Wachstumdynamik der Eckzähne des Schwarzwildes des südlichen Ukraine

Der hohe Wirtschaftswert des Wildes förderte die Entwicklung der moderner Zuchttechnologien, was sie ökonomisch günstig gemacht hat. Besonders populär ist die Trophäenjagd geblieben, die als relikt der alten Vorstellungen des Menschen aufbewahrt wird. In der Südukraine werden Rehwild, Rothwild, Damwild, Muffelwild und Schwarzwild gejagt. Es werden jetzt aber Jagdressoursen nicht aussreichend effektiv aus genutzt. Die niedriege Jagdkultur, Armut des grössten Teils der Bevölkerung, die teilweise die wilderei freissprechen, die Jagd auf besonders wertvolles des Zuchttiere zu Fleisch sind einige der wichtigsten Faktoren mit der negativen Wirkung

Population pharmacokinetic analysis of 5-FU and 5-FDHU in colorectal cancer patients: search for biomarkers associated with gastro-intestinal toxicity

Purpose The anticancer drug 5-fluorouracile (5-FU) which is indicated for the treatment of a variety of solid malignancies such as colorectal, breast, head and neck neoplasms is extensively biotransformed to 5- fluoro-5,6-dihydrouracil (5-FDHU) by the dihydropyrimidine deshydrogenase enzyme (DPD). DPD deficiency is recognized as an important risk factor, predisposing patient to undergo severe/lethal toxicities. To date, relationships between 5-FU, 5-FDHU and toxicity following iv bolus administration has not been studied using the population pharmacokinetics approach. Methods Retrospective pharmacokinetic data of 5-FU and 5-FDHU from 127 colorectal cancer patients were used for the population pharmacokinetic analysis. Treatment schedule consisted of an adjuvant therapy with 5-FU plus leucovorin. 5-FU and 5-FDHU complete plasma profiles recorded on day-1 of the first chemotherapy cycle were modeled simultaneously using NONMEM software. Gastro-intestinal adverse events graded according to the WHO criteria were recorded after the first cycle. A population logistic regression model was developed to identify predictive factors of these adverse events. Results A three-compartment pharmacokinetic mixture model best described 5-FU and 5-FDHU kinetics profiles. Linear and saturated elimination from the central compartment of 5-FU and a linear elimination from the 5-FDHU compartment were used. A bimodal distribution of the intercompartmental clearance was observed allowing two subpopulation with high (17 L/h) and low values (3.35 L/h). DPD-phenotype is suspected to explain this mixture. No covariates were introduced in the final model. Also, no relationship was found between maximal metabolism rate and DPD-phenotype. Predictive factors associated with occurrence of high grade gastro-intestinal adverse events were gender, dose and lean body mass suggesting serious cautions with the BSA- weighted dose for women. For the low-grade toxicities, 5-FU area under curve was predictive for woman and 5-FDHU area under curve for men. 3 Conclusion A population pharmacokinetic mixture model was developed to describe kinetic profiles of 5-FU and its major metabolite. This model has significant implications, to identify patients with potentially low DPD phenotype requiring earlier adjustment of the 5-FU dose. Also this analysis highlights the need for developing alternative dosing-scheme for women

Derivative Character Investments: Social Impact Bonds as Path-Changing Devices

Since 2010, social impact bonds (SIBs) have invited investors to ‘do well by doing good’: injecting capital into social welfare projects, and gaining returns based on successful attainment of impacts. A foregrounded interest in behavioral change typifies much of this market (with SIBs aiming to reduce recidivism, truancy, and addiction, for example). Commentators have situated these behavioral concerns within debates on nudging, ‘caring capitalism’, and the financialization of social welfare. Lesser attention has been paid to how SIB promotional materials transpose behavioral interests into narrative and representational terms. Given their role in fabricating consent for social impact investing, this article questions how promoters narrate SIBs’ construction of behavioral changes as objects of investment, both drawing from and reshaping conventions for representing character in the process. Analyzing three examples, I argue that behavior-focused SIB promotional videos depict societal improvement as ‘improved character’ at scale. By depicting beneficiaries as better able to morally direct their lives, they represent SIBs as path-changing devices, threading more fulfilling life paths through society. They encourage derivative character investments in bundles of bettered behavior, narratively linked to changed life paths at scale. This article draws from literary studies, critical finance studies, valuation studies, visual cultures, and SIB literature to analyse how promotional images of character lend narrative coherence to SIBs’ varied interests in behavioral reform, neocommunitarian values, and human capital. The argument’s ambition – currently developing into a larger project – is to complicate the presumed separation between social investment products and the promotional images used to justify them. Since SIBs are structurally indifferent to the underlying lives they supposedly improve (given their reliance on derivative performance data), promotional images of bettered lives are arguably not secondary to SIBs, but rather their primary objects of investment. Fundamentally, SIBs enable investment in images of bettered lives: derivative investments in character

Inhibition of the Human Proteasome by Imidazoline Scaffolds

The proteasome has emerged as the primary target for the treatment of multiple myeloma. Unfortunately, nearly all patients develop resistance to competitive-type proteasome inhibitors such as bortezomib. Herein, we describe the optimization of noncompetitive proteasome inhibitors to yield derivatives that exhibit nanomolar potency (compound <b>49</b>, IC₅₀ 130 nM) toward proteasome inhibition and overcome bortezomib resistance. These studies illustrate the feasibility of the development of noncompetitive proteasome inhibitors as additives and/or alternatives to competitive proteasome inhibitors