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Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal-binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration. Suspension microspray of potent compounds showed in vivo efficacy with a clear dose–response. Despite sustained lung levels, dry powder administration performed much less well and without proper dose–response, highlighting clear differences between the two formulations. This indicates a deficiency in the low aqueous solubility strategy for long duration lung efficacy.

The chapter develops a typology of economic agents to aid analysis. Various classifications are discussed, such as primary, secondary and tertiary sectors, public and private, and type of good . Four basic types of economic agent are identified: households, firms, associations and administrations. The point is made that there are sometimes grey areas so examples of economic entities are provided which exhibit characteristics of more than one type. There is a discussion of the features of each type, its sources of finance and revenue , tasks and goals, as well as legal aspects. Special attention is paid to households, associations and administrations as these are rarely covered in the literature on business administration despite the fact that the principles of economic efficiency and effectiveness are as relevant for them as for firms.

The chapter begins with a discussion of ratios, which are essential for management activities, as they make planning, implementation and supervision easier. There are three types of ratio: classification figures, relationship figures and indexes. Not everything can be captured in numbers, which is where different kinds of performance indicators play a role. There are two main types of calculation methods used in capital budgetin g—static and dynamic. Capital budgeting is involved in investment decisions. Cost comparison, profit comparison, profitability and payback calculations are examples of static calculations, while the present value method and internal rate of return method are dynamic calculations. Various tools are presented for optimisation, including linear programming. Forecasting is an essential business activity and tools such as time-series analysis and regression analysis are described.

The chapter discusses the role of goals for economic entities. Different types of goals are identified, such as original and derived goals, successive and simultaneous goals, complementary and competing goals. Goals become part of a goal system with formal goals and economic, ecological and social goals. Different forms of economic entity have different goal systems and goal concepts. The factors of production are discussed, and a universal system of factors is introduced consisting of seven interlinked factors of production: personnel, capital, material, energy, services, the law and the natural environment. The use of factors as inputs is discussed along with the diseconomies they can cause. The outcomes of the use of factors of production are discussed, with output, outcome and impact being identified as types of result. The chapter concludes by reviewing ways in which the effects can be measured.

This chapter is concerned with how to apply the concepts of economic efficiency and effectiveness in practice. Various areas of activity are discussed—procurement, transport, inventory management, manufacturing, administration and marketing—and in each case ways in which business entities can carry out the activities in an economically efficient way are described, and the appropriate tools are presented. The chapter additionally pays particular attention to the ecological environment and describes the circular economy, an approach to doing business that makes the production and consumption of goods part of a cycle.

The chapter discusses the different kinds of rationality and points out the limitations of the idea that economic entities are purely rational. Goals and objectives are defined, and a distinction is made between effectiveness, efficiency and economic efficiency. The point is made that there are different kinds of efficiency—economic, technical and political. The principles of maximum return and minimum means are presented as approaches to the conversion of inputs into outputs. The difference between economic efficiency and profitability is made clear and four combinations of these two concepts are outlined. Different kinds of economy are discussed: the economy of needs where the principle of solidarity is important, the economy of returns where financial goals have priority, the economy of self-interest and of common interest. Finally, the individual and the aggregate economy are presented.

The chapter discusses the relationships between needs and the supply of the tangible and intangible goods that can satisfy these needs. A shortage of resources is confronted with an unlimited number of needs, which means that choices have to be made. Efficiency and effectiveness in the use of limited resources is shown to be necessary. The various types of need are identified, categorised and described. After presenting mechanisms for determining needs, the chapter goes on to identify, categorise and describe the various types of goods and ways in which demand can be managed. Attention is paid to public tasks and ways in which they can be executed are outlined. The different economic systems (market and planned) are described and the economic constitution is presented—the components are the state, the legal system, and the social and ecological orders.

