In vivo and in vitro aspects of imidazoline-2(1/2)sites within the central nervous system

The in vivo and in vitro characteristics of the I2 binding site were probed using the technique of drug discrimination and receptor autoradiography. Data presented in this thesis indicates the I2 ligand 2-BFI generates a cue in drug discrimination. Further studies indicated agmatine, a proposed endogenous imidazoline ligand, and a number of imidazoline and imidazole analogues of 2-BFI substitute significantly for 2-BFI. In addition to specific I2 ligands the administration of NRl's (noradrenaline reuptake inhibitors), the sympathomimetic d-amphetamine, the α1-adrenoceptor agonist methoxamine, but not the β1 agonist dobutamine or the β2 agonist salbutamol, gave rise to significant levels of substitution for the 2-BFI cue. The administration of the α1-adrenoceptor antagonist WB4101, prior to 2- BFI itself significantly reduced levels of 2-BFI appropriate responding. Administration of the reversible MAO-A inhibitors moclobemide and Ro41-1049, but not the reversible MAO-B inhibitors lazabemide and Ro16-6491, gave rise to potent dose dependent levels of substitution for the 2-BFI cue. Further studies indicated the administration of a number of β-carbolines and the structurally related indole alkaloid ibogaine also gave rise to dose dependent significant levels of substitution. Due to the relationship of indole alkaloids to serotonin the 5-HT releaser fenfluramine and a number of SSRI's (selective serotonin reuptake inhibitor) were also administered and these compounds gave rise to significant partial (20-80% responses to the 2-BFI lever) levels of substitution. The autoradiographical studies reported here indicate [3H]2-BFI labels I2 sites within the rat arcuate nucleus, area postrema, pineal gland, interpeduncular nucleus and subfornical organ. Subsequent experiments confirmed that the drug discrimination dosing schedule significantly increases levels of [3H]2-BFI 12 binding within two of these nuclei. However, levels of [3H]2-BFI specific binding were significantly reduced within four of these nuclei after chronic treatment with the irreversible MAO inhibitors deprenyl and tranylcypromine but not pargyline, which only reduced levels significantly in two. Further autoradiographical studies indicated that the distribution of [3H]2-BFI within the C57/B mouse compares favourably to that within the rat. Comparison of these levels of binding to those from transgenic mice who over-express MAO-B indicates two possibly distinct populations of [3H]2-BFI 12 sites exist in mouse brain. The data presented here indicates the 2-BFI cue is associated with the selective activation of α1-adrenoceptors and possibly 5-HT receptors. 2-BFI trained rats recognise reversible MAO-A but not MAO-B inhibitors. However, data within this thesis indicates the autoradiographical distribution of I2 sites bears a closer resemblance to that of MAO-B not MAO-A and further studies using transgenic mice that over-express MAO-B suggests a non-MAO-B I2 site exists in mouse brain.

An investigation of the retail marketing mix and its effectiveness in small shops

The recent history of small shop and independent retailing has been one of decline. The most desirable form of assistance is the provision of information which will increase the efficiency model of marketing mix effeciveness which may be applied in small scale retailing. A further aim is to enhance theoretical development in the marketing field. Recent changes in retailing have affected location, product range, pricing and promotion practices. Although a large number of variables representing aspects of the marketing mix may be identified, it is not possible, on the basis of currently available information, to quantify or rank them according to their effect on sales performance. In designing a suitable study a major issue is that of access to a suitable representative sample of small retailers. The publish nature of the retail activities involved facilitates the use of a novel observation approach to data collection. A cross-sectional survey research design was used focussing on a clustered random sample of greengrocers and gent's fashion outfitters in the West Midlands. Linear multiple regression was the main analytical technique. Powerful regression models were evolved for both types of retailing. For greengrocers the major influences on trade are pedestrian traffic and shelf display space. For gent's outfitters they are centrality-to-other shopping, advertising and shelf display space. The models may be utilised by retailers to determine the relative strength of marketing mix variables. The level of precision is not sufficient to permit cost benefit analysis. Comparison of the findings for the two distinct kinds of business studied suggests an overall model of marketing mix effectiveness might be based on frequency of purchase, homogeneity of the shopping environment, elasticity of demand and bulk characteristics of the good sold by a shop.

