Zoo Basel Newsletter. 2011, Oktober
Rezension zu: Volker Herholt, Antisemitismus in der Antike. Kontinuitäten und Brüche eines historischen Phänomens (Gutenberg 2009)
Rezension zu: Karl Strobel, Kaiser Traian - Eine Epoche der Weltgeschichte (Regensburg 2010)
Rezension zu: Anne Kolb, Joachim Fugmann, Tod in Rom. Grabinschriften als Spiegel römischen Lebens (Mainz 2008)
- Das vorliegende Buch von Anne Kolb (Zürich) und Joachim Fugmann (Konstanz) beinhaltet eine Sammlung von 58 Grabinschriften aus der Stadt Rom samt den dazugehörigen Monumenten, die als „charakteristische Beispiele ihrer Gattung“ (9) fungieren und einen Überblick über die ganze Bandbreite römischer Inschriftenkultur liefern. Reich bebildert und mit ausführlichen Begleittexten versehen erfüllt das Werk gleich zwei grundlegende Funktionen: Zum einen kann es vom Leser als Handbuch genutzt werden, um sich – auf fachlich hohem Niveau und unter Zusammenfassung des aktuellen Forschungsstandes – gezielt über einzelne Monumente zu informieren. Zum anderen gewährt es, bei einer zusammenhängenden Lektüre, tiefe Einblicke in die facettenreiche Sozialgeschichte der römischen Republik und Kaiserzeit. ...
The chitinase-like protein YKL-40 modulates cystic fibrosis lung disease
Ali Önder Yildirim
Nikolaus Peter Rieber
- The chitinase-like protein YKL-40 was found to be increased in patients with severe asthma and chronic obstructive pulmonary disease (COPD), two disease conditions featuring neutrophilic infiltrates. Based on these studies and a previous report indicating that neutrophils secrete YKL-40, we hypothesized that YKL-40 plays a key role in cystic fibrosis (CF) lung disease, a prototypic neutrophilic disease. The aim of this study was (i) to analyze YKL-40 levels in human and murine CF lung disease and (ii) to investigate whether YKL-40 single-nucleotide polymorphisms (SNPs) modulate CF lung disease severity. YKL-40 protein levels were quantified in serum and sputum supernatants from CF patients and control individuals. Levels of the murine homologue BRP-39 were analyzed in airway fluids from CF-like βENaC-Tg mice. YKL-40SNPs were analyzed in CF patients. YKL-40 levels were increased in sputum supernatants and in serum from CF patients compared to healthy control individuals. Within CF patients, YKL-40 levels were higher in sputum than in serum. BRP-39 levels were increased in airways fluids from βENaC-Tg mice compared to wild-type littermates. In both CF patients and βENaC-Tg mice, YKL-40/BRP-39 airway levels correlated with the severity of pulmonary obstruction. Two YKL-40 SNPs (rs871799 and rs880633) were found to modulate age-adjusted lung function in CF patients. YKL-40/BRP-39 levelsare increased in human and murine CF airway fluids, correlate with pulmonary function and modulate CF lung disease severity genetically. These findings suggest YKL-40 as a potential biomarker in CF lung disease.
Soluble epoxide hydrolase limits mechanical hyperalgesia during inflammation
Carlo Federico Angioni
Ralf Peter Louis Brandes
Peter Werner Reeh
Clifford J. Woolf
Cytochrome-P450 (CYP450) epoxygenases metabolise arachidonic acid (AA) into four different biologically active epoxyeicosatrienoic acid (EET) regioisomers. Three of the EETs (i.e., 8,9-, 11,12- and 14,15-EET) are rapidly hydrolysed by the enzyme soluble epoxide hydrolase (sEH). Here, we investigated the role of sEH in nociceptive processing during peripheral inflammation.
In dorsal root ganglia (DRG), we found that sEH is expressed in medium and large diameter neurofilament 200-positive neurons. Isolated DRG-neurons from sEH-/- mice showed higher EET and lower DHET levels. Upon AA stimulation, the largest changes in EET levels occurred in culture media, indicating both that cell associated EET concentrations quickly reach saturation and EET-hydrolyzing activity mostly effects extracellular EET signaling. In vivo, DRGs from sEH-deficient mice exhibited elevated 8,9-, 11,12- and 14,15-EET-levels. Interestingly, EET levels did not increase at the site of zymosan-induced inflammation. Cellular imaging experiments revealed direct calcium flux responses to 8,9-EET in a subpopulation of nociceptors. In addition, 8,9-EET sensitized AITC-induced calcium increases in DRG neurons and AITC-induced calcitonin gene related peptide (CGRP) release from sciatic nerve axons, indicating that 8,9-EET sensitizes TRPA1-expressing neurons, which are known to contribute to mechanical hyperalgesia. Supporting this, sEH-/- mice showed increased nociceptive responses to mechanical stimulation during zymosan-induced inflammation and 8,9-EET injection reduced mechanical thresholds in naive mice.
Our results show that the sEH can regulate mechanical hyperalgesia during inflammation by inactivating 8,9-EET, which sensitizes TRPA1-expressing nociceptors. Therefore we suggest that influencing the CYP450 pathway, which is actually highly considered to treat cardiovascular diseases, may cause pain side effects.
