STIMULATION THROUGH TLR4 INCREASES FVIII INHIBITOR FORMATION IN A MOUSE MODEL OF HEMOPHILIA A

Hemophilia A is a clotting disorder caused by functional factor VIII (FVIII) deficiency. About 25% of patients treated with therapeutic recombinant FVIII develop antibodies (inhibitors) that render subsequent FVIII treatments ineffective. The immune mechanisms of inhibitor formation are not entirely understood, but circumstantial evidence indicates a role for increased inflammatory response, possibly via stimulation of Toll-like receptors (TLRs), at the time of FVIII immunization. I hypothesized that stimulation through TLR4 in conjunction with FVIII treatments would increase the formation of FVIII inhibitors. To test this hypothesis, FVIII K.O. mice were injected with recombinant human FVIII with or without concomitant doses of TLR4 agonist (lipopoysaccharide; LPS). The addition of LPS combined with FVIII significantly increased the rate and the production of anti-FVIII IgG antibodies and neutralizing FVIII inhibitors. In the spleen, repeated in vivo TLR4 stimulation with LPS increased the relative percentage of macrophages and dendritic cells (DCs) over the course of 4 injections. However, repeated in vivo FVIII stimulation significantly increased the density of TLR4 expressed on the surface of all spleen antigen presenting cells (APCs). Culture of splenocytes isolated from mice revealed that the combined stimulation of LPS and FVIII also synergistically increased early secretion of the inflammatory cytokines IL-6, TNF-α, and IL-10, which was not maintained throughout the course of the repeated injections. While cytokine secretion was relatively unchanged in response to FVIII re-stimulation in culture, LPS re-stimulation in culture induced increased and prolonged inflammatory cytokine secretion. Re-stimulation with both LPS and FVIII induced cytokine secretion similar to LPS stimulation alone. Interestingly, long term treatment of mice with LPS alone resulted in splenocytes that showed reduced response to FVIII in culture. Together these results indicated that creating a pro-inflammatory environment through the combined stimulation of chronic, low-dose LPS and FVIII changed not only the populations but also the repertoire of APCs in the spleen, triggering the increased production of FVIII inhibitors. These results suggested an anti-inflammatory regimen should be instituted for all hemophilia A patients to reduce or delay the formation of FVIII inhibitors during replacement therapy.

IL -24; a glycosylated dimeric cytokine affecting monocytes and cytotoxic to melanoma cells

IL-24 is an unusual member of the IL-10 family, which is considered a Th1 cytokine that exhibits tumor cell cytotoxicity. I describe the purification of this novel cytokine from the supernatant of IL-24 gene transfected human embryonic kidney cells and define the biochemical and functional properties of the soluble, human IL-24 protein. ^ I showed IL-24 non-covalently associates with bovine albumin. Immunoaffinity purification followed by cation exchange chromatography resulted in the significant enrichment of N-glycosylated IL-24. This protein elicited dose-dependent secretion of TNF-α and IL-6 from purified human monocytes and TNF-α secretion from PMA differentiated U937 cells. I showed this same protein was cytotoxic to melanoma tumor cells via the induction of IFN-α. ^ I reported IL-24 associates as at least two disulfide linked, N-glycosylated dimers. Enzymatic removal of N-linked-glycosylation from purified IL-24 partially diminished its cytokine and cytotoxic functions. Disruption of IL-24 dimers via reduction and alkylation of intermolecular disulfide bonds nearly abolished IL-24s cytokine function. ^ I elucidated IL-24 induced TNF-α secretion was pSTAT1, pSTAT3 as well as the class II heterodimeric receptors IL-20R1/IL-22R2 independent. I identified a requirement for the heterodimer of Toll-like Receptors 1 and 2 for IL-24s cytokine function and show a physical interaction between IL-24 and the extracellular domain of TLR-1. ^ Thus, I demonstrated that purified N-glycosylated, soluble, dimeric, human IL-24 exhibits both immunomodulatory and anti-cancer activities and these functions remain associated during purification. IL-24 induced TNF-α secretion required an interaction with the heterodimeric receptor TLR-1/2 and IL-24s cytotoxic affect to melanoma tumor cells was in part due to its induction of IFN-β. ^