This chapter first introduces the different economic agents and types of economy that make it possible for needs to be satisfied. Types of economic entity are presented, and the point is made that not only companies are economic entities, but also institutions like hospitals, city administrations and schools. An overview is provided of local, regional, national and supranational economies. Economic efficiency and effectiveness are discussed and it is emphasised that these principles are important for all economic entities, not just firms. Secondly, there is a discussion of the tasks of business administration and of economics as academic disciplines. The areas of interest are outlined and the links between the two areas are made clear. In addition, neighbouring disciplines that are relevant for the study of economic activities are described. Possible approaches that can be taken to study economic entities and economic activities are presented. Thirdly, the argument is made that those interested in the study of economics, business and management should understand the building blocks of reality as our actions as humans are driven by our perceptions, thought processes and learning processes. Finally, there is a discussion of research as the quest for truth.

Background CSF abnormalities and a neuroinflammatory pathophysiology have been discussed for affective and non-affective psychosis for more than 30-years. Recent studies pointed towards a specific phenotype of autoimmune-antibody mediated psychosis, but evidence is still sparse. Especially CSF data investigating autoimmune antibodies in large-scale CSF cohorts of affective and non-affective psychoses are lacking. Methods We analyzed a retrospective naturalistic cohort of 592 patients with A) schizophrenia-spectrum disorders (N = 330) or B) depressive disorders (N = 262) who underwent a lumbar puncture as part of the clinical routine in the Department of Psychiatry and Psychotherapy at the Ludwig-Maximilians University Munich between July 2012 and May 2017. We used a predefined systematic algorithm for the database search in the clinical documentation system and data was extracted by TO and AG. The study was approved by the local ethics committee. Results We identified 592 patients with standard CSF parameters. Schizophrenia spectrum patients did not differ from depressive patients with regard to the white blood cell count (cells/µl) (p = 0.774) or albumin quotient (p = 0.663). The general prevalence of oligoclonal bands did not differ between groups (schizophrenia: 37.0%, depression: 37.8%; p = 0.838). However, schizophrenia patients showed higher frequencies for intrathecal oligoclonal bands (32% of all oligoclonal bands) compared to depressive patients (19.1% of all oligoclonal bands. (p = 0.034). 124 schizophrenia-spectrum patients (54 first-episode patients) received CSF analyses for neural antibodies. None of the patients showed positive CSF results in any of the tested autoimmune-encephalitis panel (NMDA(N=119), AMPA-1(N=114), AMPA-2(N=114), CASPR(N=111), LGI-1(N=110) and GABA-B(N=112)-Antibodies) in CSF. The results for the intracellular onconeuronal and synaptic antibodies were also negative (Amphyphysin(N=93), Yo(N=58), Hu(N=94), Ri(N=94), CV2(N=93), Ma1(N=93) and Ma2(N=93)-Antibodies). Three of these patients with negative CSF titers did have low-titer neuronal antibodies in serum: CASPR-2-AB: 1:10, CASPR-2-AB: 1:50, Yo-AB: low band-intensity. 36 depression patients were also tested for autoimmune antibodies and again no positive reports could be identified in CSF. Discussion This is the first analyses of autoimmune antibodies in first-episode and recurrent schizophrenia and depressive mood disorder showing no positive CSF titers. However, schizophrenia patients have a higher prevalence of intrathecal oligoclonal bands compared to affective patients pointing towards more immunological disturbances in this population. The here presented analyses are exploratory and need to undergo confirmatory analyses and quality control.

After discussing the necessity of operationalisation and the differences between nominal and real values, the chapter presents the different payment streams, with receipts of payment and outpayments being the two fundamental concepts behind the flows of financial resources. Various ways of ensuring liquidity are described, and short-term and long-term coverage ratios are presented as measuring instruments. Cash flow calculations are shown to be significant for financial management and budgeting. The characteristics of expenditures and revenues are shown, and finance calculations and forms of financing are introduced. The different types of expenses and income are explained, as are methods for calculating earnings, including income statements. Cash flow statements and balance sheets are also presented. Operational and external costs and outputs are described, leading to the proposal for new kinds of financial statement where these are taken into account, using social and ecological accounting to produce outcome-impact statements.