Application of biowaiver tools to combat high-burden diseases
- The present work comprises different projects within the scope of public health. In detail, they all aim at combating the high-burden diseases HIV/AIDS, malaria and tuberculosis more effectively. Since there was, and still is, no harmonization between the existing biowaiver guidelines, the biowaiver dissolution test conditions by WHO and FDA were compared against each other using drug products, which had already demonstrated BE to the comparator in vivo. Thereby it could be shown that the dissolution conditions proposed by the WHO are more appropriate for granting biowaivers than those of the FDA. Further, the applicability of the WHO dissolution test conditions was investigated using the APIs ethambutol, isoniazid and pyrazinamide (all BCS Class III) as model compounds. These investigations demonstrated that the concept of the biowaiver proved to work properly, i.e. leading to no false positive BE decision and an acceptable incidence of false negative BE decisions. In addition, four new biowaiver monographs were published addressing important APIs in the treatment of HIV/AIDS and malaria. Before these efforts, there were only a very few biowaiver monographs available for antiviral or antimalarial APIs, i.e. the database of biowaiver monographs has been clearly improved. The last part of the present work dealt with the extension of the biowaiver concept to related areas such as the WHO Prequalification of Medicines Programme. Investigations revealed that the biowaiver tools are generally eligible for prequalification of drug products containing ethambutol, isoniazid, pyrazinamide, or lamivudine to prove BE between an appropriate comparator and the test candidate. By contrast, some APIs are excluded from the biowaiver procedure. In conclusion, the implementation of the biowaiver tools for prequalification of biowaivable APIs is, along with BCS-based biowaiver approval of new generics, an important step towards making essential, high-quality drug products more cost-effective and, as a consequence, more accessible for a larger percentage of the population. In that way, the treatment conditions for those in need living in the developing countries can be improved enormously, so that those who are poor do not have to receive poor treatment. The quality standard of essential medicines will increase worldwide, thereby helping to combat the high-burden diseases better and, in turn, lead to an improvement of the global health status.
Trait anxiety and the neural efficiency of cognitive processing
- The current work investigated the association of trait anxiety and the neural efficiency of
cognitive processing for affectively neutral (not threat-related) information. In a sample of 46
healthy volunteers, three fMRI experiments were conducted to test the prediction derived from
attentional control theory (Eysenck et al., 2007) that high as compared to low trait-anxious
individuals expend more neural effort on tasks requiring the top-down control of attention
to reach a given level of performance. In a colour-word Stroop task requiring the inhibition
of irrelevant stimulus information and associated responses as well as in a working-memorymanipulation
task requiring the shifting of attention between items in working memory, trait
anxiety (as measured with the State-Trait Anxiety Inventory; Spielberger et al., 1970) was positively
associated with task-related increases in the activation of two adjacent regions in the
right dorsolateral prefrontal cortex (DLPFC). The finding that along with a stronger activation
of this brain region commonly implicated in top-down control processes, the high-anxious
subjects showed equal (working memory manipulation) or worse (Stroop) performance when
compared to low-anxious subjects, does support the assumption that processing is less efficient
in the high anxious. However, in contrast to the predictions, trait anxiety did not show a significant
association with task-related brain activation in a task-switching paradigm requiring
shifting between task sets. It is discussed how different attentional control demands of the task
may account for differences in the effects of trait anxiety on overt behavioural performance
and underlying neural processes. In addition to DLPFC activation, trait anxiety modulated
the functional connectivity of distributed regions involved in processing of the Stroop and the
working-memory-manipulation task. It is discussed how the observed differences in regional
DLPFC activation and network connectivity relate to each other. A possible interpretation
suggests that activation increases in the DLPFC reflect an attempt to compensate for suboptimal
connectivity by investing more effort in prefrontally supported control processes. Overall,
the current work shows an association of trait anxiety with the neural efficiency of cognitive
processing in affectively neutral tasks involving attentional control. Furthermore, it suggests
that investigations of neural efficiency should take into account difference in functional integration
in addition to regional activation.
Immunrekonstitution nach allogener Stammzelltransplantation
- Eine verzögerte und mitunter unvollständige Immunrekonstitution nach allogener Stammzelltransplantation (SZT) birgt ein erhöhtes Risiko für Infektionen und das Auftreten eines Rezidivs. Adoptive Immuntherapien können dazu beitragen, die Immunrekonstitution zu beschleunigen. Die Indikation hierzu ist jedoch streng geregelt, da eine zusätzliche Immuntherapie mit Risiken, wie z.B. dem Auftreten einer Graft-versus-Host-Disease (GvHD), verbunden ist. Im Mittelpunkt dieser Arbeit steht die Untersuchung der Immunrekonstitution im Hinblick auf das Auftreten von Komplikationen und das Überleben nach SZT. Dazu wurde ein multivariates Normwertmodell entwickelt, das die Beurteilung der Rekonstitution verschiedener Leukozytensubpopulationen ermöglicht. Der Einfluss der Regeneration spezifischer Immunzellen wie Cytomegalievirus-spezifischer T-Zellen (CMV-CTLs) und regulatorischer T-Zellen (Tregs) auf den Verlauf nach SZT wurde insbesondere hinsichtlich CMV-bedingter Komplikationen, GvHD und Rezidiv untersucht.
"Alles was lebendig wirken soll, muß eingehüllt sein" : Formreflexion in Goethes Sonett Mächtiges Überraschen