresponding barrel. In the present study adult C57/Bl6J female laboratory mice at 6 weeks of age were placed during 2 months in a protected enrichment enclosure in a forest clearing at the Chisti Les Biological Station, Tvier, Russia. We analyzed neuropil ultrastructure in the C2 barrel using serial-section electron microscopy on a total of eight mice (n=4 enriched, n=4 standard cagemate controls). Quantitative analyses of volumes of neuropil showed a significant increase in excitatory and inhibitory synapses on spines and excitatory synapses on dendritic shafts in the C2 barrel in the enriched group compared with standard cagemate controls. These results demonstrate that naturalistic experience alters the synaptic circuitry in layer IV of the somatosensory cortex, the first cortical relay of sensory information, leaving a lasting trace that may guide subsequent behavior.

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.

Number estimates of neuronal phenotypes in layer II of the medial entorhinal cortex of rat and mouse.

Modelling entorhinal function or evaluating the consequences of neuronal losses which accompany neurodegenerative disorders requires detailed information on the quantitative cellular composition of the normal entorhinal cortex. Using design-based stereological methods, we estimated the numbers, proportions, densities and sectional areas of layer II cells in the medial entorhinal area (MEA), and its constituent caudal entorhinal (CE) and medial entorhinal (ME) fields, in the rat and mouse. We estimated layer II of the MEA to contain approximately 58,000 neurons in the rat and approximately 24,000 neurons in the mouse. Field CE accounted for more than three-quarters of the total neuron population in both species. In the rat, layer II of the MEA is comprised of 38% ovoid stellate cells, 29% polygonal stellate cells and 17% pyramidal cells. The remainder is comprised of much smaller populations of horizontal bipolar, tripolar, oblique pyramidal and small round cells. In the mouse, MEA layer II is comprised of 52% ovoid stellate cells, 22% polygonal stellate cells and 14% pyramidal cells. Significant species differences in the proportions of ovoid and polygonal stellate cells suggest differences in physiological and functional properties. The majority of MEA layer II cells contribute to the entorhinal-hippocampal pathways. The degree of divergence from MEA layer II cells to the dentate granule cells was similar in the rat and mouse. In both rat and mouse, the only dorsoventral difference we observed is a gradient in polygonal stellate cell sectional area, which may relate to the dorsoventral increase in the size and spacing of individual neuronal firing fields. In summary, we found species-specific cellular compositions of MEA layer II, while, within a species, quantitative parameters other than cell size are stable along the dorsoventral and mediolateral axis of the MEA.

Consistent behavioral phenotype differences between inbred mouse strains in the IntelliCage.

The between-laboratory effects on behavioral phenotypes and spatial learning performance of three strains of laboratory mice known for divergent behavioral phenotypes were evaluated in a fully balanced and synchronized study using a completely automated behavioral phenotyping device (IntelliCage). Activity pattern and spatial conditioning performance differed consistently between strains, i.e. exhibited no interaction with the between-laboratory factor, whereas the gross laboratory effect showed up significantly in the majority of measures. It is argued that overall differences between laboratories may not realistically be preventable, as subtle differences in animal housing and treatment will not be controllable, in practice. However, consistency of strain (or treatment) effects appears to be far more important in behavioral and brain sciences than the absolute overall level of such measures. In this respect, basic behavioral and learning measures proved to be highly consistent in the IntelliCage, therefore providing a valid basis for meaningful research hypothesis testing. Also, potential heterogeneity of behavioral status because of environmental and social enrichment has no detectable negative effect on the consistency of strain effects. We suggest that the absence of human interference during behavioral testing is the most prominent advantage of the IntelliCage and suspect that this is likely responsible for the between-laboratory consistency of findings, although we are aware that this ultimately needs direct testing.

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.

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.

Hereditary hydrocephalus internus in a laboratory strain of golden hamsters ( Mesocricetus auratus).