Spleen tyrosine kinase (Syk) is essential for signal transduction of immunoreceptors. Inhibition of Syk abrogates mast cell degranulation and B cell responses. We hypothesized that Syk inhibition in the lung by inhaled route could block airway mast cells degranulation and the early asthmatic response without the need of systemic exposure. We discovered LAS189386, a novel Syk inhibitor with suitable properties for inhaled administration. The aim of this study was to characterize the in vitro and in vivo profile of LAS189386. The compound was profiled in Syk enzymatic assay, against a panel of selected kinases and in Syk-dependent cellular assays in mast cells and B cells. Pharmacokinetics and in vivo efficacy was assessed by intratracheal route. Airway resistance and mast cell degranulation after OVA challenge was evaluated in an ovalbumin-sensitized Brown Norway rat model. LAS189386 potently inhibits Syk enzymatic activity (IC50 7.2 nM), Syk phosphorylation (IC50 41 nM), LAD2 cells degranulation (IC50 56 nM), and B cell activation (IC50 22 nM). LAS189386 inhibits early asthmatic response and airway mast cell degranulation without affecting systemic mast cells. The present results support the hypothesis that topical inhibition of Syk in the lung, without systemic exposure, is sufficient to inhibit EAR in rats. Syk inhibition by inhaled route constitutes a promising therapeutic option for asthma.

In this study, four unapproved analogues of Sildenafil (SDF) were photodegraded under synthetic sunlight in artificial freshwater. Homosildenafil (H-SDF), hydroxyhomo-sildenafil (HH-SDF), norneosildenafil (NR-SDF) and thiosildenafil (T-SDF) were selected becausetheyarefrequentlydetectedasadulterantsinnaturalherbalproducts.UsingUPLC-Orbitrap(QExactive)-MS,sixphotoproducts common to H-SDF, HH-SDF and T-SDF and nine unique transformation products of different molecular weights were identified based on their high-resolution (+)ESI product ion spectra. Mass spectral analysis of deuterated H-SDF, labeled on the N-ethyl group, allowed to gain mechanistic insight into the fragmentation pathway of the substituted piperazine ring and to support the postulated photoproduct structures. The mass spectral fragmentation confirmed the stepwise destruction of the piperazine ring eventually producing a sulfonic acid derivative (C17H20N4O5S: 392.1151Da). In contrast, the photodegradation of NR-SDF, which lacks a piperazine ring in its structure, formed only two prominent photoproducts originating from N,Ndealkylation of the sulfonamide followed by hydrolysis. The current work constitutes the first study on the photodegradation ofanalogsoferectiledysfunctiondrugsandthefirstdetectionoftwotransformationproducts(m/z449and489)inenvironmental samples. Copyright © 2014 John Wiley & Sons, Ltd. Additional supporting information may be found in the online version of this article at the publisher’s web site.

Polymers are used in high amounts in a wide range of applications from biomedicine to industry. Because of the growing awareness of the increasing amounts of plastic wastes in the aquatic environment during recent years, the evaluation of their biodegradability deserves special attention. In the past, most efforts were dedicated to studying the biodegradation of polyesters in soil and compost, while very little research has been conducted on their fate in wastewater. Here, we assessed the ability of bacterial communities residing in the aerobic and denitrification tank from a wastewater treatment plant (WWTP) to degrade the polymeric ester polycaprolactone diol (PCLD; average molecular weight of 1250 Da). Following the incubation of the solid polymer in WWTP tanks, matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) was used to provide evidence for hydrolytic reactions and to study differences in the spatial degradation on the PCLD surface. It was demonstrated that regardless of the wastewater type, the chemical structure on the PCLD surface underwent modifications after 7 days of exposure. Apart from the parent PCLD peak series in MALDI-MSI mass spectra, the presence of a second oligomer series with mass peaks spaced by m/z 114 (as in PCLD) was observed. It was proposed to correspond to polycaprolactone (PCL) originating from the hydrolytic cleavage of the diethylene glycol from PCLD. Their ion masses were detected at m/z 104 below the PCLD peaks and their structures were proposed as PCL cyclized oligomers. Differences in the spatial distribution of low MW ions (, This study has been financially supported by the EU through the FP7 project GLOBAQUA (Grant Agreement No 603629), and by the Generalitat de Catalunya (Consolidated Research Groups “2014 SGR 418—Water and Soil Quality Unit” and 2014 SGR 291—ICRA). It reflects only the author’s views. The Community is not liable for any use that may be made of the information contained therein.

