Product Market Integration and Income Taxation: Distortions and Gains from Trade

It is widely perceived that globalization is a threat to tax financed public sector activities. The argument is that public activities (public consumption and transfers) financed by income taxes may distort labour markets and cause higher wages and thus a loss of competitiveness. If the importance of the latter effect is reinforced by globalization, it is inferred that the marginal costs of public funds increase and a retrenchment of the public sector follows. We consider this issue in a Ricardian trade model in which production and specialization structures are endogenous. Even though income taxation unambiguously worsens wage competitiveness, it does not follow that tax distortions or marginal costs of public funds increase with product market integration. The reason is that gains from trade tend to reduce both. Moreover, non-cooperative fiscal policies do not have a bias towards retrenchment due to a positive terms of trade effect from taxation.labour taxation, open economy, policy spill-over, marginal costs of public funds

Development of calcium phosphate based drug delivery systems for local application of zoledronic acid

Calcium phosphate-like bone substitute materials have a long history of successful orthopaedic applications such as bone void filling and augmentation. Based on the clinical indications, these materials may be loaded with active agents by adsorption offering a perspective for providing innovative drug delivery systems. The highly effective antiporotic, nitrogen-containing, bisphosphonate zoledronic acid (ZOL) demonstrated a strong affinity to calcium phosphates. It has been shown to significantly impact anabolic and catabolic pathways in bone remodelling towards reduction of osteoclast activity. The effects of locally applied ZOL on the early bone formation are of scientific and therapeutic interest, but still not fully understood. The local application of ZOL on implants is considered to support implant stabilisation by reducing early bone resorption. Support of early bone formation and reduction of bone resorption can be expected after implantation of bioceramics releasing ZOL. The aim of the present thesis was to develop a feasible method for combining ZOL with bone substitutes by use of a dipping technique. The properties of three different materials (sintered body, granules and powder) were investigated to evaluate their potential as drug carriers for ZOL. This included the use of a range of physico-chemical methods such as light microscopy, scanning electron microscopy (SEM), true density, surface area measurement, dynamic vapour sorption (DVS), and pH value determination. In addition to the physico-chemical characterisation, the bone substitutes were evaluated for their ZOL loading capacity (time and concentration). Also, the materials were assessed as release systems in an in vitro study. Furthermore, ZOL stability under different storage conditions, cytotoxicity of ZOL with a cell line and a characterisation of modified cement formulations were performed to design a suitable implant for an animal model. In an in vivo study, ZOL was released from a drug-loaded preshaped calcium phosphate bone cement plug, which was implanted into a bone defect in the proximal tibia of rats. The aim was to gain experience about the short term effects of ZOL on bone implant contact, bone regeneration and bone area. In a short term investigation, one and three weeks post operationem, tissue reactions as well as bone regeneration capabilities at the implant site were investigated by means of histological and imaging analysis. Furthermore, tissue samples, harvested at placebo and verum plug sites were used to analyse the gene expression of selected bone-specific markers. Levels of osteocalcin (OC), alkaline phosphatase (ALP), cathepsin K (CATK), tartrate-resistant acid phosphatase (TRAP), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) were determined by using quantitative polymerase chain reaction (qPCR). Data were normalized against 18S and GAPDH ribosomal subunits. The results of the present thesis indicated differences between the bone substitute materials used and their potential use as a local drug delivery system in terms of physico-chemical properties, drug adsorption and release profiles. The in vitro investigations demonstrated a controlled ZOL load in a range of 0.04 – 1.86 µg/mg material and a release of 0.02 – 0.18 µg/mg within 30 minutes. The findings of the in vivo study showed that in the placebo interface a higher amount of cells could be detected as indicated by higher expression of small subunit ribosomal RNA (18S). Nevertheless, comparing the normalized data of the selected gene expression levels, no significant differences were detected. Histopathological analysis revealed no adverse tissue effects and provided evidence of biocompatibility for both implant types. The histomorphometric results showed a significantly higher bone to implant contact and bone area for ZOL loaded bone cement