Unsafe abortion: A neglected crisis in women's health

Women around the world risk their lives to end unwanted pregnancies. Created in 2003 and recently converted to a digital format, this short film highlights the toll that unsafe abortion takes on women and the comprehensive approach that Ipas takes to saving women's lives by improving access to safe abortion and contraception. Since this film was made, deaths from unsafe abortion have thankfully decreased to approximately 47,000 each year. However, the estimated number of unsafe abortions has risen to more than 21 million annually, largely due to the increase in population. We have a long way to go before the scourge of unsafe abortion is eliminated.

Análisis empírico del tráfico en las autopistas de peaje radiales 3 y 5 de Madrid

El propósito de la presente investigación es determinar si, a través del estudio y análisis de los estudios de tráfico en autopistas de peaje, se pueden determinar las razones de los incumplimientos en las previsiones de estos estudios. La metodología se basa en un análisis empírico ex- post facto de los estudios de tráfico contenidos en los anteproyectos de las autopistas Radial 3 y Radial 5 y los datos realmente verificados. Tras una introducción para presentar las principales características de las autopistas de peaje, se realiza una revisión de la bibliografía sobre el cumplimiento de las previsiones de tráfico. Lo anterior permite establecer una serie de aspectos que pueden contribuir a estos incumplimientos, así como una serie de medidas encontradas para mejorar las futuras previsiones. Ya en el núcleo fundamental de la investigación, esta se centra en el análisis del cumplimiento de las previsiones de tráfico contenidas en los anteproyectos de la Radial 3 y Radial 5. Se realiza un análisis crítico de la metodología adoptada, así como de las variables e hipótesis realizadas. Tras este primer análisis, se profundiza en la fase de asignación de los estudios. Siempre con base a los tráficos reales y para el año 2006, se cuantifica el efecto en los incumplimientos, por un lado de las variables utilizadas, y por otro, del propio método ó curva de asignación. Finalmente, y con base en los hallazgos anteriores, se determinan una serie de limitaciones en el método de asignación de tráficos entre recorridos alternativos para el caso de entornos urbanos usado. El planteamiento con base a las teorías del agente racional y maximización de la utilidad esperada es criticado desde la perspectiva de la teoría de decisión bajo condiciones de riesgo planteada por Kahneman y Tversky. Para superar las limitaciones anteriores, se propone una nueva curva de asignación semi empírica que relaciona la proporción del tráfico que circula por la autopista de peaje con la velocidad media en la autovía libre alternativa. ABSTRACT The aim of this research is to confirm whether the forensic analysis of the traffic forecast studies for tolled highways may bring to light the reasons behind the lack of accuracy. The methodology used on this research is empirical and is based on the ex –post facto analysis of the real traffic numbers compared to the forecasted for the tolled highways Radial 3 and Radial 5. Firstly the main features of tolled highways are presented as an introductory chapter. Secondly a broad bibliographic search is presented, this is done from a global perspective and from the Spanish perspective too. From this review, a list of the main causes behind the systematic inaccuracy together with measures to improve future traffic forecast exercises are shown. In what we could consider as the core of the research, it focuses on the ratios of actual / forecast traffic for the tolled highways Radial 3 y Radial 5 in Madrid outskirts. From a critical perspective, the methodology and inputs used in the traffic studies are analysed. In a further step, the trip assignment stage is scrutinised to quantify the influence of the inputs and the assignment model itself in the accuracy of the traffic studies. This exercise is bases on the year 2006. Finally, the assignment model used is criticised for its application in tolled urban highways. The assumptions behind the model, rational agent and expected utility maximization theories, are questioned under the theories presented by Kahneman and Tversky (Prospect Theory). To overcome these assignment model limitations, the author presents a semi empiric new diversion curve. This curve links the traffic proportion using the tolled highway and the average speed in the toll free alternative highway.

