Why does low dose morphine augment fentanyl analgesia?

Opioids dominate the field of pain management because of their ability to provide analgesia in many medical circumstances. However, side effects including respiratory depression, constipation, tolerance, physical dependence, and the risk of addiction limit their clinical utility. Fear of these side effects results in the under-treatment of acute pain. For many years, research has focused on ways to improve the therapeutic index (the ratio of desirable analgesic effects to undesirable side effects) of opioids. One strategy, combining opioid agonists that bind to different opioid receptor types, may prove successful.^ We discovered that subcutaneous co-administration of a moderately analgesic dose of the mu-opioid receptor (MOR) selective agonist fentanyl (20μg/kg) with subanalgesic doses of the less MOR-specific agonist morphine (100ng/kg-100μg/kg), augmented acute fentanyl analgesia in rats. Parallel [35S]GTPγS binding studies using naïve rat substantia gelatinosa membrane treated with fentanyl (4μM) and morphine (1nM-1pM) demonstrated a 2-fold increase in total G-protein activation. This correlation between morphine-induced augmentation of fentanyl analgesia and G-protein activation led to our proposal that interactions between MORs and DORs underlie opioid-induced augmentation. We discovered that morphine-induced augmentation of fentanyl analgesia and G-protein activity was mediated by DORs. Adding the DOR-selective antagonist naltrindole (200ng/kg, 40nM) at doses that did not alter the analgesic or G-protein activation of fentanyl, blocked increases in analgesia and G-protein activation induced by fentanyl/morphine combinations. Equivalent doses of the MOR-selective antagonist cyprodime (20ng/kg, 4nM) did not block augmentation. Substitution of the DOR-selective agonist SNC80 for morphine yielded similar results, further supporting our conclusion that interactions between MORs and DORs are responsible for morphine-induced augmentation of fentanyl analgesia and G-protein activation. Confocal microscopy of rat substantia gelatinosa showed that changes in the rate of opioid receptor internalization did not account for these effects.^ In conclusion, fentanyl analgesia augmentation by subanalgesic morphine is mediated by increased G-protein activation resulting from functional interactions between MORs and DORs, not changes in MOR internalization. Additional animal and clinical studies are needed to determine whether side effect incidence changes following opioid co-administration. If side effect incidence decreases or remains unchanged, these findings could have important implications for clinical pain treatment. ^

Determinants of patients' expectations about total knee arthroplasty outcomes

Knee osteoarthritis (OA) is the most prevalent form of arthritis in the US, affecting approximately 37% of adults. Approximately 300,000 total knee arthroplasty (TKA) procedures take place in the United States each year. Total knee arthroplasty is an elective procedure available to patients as an irreversible treatment after failure of previous medical treatments. Some patients sacrifice quality of life and endure many years of pain before making the decision to undergo total knee replacement. In making their decision, it is therefore imperative for patients to understand the procedure, risks and surgical outcomes to create realistic expectations and increase outcome satisfaction. ^ From 2004-2007, 236 OA patients who underwent TKA participated in the PEAKS (Patient Expectations About Knee Surgery) study, an observational longitudinal cohort study, completed baseline and 6 month follow-up questionnaires after the surgery. We performed a secondary data analysis of the PEAKS study to: (1) determine the specific presurgical patient characteristics associated with patients’ presurgical expectations of time to functional recovery; and (2) determine the association between presurgical expectations of time to functional recovery and postsurgical patient capabilities (6 months after TKA). We utilized the WOMAC to measure knee pain and function, the SF-36 to measure health-related quality of life, and the DASS and MOS-SSS to measure psychosocial quality of life variables. Expectation and capability measures were generated from panel of experts. A list of 10 activities was used for this analysis to measure functional expectations and postoperative functional capabilities. ^ The final cohort consisted of 236 individuals, was predominately White with 154 women and 82 men. The mean age was 65 years. Patients were optimistic about their time to functional recovery. Expectation time of being able to perform the list activities per patient had a median of less than 3 months. Patients who expected to be able to perform the functional activities by 3 months had better knee function, less pain and better overall health-related quality of life. Despite expectation differences, all patients showed significant improvement 6 months after surgery. Participant expectation of time to functional recovery was not an independent predictor of capability to perform functional activities at 6 months. Better presurgical patient characteristics were, however, associated with a higher likelihood of being able to perform all activities at 6 months. ^ This study gave us initial insight on the relationship between presurgical patient characteristics and their expectations of functional recovery after total knee replacement. Future studies clarifying the relationship between patient presurgical characteristics and postsurgical functional capabilities are needed.^