10 pages, 5 figures, 1 table, supplementary material https://dx.doi.org/10.1007/s00216-017-0467-7, The widespread occurrence of pharmaceuticals in the aquatic environment has raised concerns about potential adverse effects on exposed wildlife. Very little is currently known on exposure levels and clearance mechanisms of drugs in marine fish. Within this context, our research was focused on the identification of main metabolic reactions, generated metabolites, and caused effects after exposure of fish to carbamazepine (CBZ) and ibuprofen (IBU). To this end, juveniles of Solea senegalensis acclimated to two temperature regimes of 15 and 20 °C for 60 days received a single intraperitoneal dose of these drugs. A control group was administered the vehicle (sunflower oil). Bile samples were analyzed by ultra-high-performance liquid chromatography–high-resolution mass spectrometry on a Q Exactive (Orbitrap) system, allowing to propose plausible identities for 11 metabolites of CBZ and 13 metabolites of IBU in fish bile. In case of CBZ metabolites originated from aromatic and benzylic hydroxylation, epoxidation, and ensuing O-glucuronidation, O-methylation of a catechol-like metabolite was also postulated. Ibuprofen, in turn, formed multiple hydroxyl metabolites, O-glucuronides, and (hydroxyl)-acyl glucuronides, in addition to several taurine conjugates. Enzymatic responses after drug exposures revealed a water temperature-dependent induction of microsomal carboxylesterases. The metabolite profiling in fish bile provides an important tool for pharmaceutical exposure assessment, This study has been financially supported by the EU through the FP7 project GLOBAQUA (Grant agreement no. 603629), partly supported by the MEC [NET-SCARCE (CTM2015-69780-REDC) and by the Generalitat de Catalunya (Consolidated Research Group “2014 SGR 418—Water and Soil Quality Unit”). This work is also integrated in the MINECO project CTM 2010-16611, DEPURAMAR

Background Autoantibodies, in particular those against aquaporin-4 and myelin-oligodendrocyte glycoprotein (MOG), aid as biomarkers in the differential diagnosis of demyelination. Here, we report on discovery of autoantibodies against flotillin in patients with multiple sclerosis (MS). Methods The target antigen was identified by histo-immunoprecipitation using the patients’ sera and cryosections of rat or pig cerebellum combined with mass spectrometrical analysis. Correct identification was ascertained by indirect immunofluorescence and neutralization tests using the target antigens recombinantly expressed in HEK293 cells. Results Serum and CSF of the index patient produced a fine-granular IgG indirect immunofluorescence staining of the hippocampal and cerebellar molecular layers. Flotillin-1 and flotillin-2 were identified as target autoantigens. They also reacted with recombinant human flotillin-1/2 co-expressed in HEK293 cells, but not with the individual flotillins in fixed- and live-cell assays. Moreover, neutralization using flotillin-1/2, but not the single flotillins, abolished the tissue reactivity of patient serum. Screening of 521 patients, for whom anti-aquaporin-4 testing was requested and negative, revealed 8 additional patients with anti-flotillin-1/2 autoantibodies. All eight were negative for anti-MOG. Six patients ex post fulfilled the revised McDonald criteria for MS. Vice versa, screening of 538 MS sera revealed anti-flotillin-1/2 autoantibodies in eight patients. The autoantibodies were not found in a cohort of 67 patients with other neural autoantibody-associated syndromes and in 444 healthy blood donors. Conclusions Autoantibodies against the flotillin-1/2 heterocomplex, a peripheral membrane protein that is involved in axon outgrowth and regeneration of the optic nerve, are present in 1–2% of patients with bona fide MS. Electronic supplementary material The online version of this article (doi:10.1186/s12974-017-0900-z) contains supplementary material, which is available to authorized users.