plug at three weeks after implantation. The study showed some significant differences in the biological tissue response to loaded and non-loaded bone cement plugs. In this model, ZOL was demonstrated to be effective in impacting the bone regeneration process towards reduction of early bone resorption and enhanced bone formation.Calciumphosphat-basierte Knochenersatzmaterialien werden seit langem erfolgreich in der Orthopädie zur Füllung von Knochendefekten und zum Knochenaufbau eingesetzt. Diese Materialien könnten, je nach klinischer Indikation, durch Adsorption mit Arzneistoffen beladen werden, was eine Perspektive für innovative arzneistofffreisetzende Systeme darstellt. Das hochpotente, antiporotisch wirkende, stickstoffhaltige Bisphosphonat Zoledronsäure (ZOL) weist eine hohe Affinität zu Calciumphosphaten auf. Der Arzneistoff hat bereits einen signifikanten Einfluss auf anabole und katabole Stoffwechselvorgänge während des Knochenumbaus hin zu einer reduzierten Osteoklastenaktivität gezeigt. Die Effekte von lokal applizierter ZOL auf die frühe Knochenneubildung sind von wissenschaftlichem und therapeutischem Interesse, bisher aber noch nicht vollständig verstanden. Eine gezielte, lokale Applikation von ZOL mit Hilfe eines Calciumphosphatträgers könnte zu einer verminderten Knochenresorption und einer erhöhten Knochenneubildung führen, wodurch ein Implantat gerade in einer frühen Heilungsphase stabilisiert werden könnte. Das Ziel der vorliegenden Dissertation war es, eine einfach durchzuführende Beladungstechnik von Knochenersatzmaterialien mit ZOL zu entwickeln. Die Eigenschaften von drei verschiedenen Knochenersatzmaterialien wurden mit Hilfe einer Vielzahl von physiko-chemischen Methoden wie z.B. Lichtmikroskopie, Rasterelektronenmikroskopie, Dichtebestimmungen, Oberflächenbestimmungen, dynamischer Wassersorption und pH-Wert Bestimmungen charakterisiert, um die Möglichkeiten eines potenziellen Arzneistoffträgers zu ermitteln. Neben der physiko-chemischen Charakterisierung wurden die ZOL Beladungskapazitäten der verschiedenen Materialien zeit- und konzentrationsabhängig ermittelt. Zusätzlich wurden die in vitro Freisetzungskinetiken der beladenen Materialien bestimmt. Des Weiteren wurde die ZOL Stabilität unter verschiedenen Lagerungsbedingungen, die Zytotoxizität auf eine Zelllinie und die Charakterisierung von modifizierten Zementformulierungen experimentell getestet, um ein geeignetes Implantat für einen Tierversuch zu entwickeln. In einer in vivo Studie wurde ZOL aus einem vorgeformten, arzneistoffbeladenen Calciumphosphat-Knochenzementimplantat freigesetzt, welches in die proximale Rattentibia implantiert wurde. Das Ziel war es, Kenntnis über die kurzeitigen Effekte von ZOL in Bezug auf die Knochenimplantatkontaktfläche, die Knochenregeneration und die Knochenfläche zu erlangen. Innerhalb des Untersuchungszeitraumes von ein und drei Wochen nach Operation wurden sowohl Gewebereaktionen als auch Knochenregenerationsmöglichkeiten mit Hilfe von histologischen und bildgebenden Analysen untersucht. Ergänzend wurden Gewebeproben, die von Placebo- und Verumimplantaten entnommen wurden, einer Genexpressionsanalyse von ausgewählten knochenspezifischen Markern unterzogen. Die Konzentrationen von Osteocalcin (OC), Alkaliphosphatase (ALP), Kathepsin K (CATK), Tartrat-resistenter saurer Phosphatase (TRAP), Interleukin-1β und Tumornekrosefaktor α wurden über ein quantitatives Polymerasekettenreaktionsverfahren (qPCR) bestimmt. Die Daten wurden gegen 18S und GAPDH ribosomale Untereinheiten normalisiert. Die Ergebnisse der physiko-chemischen Untersuchungen, der Arzneistoff-adsorption und der Freisetzungskinetiken der vorliegenden Arbeit zeigten Unterschiede der verwendeten Knochenersatzmaterialien im Gebrauch als lokales, arzneistofffreisetzendes System. Die in vitro Untersuchungen präsentierten die Möglichkeit einer kontrollierten ZOL Beladung in einem Bereich von 0,04 – 1,86 µg/mg der jeweiligen Materialen und eine Freisetzung von 0,02 – 0,18 µg/mg innerhalb von 30 Minuten. Die Ergenisse der in vivo Studie zeigten, dass eine vermehrte Zellzahl an der Placebokontaktfläche ermittelt werden konnte, was aus einer höheren Expression der 18S RNA Untereinheit geschlussfolgert wurde. Beim Vergleich der normalisierten Daten der Genexpression konnten keine signifikanten Unterschiede ermittelt werden. Eine histopathologische Auswertung ergab, dass keine nachteiligen Gewebereaktionen für beide Implantattypen nachgewiesen werden konnten, was die Vermutung einer guten Biokompatibilität unterstützt. Die histo-morphometrischen Ergebnisse demonstrierten eine signifikant erhöhte Knochen-Implantat-Kontaktfläche und Knochenfläche für die ZOL-beladenen Implantate nach drei Wochen. Zusammengefasst konnten mit Hilfe der durchgeführten Tierstudie signifikante Unterschiede in der biologischen Gewebeantwort von ZOL-beladenen Knochenzementimplantaten gezeigt werden. In dem verwendeten Modell beeinflusste ZOL den Knochenregenerationsprozess hin zu einer Verringerung der frühen Knochenresorption und einer erhöhten Knochenneubildung