E.1027. Maison en bord de mer: Theoretical Restoration

E.1027, Maison en bord de mer is a small villa in Roquebrune Cap-Martin, built by architects Eileen Gray and Jean Badovici between 1926 and 1929. It was hailed as a landmark of modern architecture, and then forgotten. Over the years many transformations have been carried out, and these changes have altered the spatial qualities of the original project. Time and neglect have taken their toll, and until 2008 the villa was abandoned, a shadow of its former self. In order to state an appropriate restoration, a description of the house and its historic evolution has been made, comparing plans of its different transformations. After compiling the most common pathologies and restoration procedures in buildings of the Modern Movement in general, the particular pathologies of E.1027 are presented, concluding with a restoration proposal for E.1027 that considers aesthetical as well as technical aspects. This study involves an attempt to establish guidelines for the theoretical and technical aspects for restoration of architecture of the Modern Movement, using the Maison en bord de mer as an example.

Optimal and Long-Term Dynamic Transport Policy Design: Seeking Maximum Social Welfare through a Pricing Scheme.

This article presents an alternative approach to the decision-making process in transport strategy design. The study explores the possibility of integrating forecasting, assessment and optimization procedures in support of a decision-making process designed to reach the best achievable scenario through mobility policies. Long-term evaluation, as required by a dynamic system such as a city, is provided by a strategic Land-Use and Transport Interaction (LUTI) model. The social welfare achieved by implementing mobility LUTI model policies is measured through a cost-benefit analysis and maximized through an optimization process throughout the evaluation period. The method is tested by optimizing a pricing policy scheme in Madrid on a cordon toll in a context requiring system efficiency, social equity and environmental quality. The optimized scheme yields an appreciable increase in social surplus through a relatively low rate compared to other similar pricing toll schemes. The results highlight the different considerations regarding mobility impacts on the case study area, as well as the major contributors to social welfare surplus. This leads the authors to reconsider the cost-analysis approach, as defined in the study, as the best option for formulating sustainability measures.

Energy- and environmentally efficient road management: The case of the Spanish motorway network

Transport is responsible for 41% of CO2 emissions in Spain, and around 65% of that figure is due to road traffic. Tolled motorways are currently managed according to economic criteria: minimizing operational costs and maximizing revenues from tolls. Within this framework, this paper develops a new methodology for managing motorways based on a target of maximum energy efficiency. It includes technological and demand-driven policies, which are applied to two case studies. Various conclusions emerge from this study. One is, that the use of intelligent payment systems is recommended; and another, is that the most sustainable policy would involve defining the most efficient strategy for each motorway section, including the maximum use of its capacity, the toll level which attracts the most vehicles, and the optimum speed limit for each type of vehicle.

Improving the analysis of road pricing acceptability surveys by using hybrid models

Several international studies have analyzed the acceptability of road pricing schemes by means of an attitude survey in combination with the results of a stated choice experiment using both a descriptive analysis and a discrete-choice model with binary choice (?accept? or ?not accept? the toll). However, the use of hybrid discrete choice models constitutes an innovative alternative for integrating subjective attitudes and perceptions deriving from the survey of attitudes with the more objective variables from the stated choice experiment. This paper analyzes the results of applying these models to measure the acceptability of interurban road pricing among different groups of stakeholders (road freight and passenger operators, highway concessionaires, and associations of private car users) with qualitatively significant opinions on road pricing measures. Our results show that hybrid models are better suited to explaining the acceptability of a road pricing scheme by different groups of stakeholders than a separate analysis of the survey of attitudes and a discrete-choice model applied on a stated choice experiment. A particular finding was that the strong psycho-social latent variable of the perception of fairness explains the rejection or acceptance of a toll scheme by road stakeholders.