Pruritus is a major symptom of several dermatological diseases but has limited therapeutic options available. Animal models replicating the pathophysiology of pruritus are needed to support the development of new drugs. Induction of pruritus by chloroquine (CQ) in mice is widely used, although, as with similar models, it has low throughput and does not distinguish between antipruritic effects and confounding factors such as sedation. To overcome these issues, we incorporated into the model an automated system that measures both scratching and locomotor behaviour simultaneously. We combined this system with the determination of CQ levels in different tissues to understand the impact of the route of CQ administration on the pruritogenic response. We concluded that whereas oral CQ does not induce pruritus due to insufficient skin levels, the bell-shaped curve of pruritus observed following subcutaneous administration is due to toxicity at high doses. We validated the model with several drugs currently used in humans: nalfurafine, aprepitant, cyproheptadine and amitriptyline. By comparing the effects of the drugs on both scratching and locomotor activity, we concluded that nalfurafine and aprepitant can exhibit efficacy at doses devoid of central effects, whereas central effects drove the efficacy of the other two drugs. This was further confirmed using non-brain-penetrant drugs. Moreover, as anticipated, anti-inflammatory drugs showed no efficacy. In conclusion, the use of an automated integrated behavioural assessment in CQ-induced pruritus makes the assay suitable for screening purposes and allows for a correct interpretation of the antipruritic effect of the compounds evaluated.

Extensive structure–activity relationship (SAR) and structure–kinetic relationship (SKR) studies in the bicyclic heteroaromatic series of CRTh2 antagonists led to the identification of several molecules that possessed both excellent binding and cellular potencies along with long receptor residence times. A small substituent in the bicyclic core provided an order of magnitude jump in dissociation half-lives. Selected optimized compounds demonstrated suitable pharmacokinetic profiles.

Pyrrolopiperidinone acetic acids (PPAs) were identified as highly potent CRTh2 receptor antagonists. In addition, many of these compounds displayed slow-dissociation kinetics from the receptor. Structure–kinetic relationship (SKR) studies allowed optimisation of the kinetics to give potent analogues with long receptor residence half-lives of up to 23 h. Low permeability was a general feature of this series, however oral bioavailability could be achieved through the use of ester prodrugs.

In this manuscript, the synthesis and biological activity of a series of pyrazole acetic acid derivatives as CRTh2 antagonists is presented. Biological evaluation in vitro revealed that the pyrazole core showed in several cases a different structure-activity relationship (SAR) to that of related indole acetic acid. A potent series of ortho-sulfonyl benzyl substituents was found, from which compounds 27 and 63 were advanced to in vivo profiling.

Cyclic nucleotide cAMP is a ubiquitous secondary messenger involved in a plethora of cellular responses to biological agents involving activation of adenylyl cyclase. Its intracellular levels are tightly controlled by a family of cyclic nucleotide degrading enzymes, the PDEs. In recent years, cyclic nucleotide phosphodiesterase type 4 (PDE4) has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases, particularly in the management of asthma and COPD. Here we describe our efforts to discover novel, highly potent inhaled inhibitors of PDE4. Through structure based design, with the inclusion of a variety of functional groups and physicochemical profiles in order to occupy the solvent-filled pocket of the PDE4 enzyme, we modified the structure of our oral PDE4 inhibitors to reach compounds down to picomolar enzymatic potencies while at the same time tackling successfully an uncovered selectivity issue with the adenosine receptors. In vitro potencies were demonstrated in a rat lung neutrophilia model by administration of a suspension with a Penn-Century MicroSprayer Aerosolizer.

In the 19th and 20th century, national states were a dominant force, but it seems that a reorganization of the states in the 21st century is taking place, created by both internal and external reasons. What could legislation in a new adjusted system look like? The author searches for an approach following the hierarchical structure of sovereign rights.