The stable cyclic adenosine monophosphate analogue, dibutyryl cyclo-adenosine monophosphate (bucladesine), is active in a model of acute skin inflammation

Anti-inflammatory therapeutic options for the topical treatment of skin diseases with inflammatory or allergic contribution are mostly limited to topical glucocorticoids and calcineurin inhibitors. Both compound classes induce adverse effects. Elevation of intracellular cyclic adenosine monophosphate (cAMP) by inhibition of phosphodiesterase 4 was shown to induce potent anti-inflammatory effects, but the safety profile of currently available compounds is not sufficient. A different approach to increase intracellular cAMP is the substitution of chemically stabilized cAMP analogues. Bucladesine is a stabilized cAMP analogue with an excellent safety profile which had been marketed as topical treatment of impaired wound healing. In the current study, a novel water free emulsion containing bucladesine was evaluated for anti-inflammatory effects. In the arachidonic acid induced ear oedema model in mice, single or multiple administration of an emulsion containing 1.5% was capable of significantly reducing the inflammatory oedema. The data indicate that bucladesine represents an interesting treatment option for skin diseases where an anti-inflammatory activity is indicated. Due to the established clinical safety, this agent may bridge the gap between potent agents such as glucocorticoids or calcineurin inhibitors and emollients without active compounds

Impact of Biomechanical Forces on Antibiotics Release Kinetics from Hydroxyapatite Coated Surgical Fixation Pins