Golden hamsters of one common laboratory strain had a high incidence of hydrocephalus internus. When a severity score of hydrocephalus was used, a major autosomal recessive locus could be identified. However, when a binary score (hydrocephalus, no hydrocephalus) was used, no such major locus could be detected and results of test matings were not consistent with Mendelian inheritance. Golden hamsters with severe forms of hydrocephalus had a dorsally compressed and ventrally intact hippocampus. Implications for the behavior and well-being of affected hamsters are unknown but researchers using this strain should be aware of the likely presence of hydrocephalus.

Bevacizumab, a humanized anti-angiogenic monoclonal antibody for the treatment of colorectal cancer.

Angiogenesis is the process by which new blood vessels are created from pre-existing vessels. It is essential for the growth and development of normal cells and tissues during embryonic and neonatal development and of tumour cells. Solid tumours rely on having an extensive network of blood vessels for growth and survival. The key mediator of angiogenesis, vascular endothelial growth factor-A (VEGF-A), is critical for the growth of tumours and their subsequent metastasis and is known to initiate angiogenesis. Bevacizumab is a humanized immunoglobulin G monoclonal antibody that binds to VEGF with high specificity, thereby blocking VEGF-mediated signalling pathways and thus angiogenesis. Clinical trials have shown that bevacizumab is effective in prolonging survival in patients with metastatic colorectal cancer (CRC) when combined with standard chemotherapy. Consequently, bevacizumab has been approved in combination with 5-fluorouracil-based chemotherapy for first-line treatment of patients with metastatic CRC. Bevacizumab is generally well tolerated in most patients and does not exacerbate the adverse events associated with conventional chemotherapy. Bevacizumab-related side effects are generally manageable; however, monitoring for hypertension, gastrointestinal perforation, bleeding, proteinuria and thromboembolism is advised, especially in patients with predisposing factors. In addition to demonstrated survival benefits, the convenient dosing schedule and lack of interactions should ensure the successful integration of this novel agent into clinical practice.

Deletion of the Coffin-Lowry syndrome gene Rsk2 in mice is associated with impaired spatial learning and reduced control of exploratory behavior.

Coffin-Lowry Syndrome (CLS) is an X-linked syndromic form of mental retardation associated with skeletal abnormalities. It is caused by mutations of the Rsk2 gene, which encodes a growth factor regulated kinase. Gene deletion studies in mice have shown an essential role for the Rsk2 gene in osteoblast differentiation and function, establishing a causal link between Rsk2 deficiency and skeletal abnormalities of CLS. Although analyses in mice have revealed prominent expression of Rsk2 in brain structures that are essential for learning and memory, evidence at the behavioral level for an involvement of Rsk2 in cognitive function is still lacking. Here, we have examined Rsk2-deficient mice in two extensive batteries of behavioral tests, which were conducted independently in two laboratories in Zurich (Switzerland) and Orsay (France). Despite the known reduction of bone mass, all parameters of motor function were normal, confirming the suitability of Rsk2-deficient mice for behavioral testing. Rsk2-deficient mice showed a mild impairment of spatial working memory, delayed acquisition of a spatial reference memory task and long-term spatial memory deficits. In contrast, associative and recognition memory, as well as the habituation of exploratory activity were normal. Our studies also revealed mild signs of disinhibition in exploratory activity, as well as a difficulty to adapt to new test environments, which likely contributed to the learning impairments displayed by Rsk2-deficient mice. The observed behavioral changes are in line with observations made in other mouse models of human mental retardation and support a role of Rsk2 in cognitive functions.

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.

mPer1 and mPer2 mutant mice show regular spatial and contextual learning in standardized tests for hippocampus-dependent learning.

Learning and memory, like most physiological processes, seem to be under the control of circadian rhythm. The recently cloned mPer1 and mPer2 genes play an important role in the regulation of the circadian rhythm. In this study, we tested mPer1 and mPer2 mutant mice in two different learning and memory paradigms, a water-maze place navigation task and contextual fear conditioning. In both learning tests, the hippocampus is critically involved. None of these learning types were affected by the mutations, suggesting that mPer1 and mPer2 do not play a major role in the regulation of hippocampus-dependent learning and memory.

[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.

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.