BACKGROUND: A polyspecific, intrathecal humoral immune response against neurotropic viruses such as measles, rubella and varicella zoster virus (MRZ reaction, MRZR) is present in 80-100% of patients with multiple sclerosis (MS), but has not to date been evaluated in patients with neuromyelitis optica (NMO). AIMS: To evaluate whether MRZR distinguishes NMO and MS. METHODS: 20 patients with NMO and 42 with MS were included. The intrathecal synthesis of antibodies against measles, rubella and varicella zoster virus was detected by calculation of the respective antibody indices (AI). RESULTS: A positive MRZ reaction, as defined by a combination of at least two positive AIs, was found in 37/42 MS, but in only 1/20 NMO patients (p

The chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTh2) is a G protein-coupled receptor expressed on the leukocytes most closely associated with asthma and allergy like eosinophils, mast cells, Th2-lymphocytes and basophils. At present it is clear that CRTh2 mediates most prostaglandin D2 (PGD2) pro-inflammatory effects and as a result antagonists for this receptor have reached asthma clinical studies showing a trend of lung function improvement. The challenge remains to identify compounds with improved clinical efficacy when administered once a day. Herein we described the pharmacological profile of LAS191859, a novel, potent and selective CRTh2 antagonist. In vitro evidence in GTPγS binding studies indicate that LAS191859 is a CRTh2 antagonist with activity in the low nanomolar range. This potency is also maintained in cellular assays performed with human eosinophils and whole blood. The main differentiation of LAS191859 vs other CRTh2 antagonists is in its receptor binding kinetics. LAS191859 has a residence time half-life of 21h at CRTh2 that translates into a long-lasting in vivo efficacy that is independent of plasma levels. We believe that the strategy behind this compound will allow optimal efficacy and posology for chronic asthma treatment.

Ziele sind erwunschte Zustande. Um diese zu erreichen, werden Ziele gesetzt, und zwar von Personen und Institutionen. Grundsatzlich und verallgemeinernd betrachtet steht bei Haushaltungen Selbstentfaltung oben an, streben Unternehmungen nach Gewinn oder Kostendeckung und suchen Vereinigungen Gruppenbedarf, Verwaltungen Allgemeinbedarf zu befriedigen. Die zwei erstgenannten Wirtschaftssubjekte zielen also auf Eigenbedarfsdeckung, die beiden anderen auf Fremdbedarfsdeckung. Obwohl gegensatzlich, schliesen sich diese Ziele nicht gegenseitig aus, sondern sie erganzen sich.

Die Welt, in der wir leben, wird durch unsere Sinnesorgane wahrgenommen. Dinge, Lebewesen und Ereignisse bilden Reize, die Empfindungen und Reaktionen hervorrufen. Die funf Sinne (riechen, schmecken, tasten, horen und sehen) sind bei den Individuen unterschiedlich entwickelt und entsprechend vielfaltig wird die Welt wahrgenommen. Da man wissen mochte, ob die eigene Wahrnehmung richtig ist und wie andere die Welt wahrnehmen, muss man die Gemeinsamkeiten der subjektiven Wahrnehmung erforschen. Durch Verallgemeinerung lassen sich unter Umstanden objektive Wahrnehmungen ableiten. Allerdings kann die Unverlasslichkeit der Sinne dazu fuhren, dass eine als objektiv geltende Wahrnehmung doch auf Tauschung beruht und eines Tages zu revidieren ist. Unsere unsichere und begrenzte Wahrnehmungsfahigkeit verschliest uns ein getreues Abbild der wirklichen Gegebenheiten.

Nachdem die Wirtschaft als Analyseobjekt betrachtet worden ist und Grunde und Bedingungen des Wirtschaftens herausgearbeitet wurden, sollen im Folgenden die Wirtschaftssubjekte vorgestellt werden. Ein Blick in das Wirtschaftsleben zeigt zahlreiche Personen und Institutionen, die als Anbieter und Nachfrager in unterschiedlichen Bereichen und auf verschiedene Art und Weise — unter anderem entgeltlich und unentgeltlich — tatig sind und folglich ganz unterschiedliche Zielsetzungen, Rechtsformen und Grosenordnungen aufweisen. Gemeinsam ist der nachstehenden Auswahl alphabetisch angeordneter Wirtschaftssubjekte, dass sie als abgrenzbare betriebliche Einheiten in der Praxis vorkommen.