In vivo longitudinal studies of spinal cord injury and vascular endothelial growth factor treatment

Approximately 12,000 new cases of spinal cord injury (SCI) are added each year to the estimated 259,000 Americans living with SCI. The majority of these patients return to society, their lives forever changed by permanent loss of sensory and motor function. While there are no FDA approved drugs for the treatment of SCI or a universally accepted standard therapy, the current though controversial treatment includes the delivery of high dosages of the corticosteroid methyliprednisolone sodium succinate, surgical interventions to stabilize the spinal column, and physical rehabilitation. It is therefore critically important to fully understand the pathology of injury and determine novel courses and rationally-based therapies for SCI. ^ Vascular endothelial growth factor (VEGF) is an attractive target for treating central nervous system (CNS) injury and disease because it has been shown to influence angiogenesis and neuroprotection. Preliminary studies have indicated that increased vasculature may be associated with functional recovery; therefore exogenous delivery of a pro-angiogenic growth factor such as VEGF may improve neurobehavioral outcome. In addition, VEGF may provide protection from secondary injury and result in increased survival and axonal sprouting. ^ In these studies, SCI rats received acute intraspinal injections of VEGF, the antibody to VEGF, or vehicle control. The effect of these various agents was investigated using longitudinalmulti-modal magnetic resonance imaging (MRI), neuro- and sensory behavioral assays, and end point immunohistochemistry. We found that rats that received VEGF after SCI had increased tissue sparing and improved white matter integrity at the earlier time points as shown by advanced magnetic resonance imaging (MRI) techniques. However, these favorable effects of VEGF were not maintained, suggesting that additional treatments with VEGF at multiple time points may be more beneficial, Histological examinations revealed that VEGF treatment may result in increased oligodendrogenesis and therefore may eventually lead to remyelination and improved functional outcome. ^ On the neurobehavioral studies, treatments with VEGF and Anti-VEGF did not significantly affect performance on tests of open-field locomotion, grid walk, inclined plane, or rearing. However, VEGF treatment resulted in significantly increased incidence of chronic neuropathic pain. This phenomenon could possibly be attributed to the fact that VEGF treatment may promote axonal sprouting and also results in tissue sparing, thereby providing a substrate for the growth of new axons. New connections made by these sprouting axons may involve components of pathways involved in the transmission of pain and therefore result in increased pain in those animals. ^

Process to develop a State Model Law to reduce prescription drug trafficking while protecting pain management

This paper will discuss the intersection of pill mills and the under-treatment of pain, while addressing the unintended consequence that cracking down on pill mills actually has on medical professionals' treatment of legitimate pain in clinical settings. Moreover, the impact each issue has on the spectrum of related policy, regulatory issues and legislation will be analyzed while addressing the national impact on medical care. Lastly, this paper will outline a process to develop a State Model Law on this subject. This process will include suggestions for the future and how we can move forward to adequately address public safety needs and how we can attempt to mitigate the unintended impact prescription drug trafficking has had on a patient's right to appropriate pain management. This balance is achievable and this paper will address ways we can find this elusive balancing point through the development of a State Model Law. ^