A rationale for the optimisation by computer methods of the efficient use of metals and materials

The aim of the research project was to gain d complete and accurate accounting of the needs and deficiencies of materials selection and design data, with particular attention given to the feasibility of a computerised materials selection system that would include application analysis, property data and screening techniques. The project also investigates and integrates the three major aspects of materials resources, materials selection and materials recycling. Consideration of the materials resource base suggests that, though our discovery potential has increased, geologic availability is the ultimate determinant and several metals may well become scarce at the same time, thus compounding the problem of substitution. With around 2- to 20- million units of engineering materials data, the use of a computer is the only logical answer for scientific selection of materials. The system developed at Aston is used for data storage, mathematical computation and output. The system enables programs to be run in batch and interactive (on-line) mode. The program with modification can also handle such variables as quantity of mineral resources, energy cost of materials and depletion and utilisation rates of strateqic materials. The work also carries out an in-depth study of copper recycling in the U.K. and concludes that, somewhere in the region of 2 million tonnes of copper is missing from the recycling cycle. It also sets out guidelines on product design and conservation policies from the recyclability point of view.

Effects of pharmaceutical marketing:a re-analysis of the study of Windmeijer et al

Despite a growing body of scientific research, there is still much uncertainty about the effects of marketing expenditures on the demand for pharmaceuticals. Recently it was found that higher marketing expenditures for a brand may reduce the price elasticity of demand, and hence allow firms to charge higher prices (Windmeijer et al [1]). In this study we reconsider the study by Windmeijer et al. We find that their econometric models are based on an incorrect assumption of homogeneous parameters across brands. As a consequence, our conclusions concerning the effects of pharmaceutical marketing are different from theirs.

Modeling the effects of pharmaceutical marketing

Successful innovation of prescription drugs requires a substantial amount of marketing support. There is, however, much concern about the effects of marketing expenditures on the demand of pharmaceutical products (Manchanda et al., Market Lett 16(3/4):293–308, 2005). For example, excessive marketing could stimulate demand for products in the absence of a fundamental need. It also has been suggested that increased marketing expenditures may reduce the price elasticity of demand and allow firms to charge higher prices (Windmeijer et al., Health Econ 15(1):5–18, 2005). In this paper, we present the outcomes of an empirical study in which we determine the effects of pharmaceutical marketing expenditures using a number of frequently used “standardized” models. We determine which models perform best in terms of predictive validity and adequate descriptions of reality. We demonstrate, among others, that the effects of promotional efforts are brand specific and that most standardized models do not provide adequate descriptions of reality. We find that marketing expenditures have no or moderate effects on demand for pharmaceutical products in The Netherlands.

Preferences of Hungarian consumers for quality, access and price attributes of health care services — result of a discrete choice experiment

In 2010, a household survey was carried out in Hungary among 1037 respondents to study consumer preferences and willingness to pay for health care services. In this paper, we use the data from the discrete choice experiments included in the survey, to elicit the preferences of health care consumers about the choice of health care providers. Regression analysis is used to estimate the effect of the improvement of service attributes (quality, access, and price) on patients’ choice, as well as the differences among the socio-demographic groups. We also estimate the marginal willingness to pay for the improvement in attribute levels by calculating marginal rates of substitution. The results show that respondents from a village or the capital, with low education and bad health status are more driven by the changes in the price attribute when choosing between health care providers. Respondents value the good skills and reputation of the physician and the attitude of the personnel most, followed by modern equipment and maintenance of the office/hospital. Access attributes (travelling and waiting time) are less important. The method of discrete choice experiment is useful to reveal patients’ preferences, and might support the development of an evidence-based and sustainable health policy on patient payments.

Spontaneous Unfolding and Refolding of FNIII Domains Assayed by Thiol Exchange

Fibronectin (FN) is a large extracellular matrix (ECM) protein that is made up of

type I (FNI), type II (FNII), & type III (FNIII) domains. It assembles into an insoluble

supra-­‐‑molecular structure: the fibrillar FN matrix. FN fibrillogenesis is a cell‐‑mediated process, which is initiated when FN binds to integrins on the cell surface. The FN matrix plays an important role in cell migration, proliferation, signaling & adhesion. Despite decades of research, the FN matrix is one of the least understood supra-­‐‑molecular protein assemblies. There have been several attempts to elucidate the exact mechanism of matrix assembly resulting in significant progress in the field but it is still unclear as to what are FN-­‐‑FN interactions, the nature of these interactions and the domains of FN that

are in contact with each other. FN matrix fibrils are elastic in nature. Two models have been proposed to explain the elasticity of the fibrils. The first model: the ‘domain unfolding’ model postulates that the unraveling of FNIII domains under tension explains fibril elasticity.