Im Rahmen der Beschaffung von Sachgutern nimmt die Alternative „Kauf oder Miete?“ zentrale Bedeutung ein. Eine dritte Wahlmoglichkeit bildet Leasing wegen etwaiger steuerlicher Aspekte. Ublicherweise stellt man die mit den Alternativen verbundenen Zahlungsstrome gegenuber, ermittelt die jeweiligen Barwerte, vergleicht sie und wahlt die Alternative mit dem hochsten Barwert aus. Von Einfluss auf das Ergebnis sind dabei richtig geschatzte Nutzungsdauern, die Hohe der Abschreibungen und Mietzahlungen und die Abschreibungsmethode; z.B. wird bei degressiver Abschreibung auf das gekaufte Gut ein hoherer Steuerstundungs- und Liquiditatseffekt erzielt als bei konstanter Miete. Wird das gekaufte Gut fremdfinanziert, kann sich ein unvollkommener Kapitalmarkt finanziell nachteilig auswirken und es sind Risikozuschlage auf den Kalkulationszinssatz vonnoten. Kundbare Mietvertrage erhohen die Flexibilitat bei Beschaffungen — sowohl beim Mieter als auch beim Vermieter.

Wirtschaftliches Handeln wird gern mit rationalem Handeln gleichgesetzt. Das geht so weit, dass man das Rationalprinzip schlicht als okonomisches Prinzip und den rational handelnden Menschen als homo oeconomicus identifiziert. Diese Auffassung ist abzulehnen, denn wirtschaftliches Handeln kann sowohl rational als auch irrational erfolgen. Daruber hinaus lasst sich die Ratio gedanklich in eine okonomische und metaokonomische Ratio (synonym: wirtschaftliche und auserwirtschaftliche Vernunft) unterteilen. Beide stehen zueinander in komplementarer oder konkurrierender, vereinzelt auch in indifferenter Beziehung. Die konkurrierende Interdependenz durfte am haufigsten vorkommen. Was wirtschaftlich vernunftig ist, mag vom Blickwinkel etwa der Bildung, Demokratie, Gesundheit, Gerechtigkeit, Kunst, Politik oder Technik aus unvernunftig sein. Umgekehrt kann das Handeln wirtschaftlicher Vernunft widersprechen, wenn es von der auserwirtschaftlichen Vernunft geleitet wird. Selbst bei wirtschaftlich vernunftigem Handeln muss man fragen, ob und inwieweit es einzel- und/oder gesamtwirtschaftlich vernunftig bzw. unvernunftig ist. Da sich die Vernunft letztlich als unteilbar erweist, sind die Wahrnehmungen und Erkenntnisse im metaokonomischen Umfeld mit der okonomischen Ratio zum Ausgleich zu bringen.