Integration of congestion pricing and intertemporal preference rate in social welfare function

Assessing social benefits in transport policy implementation has been studied by many researchers using theoretical or empirical measures. However, few of them measure social benefit using different discount rates including the inter-temporal preferences rate of users, the private investment discount rate and the inter-temporal preferences rate of the government. In general, the social discount rate used is the same for all social actors. Therefore, this paper aims to assess a new method by integrating different types of discount rate belonging to different social actors in order to measure the real benefits of each actor in the short, medium and long term. A dynamic simulation is provided by a strategic Land-Use and Transport Interaction (LUTI) model. The method is tested by optimizing a cordon toll scheme in Madrid considering socio- economic efficiency and environmental criteria. Based on the modified social welfare function (WF), the effects on the measure of social benefits are estimated and compared with the classical WF results as well. The results of this research could be a key issue to understanding the relationship between transport system policies and social actors' benefits distribution in a metropolitan context. The results show that the use of more suitable discount rates for each social actor had an effect on the selection and definition of optimal strategy of congestion pricing. The usefulness of the measure of congestion toll declines more quickly overtime.

Integration of congestion pricing and intertemporal preferences rate integration in social welfare function

Many researchers have used theoretical or empirical measures to assess social benefits in transport policy implementation. However, few have measured social benefits by using discount rates, including the intertemporal preference rate of users, the private investment discount rate, and the intertemporal preference rate of the government. In general, the social discount rate used is the same for all social actors. This paper aims to assess a new method by integrating different types of discount rates belonging to different social actors to measure the real benefits of each actor in the short term, medium term, and long term. A dynamic simulation is provided by a strategic land use and transport interaction model. The method was tested by optimizing a cordon toll scheme in Madrid, Spain. Socioeconomic efficiency and environmental criteria were considered. On the basis of the modified social welfare function, the effects on the measure of social benefits were estimated and compared with the classical welfare function measures. The results show that the use of more suitable discount rates for each social actor had an effect on the selection and definition of optimal strategy of congestion pricing. The usefulness of the measure of congestion toll declines more quickly over time. This result could be the key to understanding the relationship between transport system policies and the distribution of social actors? benefits in a metropolitan context.

A comparative analysis of road financing approaches in Europe and the United States

• The viability of the present system of road funding has in recent years been widely questioned, for it has proved insufficient to support spending programs at their current levels. • Some transfers from the general fund have been needed since 2008 to keep the HTF solvent. • Fuel taxes, the primary source for funding roads in the US, have not kept pace with inflation for years. • A wide variety of measures to increase revenue has been presented: raising fuel taxes, extending toll highways, implementing a VMT fee, etc.

Assessing the impact of adaptive accessibility on the optimal transport policy implementation by using an integrated land-use/transport model for Madrid

Accessibility is an essential concept widely used to evaluate the impact of land-use and transport strategies in transport and urban planning. Accessibility is typically evaluated by using a transport model or a land-use model independently or successively without a feedback loop, thus neglecting the interaction effects between the two systems and the induced competition effects among opportunities due to accessibility improvements. More than a mere methodological curiosity, failure to account for land- use/transport interactions and the competition effect may result in large underestimation of the policy effects. With the recent development of land-use and transport interaction (LUTI) models, there is a growing interest in using these models to adequately measure accessibility and evaluate its impact. The current study joins this research stream by embedding an accessibility measure in a LUTI model with two main aims. The first aim is to account for adaptive accessibility, namely the adjustment of the potential accessibility due to the effect of competition among opportunities (e.g., workplaces) as a result of improved accessibility. LUTI models are particularly suitable for assessing adaptive accessibility because the competition factor is a function of the number of jobs, which is related to land-use attractiveness and the number of workers which is related, among other factors, to the transport demand. The second aim is to identify the optimal implementation scenario of policy measures on the basis of the potential and adaptive accessibility and analyse the results in terms of social welfare and accessibility. The metropolitan area of Madrid is used as a case-study and two transport policy instruments, namely a cordon toll and bus frequency increase, have been chosen for the simulation study in order to present the usefulness of the approach to urban planners and policy makers. The MARS model (Metropolitan Activity Relocation Simulator) calibrated for Madrid was employed as the analysis tool. The impact of accessibility is embedded in the model through a social welfare function that includes not only costs and benefits to both road users and transport operators, but also costs and benefits for the government and society in general (external costs). An optimisation procedure is performed by the MARS model for maximizing the value of objective function in order to find the best (optimal) policy imp lementations intensity (i.e., price, frequency). Last, the two policy strategies are evaluated in terms of their accessibility. Results show that the accessibility with competition factor influences the optimal policy implementation level and also generates different results in terms of social welfare. In addition, mapping the difference between the potential and the adaptive accessibility indicators shows that the main changes occur in areas where there is a strong competition among land-use opportunities.