This work investigates the impact of biomechanical wear and abrasion on the antibiotic release profiles of hydroxyapa-tite (HA) coated fixation pins during their insertion into synthetic bone. Stainless steel fixation pins are coated with crystalline TiO2 by cathodic arc evaporation forming the bioactive layer for biomimetic deposition of Tobramycin con-taining HA. Tobramycin is either introduced by co-precipitation during HA formation or by adsorption-loading after HA deposition. The samples containing antibiotics are inserted into bone mimicking polyethylene foam after which the drug release is monitored using high performance liquid chromatography. This analysis shows that HA coating wear and delamination significantly decrease the amount of drug released during initial burst, but only marginally influence the sustained release period. Spalled coating fragments are found to remain within the synthetic bone material structure. The presence of HA within this structure supports the assumption that the local release of Tobramycin is not only ex-pected to eliminate bacteria growth directly at the pin interface but as well at some distance from the implant. Further-more, no negative effect of gamma sterilization could be observed on the drug release profile. Overall, the observed results demonstrate the feasibility of a multifunctional implant coating that is simultaneously able to locally deliver clinically relevant doses of antibiotics and an HA coating capable of promoting osteoconduction. This is a potentially promising step toward orthopaedic devices that combine good fixation with the ability to treat and prevent post-surgical infections

Impact of Biomechanical Forces on Antibiotics Release Kinetics from Hydroxyapatite Coated Surgical Fixation Pins

This work investigates the impact of biomechanical wear and abrasion on the antibiotic release profiles of hydroxyapa-tite (HA) coated fixation pins during their insertion into synthetic bone. Stainless steel fixation pins are coated with crystalline TiO2 by cathodic arc evaporation forming the bioactive layer for biomimetic deposition of Tobramycin con-taining HA. Tobramycin is either introduced by co-precipitation during HA formation or by adsorption-loading after HA deposition. The samples containing antibiotics are inserted into bone mimicking polyethylene foam after which the drug release is monitored using high performance liquid chromatography. This analysis shows that HA coating wear and delamination significantly decrease the amount of drug released during initial burst, but only marginally influence the sustained release period. Spalled coating fragments are found to remain within the synthetic bone material structure. The presence of HA within this structure supports the assumption that the local release of Tobramycin is not only ex-pected to eliminate bacteria growth directly at the pin interface but as well at some distance from the implant. Further-more, no negative effect of gamma sterilization could be observed on the drug release profile. Overall, the observed results demonstrate the feasibility of a multifunctional implant coating that is simultaneously able to locally deliver clinically relevant doses of antibiotics and an HA coating capable of promoting osteoconduction. This is a potentially promising step toward orthopaedic devices that combine good fixation with the ability to treat and prevent post-surgical infections

Application of High-Sensitivity Troponin in Suspected Myocardial Infarction

BackgroundData regarding high-sensitivity troponin concentrations in patients presenting to the emergency department with symptoms suggestive of myocardial infarction may be useful in determining the probability of myocardial infarction and subsequent 30-day outcomes.MethodsIn 15 international cohorts of patients presenting to the emergency department with symptoms suggestive of myocardial infarction, we determined the concentrations of high-sensitivity troponin I or high-sensitivity troponin T at presentation and after early or late serial sampling. The diagnostic and prognostic performance of multiple high-sensitivity troponin cutoff combinations was assessed with the use of a derivation-validation design. A risk-assessment tool that was based on these data was developed to estimate the risk of index myocardial infarction and of subsequent myocardial infarction or death at 30 days.ResultsAmong 22,651 patients (9604 in the derivation data set and 13,047 in the validation data set), the prevalence of myocardial infarction was 15.3%. Lower high-sensitivity troponin concentrations at presentation and smaller absolute changes during serial sampling were associated with a lower likelihood of myocardial infarction and a lower short-term risk of cardiovascular events. For example, high-sensitivity troponin I concentrations of less than 6 ng per liter and an absolute change of less than 4 ng per liter after 45 to 120 minutes (early serial sampling) resulted in a negative predictive value of 99.5% for myocardial infarction, with an associated 30-day risk of subsequent myocardial infarction or death of 0.2%; a total of 56.5% of the patients would be classified as being at low risk. These findings were confirmed in an external validation data set.ConclusionsA risk-assessment tool, which we developed to integrate the high-sensitivity troponin I or troponin T concentration at emergency department presentation, its dynamic change during serial sampling, and the time between the obtaining of samples, was used to estimate the probability of myocardial infarction on emergency department presentation and 30-day outcomes