Recent publications on pharmaceutical monitoring are increasingly covering the field of illicit drugs and lately the forensic evaluation of designing illegal analogs of lifestyle drugs like the phosphodiesterase type 5 (PDE-5) inhibitors Viagra (sildenafil), Levitra (vardenafil) and Cialis (tadalafil). Recently, the presence of all three erectile dysfunction treatment drugs has been reported in wastewaters at very low concentrations. In the environment, contaminants undergo various physical or chemical processes classified into abiotic (photolysis, hydrolysis) and biotic (biodegradation) reactions. Thus, changes in the chemical structure lead to the formation of new transformation products, which may persist in the environment or be further degraded. This study describes the photolysis of sildenafil (SDF) and its human metabolite N-demethylsildenafil (DM-SDF) under simulated solar radiation (Xenon lamp). Following chromatographic separation of the irradiated samples, eight photoproducts in the SDF samples and six photoproducts for DM-SDF were detected and characterized. The combination of ultra performance liquid chromatography-electrospray ionization-quadrupole time-of-flight-mass spectrometry (UPLC-ESI-QToF-MS), liquid chromatography-atmospheric pressure chemical ionization-triple quadrupole mass spectrometry (LC-APCI-QqQ-MS) and hydrogen/deuterium-exchange experiments allowed to propose plausible chemical structures for the photoproducts, taking into account the characteristic fragmentation patterns and the accurate mass measurements. These mass spectral data provided sound evidence for the susceptibility of the piperazine ring toward photodegradation. A gradual breakdown of this heterocyclic structure gave rise to a series of products, which in part were identical for SDF and DM-SDF. The sulfonic acid, as the formal product of sulfonamide hydrolysis, was identified as key intermediate in the photolysis pathway. In both drug/metabolite molecules, phototransformation processes taking place beyond the sulfonamide group were deemed to be of minor relevance.

Primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis are the three major immune-mediated liver diseases. The etiologies of primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis are largely unknown, but seem to be influenced by genetic and environmental factors. Autoantibodies can be found in nearly all patients with primary sclerosing cholangitis and autoimmune hepatitis, and in the vast majority of patients with primary sclerosing cholangitis. In addition, autoimmune hepatitis is associated with high concentrations of serum globulins. Enhanced liver cell death by apoptosis has been described in all of these liver diseases, although the precise mechanisms remain unclear. In general, apoptosis can be initiated via an extrinsic pathway that is triggered by engagement of death receptors on the cell surface, or via an intrinsic pathway that is induced by mitochondrial injury and is influenced by members of the Bcl-2 family. In both pathways, effector caspases are finally activated that cleave and degrade cell structures, resulting in the release of apoptotic products into the circulation. New diagnostic tests can detect these apoptotic markers and programmed cell death ligands such as Fas and Fas-ligands, nucleosomes, caspases, cytokeratin fragments, macrophage migration inhibitory factor, soluble intracellular adhesion molecule, natural killer cells group 2D and programmed death ligands. Several of these markers have been found to be altered in tissue and/or blood of immune-mediated liver diseases, some also in nonimmune-mediated liver diseases. Beyond their potential usefulness as additional diagnostic markers, they may be valuable for the estimation of disease severity and therapy monitoring. This review summarizes current knowledge on apoptotic mechanisms, death receptor ligands and circulating apoptotic markers in immune-mediated liver diseases.

Introduction: Treatment of chronic cough is an unmet medical need impairing patients9 quality of life. Transient Receptor Potential Ankyrin 1 (TRPA1) channels may provide a safe opportunity to target cough response at the periphery of the cough reflex arc. Poor potency and physicochemical properties of available TRPA1 antagonists are hampering their advance in the clinics. Here we describe a novel, potent and orally available TRPA1 antagonist, compound A, and its profile in preclinical models of cough. Objectives To profile the TRPA1 antagonist Compound A in in vitro assays and in a preclinical model of induced cough. In vitro profile was compared with that of HC030031. Methods: Potency of the compounds was assessed in calcium fluorescence based assays and electrophysiology in cells overexpressing TRPA1. Inhibition of isolated guinea pig (gp) vagus nerve depolarization induced by acrolein was used as functional in vitro assay. Cough was induced upon nebulization of 10mM Allyl Isothiocyanate (AITC) for 10 minutes in conscious gp individually placed into whole body plethysmography chambers (Buxco). Results: Compound A showed a potent TRPA1 antagonist activity with enhanced efficacy at inhibiting isolated gp vagus nerve depolarization (EC50=80nM). Favorable oral pharmacokinetic profile translated in a relevant efficacy at inhibiting cough induced by AITC in gp (ED50=0.17mg/kg). Conclusions: Compound A is an orally available, potent and novel TRPA1 antagonist that has proven to be efficacious in a mechanistic model of induced cough. Promising profile of Compound A suggests it could be useful for the treatment of chronic cough associated to respiratory diseases.