Empirical analysis of traffic volume for the application of the options theory to highway concessions

*************************************************************************************** EL WCTR es un Congreso de reconocido prestigio internacional en el ámbito de la investigación del transporte que hasta el 2010 publicaba sus libros de abstracts con ISBN. Por ello consideramos que debería seguir teníendose en cuenta para los indicadores de calidad ******************************************************************************************* Investment projects in the field of transportation infrastructures have a high degree of uncertainty and require an important amount of resources. In highway concessions in particular, the calculation of the Net Present Value (NPV) of the project by means of the discount of cash flows, may lead to erroneous results when the project incorporates certain flexibility. In these cases, the theory of real options is an alternative tool for the valuation of concessions. When the variable that generates uncertainty (in our case, the traffic) follows a random walk (or Geometric Brownian Motion), we can calculate the value of the options embedded in the contract starting directly from the process followed by that variable. This procedure notably simplifies the calculation method. In order to test the hypothesis of the evolution of traffic as a Geometric Brownian Motion, we have used the available series of traffic in Spanish highways, and we have applied the Augmented Dickey-Fuller approach, which is the most widely used test for this kind of study. The main result of the analysis is that we cannot reject the hypothesis that traffic follows a Geometric Brownian Motion in the majority of both toll highways and free highways in Spain.

Optimal and Long-Term Dynamic Transport Policy Design: Seeking Maximum Social Welfare through a Pricing Scheme

This article presents an alternative approach to the decision-making process in transport strategy design. The study explores the possibility of integrating forecasting, assessment and optimization procedures in support of a decision-making process designed to reach the best achievable scenario through mobility policies. Long-term evaluation, as required by a dynamic system such as a city, is provided by a strategic Land-Use and Transport Interaction (LUTI) model. The social welfare achieved by implementing mobility LUTI model policies is measured through a cost-benefit analysis and maximized through an optimization process throughout the evaluation period. The method is tested by optimizing a pricing policy scheme in Madrid on a cordon toll in a context requiring system efficiency, social equity and environmental quality. The optimized scheme yields an appreciable increase in social surplus through a relatively low rate compared to other similar pricing toll schemes. The results highlight the different considerations regarding mobility impacts on the case study area, as well as the major contributors to social welfare surplus. This leads the authors to reconsider the cost-analysis approach, as defined in the study, as the best option for formulating sustainability measures.

Regret theory-based scenario building using an interacttive process

This paper is an introduction of the regret theory-based scenario building approach combining with a modified Delphi method that uses an interactive process to design and assess four different TDM measures (i.e., cordon toll, parking charge, increased bus frequency and decreased bus fare). The case study of Madrid is used to present the analysis and provide policy recommendations. The new scenario building approach incorporates expert judgement and transport models in an interactive process. It consists of a two-round modified Delphi survey, which was answeared by a group of Spanish transport experts who were the participants of the Transport Engineering Congress (CIT 2012), and an integrated land-use and transport model (LUTI) for Madrid that is called MARS (Metropolitan Activity Relocation Simulator).