The second model relies on the conformational change of FN from compact to extended to explain fibril elasticity. FN contain 15 FNIII domains, each a 7-­‐‑strand beta sandwich. Earlier work from our lab used the technique of labeling a buried Cys to study the ‘domain unfolding’ model. They used mutant FNs containing a buried Cys in a single FNIII domain and found that 6 of the 15 FNIII domains label in matrix fibrils. Domain unfolding due to tension, matrix associated conformational changes or spontaneous folding and unfolding are all possible explanation for labeling of the buried Cys. The present study also uses the technique of labeling a buried Cys to address whether it is spontaneous folding and unfolding that labels FNIII domains in cell culture. We used thiol reactive DTNB to measure the kinetics of labeling of buried Cys in eleven FN III domains over a wide range of urea concentrations (0-­‐‑9M). The kinetics data were globally fit using Mathematica. The results are equivalent to those of H-­‐‑D exchange, and

provide a comprehensive analysis of stability and unfolding/folding kinetics of each

domain. For two of the six domains spontaneous folding and unfolding is possibly the reason for labeling in cell culture. For the rest of the four domains it is probably matrix associated conformational changes or tension induced unfolding.

A long-­‐‑standing debate in the protein-­‐‑folding field is whether unfolding rate

constants or folding rate constants correlate to the stability of a protein. FNIII domains all have the same ß sandwich structure but very different stabilities and amino acid sequences. Our study analyzed the kinetics of unfolding and folding and stabilities of eleven FNIII domains and our results show that folding rate constants for FNIII domains are relatively similar and the unfolding rates vary widely and correlate to stability. FN forms a fibrillar matrix and the FN-­‐‑FN interactions during matrix fibril formation are not known. FNI 1-­‐‑9 or the N-­‐‑ terminal region is indispensible for matrix formation and its major binding partner has been shown to be FNIII 2. Earlier work from our lab, using FRET analysis showed that the interaction of FNI 1-­‐‑9 with a destabilized FNIII 2 (missing the G strand, FNIII 2ΔG) reduces the FRET efficiency. This efficiency is restored in the presence of FUD (bacterial adhesion from S. pyogenes) that has been known to interact with FNI 1-­‐‑9 via a tandem ß zipper. In the present study we

use FRET analysis and a series of deletion mutants of FNIII 2ΔG to study the shortest fragment of FNIII 2ΔG that is required to bind FNI 1-­‐‑9. Our results presented here are qualitative and show that FNIII 2ΔC’EFG is the shortest fragment required to bind FNI 1-­‐‑9. Deletion of one more strand abolishes the interaction with FNI 1-­‐‑9.

Radiological and material characterization of high volume fly ash concrete

The main goal of research presented in this paper was the material and radiological characterization of high volume fly ash concrete (HVFAC) in terms of determination of natural radionuclide content and radon emanation and exhalation coefficients. All concrete samples were made with a fly ash content between 50% and 70% of the total amount of cementitious materials from one coal burning power plant in Serbia. Physical (fresh and hardened concrete density) and mechanical properties (compressive strength, splitting tensile strength and modulus of elasticity) of concrete were tested. The radionuclide content (226Ra, 232Th and 40K) and radon massic exhalation of HVFAC samples were determined using gamma spectrometry. Determination of massic exhalation rates of HVFAC and its components using radon accumulation chamber techniques combined with a radon monitor was performed. The results show a beneficial effect of pozzolanic activity since the increase in fly ash content resulted in an increase in compressive strength of HVFAC by approximately 20% for the same mass of cement used in the mixtures. On the basis of the obtained radionuclide content of concrete components the I -indices of different HVFAC samples were calculated and compared with measured values (0.27e0.32), which were significantly below the recommended 1.0 index value. The prediction was relatively close to the measured values as the ratio between the calculated and measured I-index ranged between 0.89 and 1.14. Collected results of mechanical and radiological properties and performed calculations clearly prove that all 10 designed concretes with a certain type of fly ash are suitable for structural and non-structural applications both from a material and radiological point of view.

Pass-through of International food prices to domestic ination during and after the great recession: evidence from a set of Latin American economies

We examined how international food price shocks have impacted local ination processes in Brazil, Chile, Colombia, Mexico, and Peru in the past decade -- Using impulse-response analysis coming from cointegrated VARs, we wind that international food ination shocks take from one to six quarters to pass through to domestic head-line ination, depending on the country -- In addition, by calculating the elasticity of local prices to an international food price shock, we found that this pass-through is not complete -- We also take a closer look at how this type of shock affects local food and core prices separately, and asses the possibility second round effects over core ination stemming from the shock -- We wind that a transmission to headline prices does occur, and that part of the transmission is associated with rising core prices both directly and through possible second round effects, which implies a role for monetary policy when such a shock takes place -- This is especially relevant given that international food prices have recently been on an upward trend after falling considerably during the Great Recession

Effects of subsidizing the first employee – Empirical evidence from Finland

Small businesses form a significant share of all businesses and employ a large share of all employees. Therefore, governments are often interested in subsidizing them and especially employment in smaller firms. Nonemployer firms have received special interest, especially in Finland, due to their large share of all businesses. It has been argued that the government should encourage them to hire by subsidizing employment. However, there is no evidence on the effectiveness of such policies. In general, there is surprisingly little evidence on how small firms react to employment subsidies or of employment subsidies targeted according to firm characteristics. The subject of this thesis is the effects of subsidizing the first employee. While theoretical background suggests the subsidy might have efficiency gains, because there might be market inefficiencies that lead to too little employment in small firms. The focus of this research, however, is on the empirical evidence. There was a regional subsidy for hiring the first employee in Finland between 2007 and 2011. Nonemployer firms in the subsidy area were eligible for a wage subsidy for two years when they hired the first employee. The design of the subsidy enables studying the effects in a natural experiment framework that are nowadays popular in public economics. It can be shown that the area without the subsidy provides a good counterfactual to the area where the subsidy was available. Therefore, the effects of the subsidy can be estimated with difference-in-differences method. This method compares the change in the subsidy area to the change in the area without the subsidy. The data used is firm level data spanning from 2000 to 2013. The data is provided by the Finnish Tax Administration including tax declarations by all Finland based companies. The effects for hiring decisions are estimated by examining the effects for alternative variables such as employment, wage expenditure and turnover. According to the results, the subsidy did not have statistically significant effect on any of the variables of interest. Therefore, it can be concluded that the subsidy did not increase hires in nonemployer firms. This implies that the labour demand elasticity of nonemployer firms is very small. The results are in line with previous literature on the effectiveness of general employment subsidies in Scandinavia that suggest that labour demand elasticity is rather small resulting in small or no effects of employment subsidies. However, my research provides new evidence on labour demand of nonemployer firms especially that has not been studied before. The results are in line with the observation that most nonemployer firms are self-employed persons who are not interested in growing their business to employ others as well, but only provide for themselves. Because of this employment subsidies to the self-employed are not particularly well targeted. The theoretical grounds for the subsidy actually hold for other small firms as well, so it can be argued the subsidy would be more effective if it was extended for hiring the first few employees.

A Spatial Analysis to Permanent Income as Deterrent of Homicides: the case of Medellin City

This paper studies the relationship between permanent income and homicides, estimating an income-crime elasticity. We assume that this elasticity varies across geographical areas. We estimate different specifications of Spatial Panel Models using information of urban areas in Medellin (Colombia), areas known as communes. Spatial Models consider the importance of location and the type of neighbors of each commune. We simulate an intervention over permanent income in order to estimate the income elasticity for each commune and the average elasticity of income-crime on the city. We provide evidence about spatial dependence between the homicides per commune and their neighbors, and about a relationship between homicides and neighbor’s income. In our case of study, the average estimated impact of 1% increase in permanent income in a specific commune produces a decrease in the homicide rate on average in 0.39%. Finally, permanent income plays a crime deterrent role, but also this effect of income on crime varies across the city, showing that some areas are strategically located to this kind of intervention.

Essays on the Effects of Social Insurance for Disability

This dissertation examines how social insurance, family support and work capacity enhance individuals' economic well-being following significant health and income shocks. I first examine the extent to which the liquidity-enhancing effects of Worker's Compensation (WC) benefits outweigh the moral hazard costs. Analyzing administrative data from Oregon, I estimate a hazard model exploiting variation in the timing and size of a retroactive lump-sum WC payment to decompose the elasticity of claim duration with respect to benefits into the elasticity with respect to an increase in cash on hand, and a decrease in the opportunity cost of missing work. I find that the liquidity effect accounts for 60 to 65 percent of the increase in claim duration among lower-wage workers, but less than half of the increase for higher earners. Using the framework from Chetty (2008), I conclude that the insurance value of WC exceeds the distortionary cost, and increasing the benefit level could increase social welfare. Next, I investigate how government-provided disability insurance (DI) interacts with private transfers to disabled individuals from their grown children. Using the Health and Retirement Study, I estimate a fixed effects, difference in differences regression to compare transfers between DI recipients and two control groups: rejected applicants and a reweighted sample of disabled non-applicants. I find that DI reduces the probability of receiving a transfer by no more than 3 percentage points, or 10 percent. Additional analysis reveals that DI could increase the probability of receiving a transfer in cases where children had limited prior information about the disability, suggesting that DI could send a welfare-improving information signal. Finally, Zachary Morris and I examine how a functional assessment could complement medical evaluations in determining eligibility for disability benefits and in targeting return to work interventions. We analyze claimants' self-reported functional capacity in a survey of current DI beneficiaries to estimate the share of disability claimants able to do work-related activity. We estimate that 13 percent of current DI beneficiaries are capable of work-related activity. Furthermore, other characteristics of these higher-functioning beneficiaries are positively correlated with employment, making them an appropriate target for return to work interventions.

Charged pullulan derivatives for the development of nanocarriers by polyelectrolyte complexation

Pullulan, a neutral polysaccharide, was chemically modified in order to obtain two charged derivatives: reaction with SO3(.)DMF complex afforded a sulfate derivative (SP), while reaction with glycidyltrimethylammonium chloride gave a quaternary ammonium salt (AP). The presence of the charged groups was confirmed by FTIR. Assessment of the positions where the reaction took place was based on (1)H- and (13)C NMR (COSY, HSQC-TOCSY, HSQC-DEPT, and HMBC) experiments. Estimation of the degree of substitution (DS) was made from elemental analysis data, and further confirmed by NMR peak areas in the case of AP. These new derivatives showed the capability to condense with each other, forming nanoparticles with the ability to associate a model protein (BSA) and displaying adequate size for drug delivery applications, therefore making them good candidates for the production of pullulan-based nanocarriers by polyelectrolyte complexation.

Rs266882 polymorphism analysis in KLK3 gene by RFLPPCR in cases of prostate cancer

Poster presented at the From Basic Sciences to Clinical Research - First International Congress of CiiEM. Egas Moniz, Caparica, Portugal, 27-28 November 2015

Structural and mechanical properties of La0.6Sr0.4M0.1Fe0.9O3-δ (M: Co, Ni and Cu) perovskites

La0.6Sr0.4M0.1Fe0.9O3-δ (M: Co, Ni and Cu) perovskite nanostructures were synthesized using low frequency ultrasound assisted synthesis technique and effect of substitution of Fe by Co, Ni and Cu on crystal structure and mechanical properties in La0.6Sr0.4FeO3-δ perovskite were studied. The HRTEM and Rietveld refinement analyses revealed the uniform equi-axial shape of the obtained nanostructures with the existence of La0.6Sr0.4M0.1Fe0.9O3−δ with mixed rhombohedral and orthorhombic structures. Substitution of Cu decreases the melting point of La0.6Sr0.4FeO3-δ. The results of mechanical characterizations show that La0.6Sr0.4Co0.1Fe0.9O3−δ and La0.6Sr0.4Ni0.1Fe0.9O3−δ have ferroelastic behavior and comparable elastic moduli, however, subtitution of Ni shows higher hardness and lower fracture toughness than Co in Bsite doping