Distribution of quality adjusted life expectancy: A systems approach

Statistical methods are developed which assess survival data for two attributes; (1) prolongation of life, (2) quality of life. Health state transition probabilities correspond to prolongation of life and are modeled as a discrete-time semi-Markov process. Imbedded within the sojourn time of a particular health state are the quality of life transitions. They reflect events which differentiate perceptions of pain and suffering over a fixed time period. Quality of life transition probabilities are derived from the assumptions of a simple Markov process. These probabilities depend on the health state currently occupied and the next health state to which a transition is made. Utilizing the two forms of attributes the model has the capability to estimate the distribution of expected quality adjusted life years (in addition to the distribution of expected survival times). The expected quality of life can also be estimated within the health state sojourn time making more flexible the assessment of utility preferences. The methods are demonstrated on a subset of follow-up data from the Beta Blocker Heart Attack Trial (BHAT). This model contains the structure necessary to make inferences when assessing a general survival problem with a two dimensional outcome. ^

Health status of Saudi women, the case of Yanbu al-Sinaiya

Detailed data on the health status of Saudi women are lacking. This cross sectional study attempts to provide a comprehensive description of the health status of Saudi females between the ages of 15-45 residing in Yanbu Al-Siniyah. The purpose is to assess women's needs for health services. The health status indicators are chronic tracer conditions, reported symptoms and multidimensional functioning levels. The generic functioning instrument of the Medical Outcome Study was used to estimate physical, social, and role functioning; degree of pain and health perceptions. The information was obtained by interviewing subjects and abstracting facts from their medical records. The results show functioning scores are in the "well health" range for physical, social, role and pain. Crowding and education have an equal or stronger effect of reducing functioning levels than the diagnosed tracer conditions. The highest prevalence conditions having a definite functional impact and diagnosed adequately in primary care are anemia, urinary tract infection, hemorrhoids, rheumatoid arthritis, caries and gingivitis. Reported symptoms strongly reducing function levels in this study are dyspnea, heart pain, incontinence, eye and skin problems, and joint ache. The impact of the reliability and validity of the measures used and other limitations of the results are discussed. Finally, some policy implications and suggestions for future study are presented. ^

Escala de medición del miedo a la atención dental

El miedo al dolor constituye un obstáculo que interfiere la consul- ta dental del paciente y, con el objeto de prevenirlos, se diseña una escala de exploración del miedo a la consulta dental y de las estra- tegias deseables para disminuirlo. Se utilizó el Método de Escalonamiento de Likert y se aplicó a 105 pacientes en la Facultad de Odontología de la Universidad Nacional de Cuyo, Mendoza. Los pacientes responden que sienten mucho miedo a que el odontólo- go pueda trasmitirles una infección, ser revisados sin guantes, o que no se los cambie, y a las consecuencias de la mala higiene. En segundo lugar tienen mucho miedo a que el odontólogo pueda tocar un nervio, que perfore excesivamente, que se quiebre una pieza dentaria o se equivoque en el diagnóstico. La mayoría desea ser tratada comprensivamente y que se le explique los procedi- mientos y anticipe lo que va a sentir.

Strength and stiffness of repaired tendons

Rotator cuff tears of the shoulder are a common cause of pain and disability. Although surgery is frequently beneficial, re-tearing of the tendons is likely to re-occur. In many cases even if the reparation is successful it will still generate discomfort, problems with mobility, as well as a sharp pain. This project is funded in the cooperation with the Hospital Clinico San Carlos de Madrid. The purpose of this work is to analyze the effect of the surgical repair and the application of different therapies, including mesenchymal stem cell therapy on the biomechanical properties (strength and stiffness) of the repaired tendon. An animal model of rotator cuff tendon reparations has been developed on laboratory rats.To obtain the mechanical response of the healthy and repaired tendons, it was necessary to develop an experimental set up to reproduce the in-vivo working conditions of the tendons (37 ºC, immersed in physiological serum), and especially the load transfer. The biomechanical properties (maximum load and stiffness) have been measured in healthy and repaired tendons. A total of 70 rats are used in this particular study. It has been found that the repaired tendon is stronger than the original on. However, the repaired tendons demonstrate less flexibility than the healthy (original) ones prior to the damage

Central pain augmentation in fibromyalgia during subjectively-matched mechanical stimulation

The precise pathophysiology of fibromyalgia, a syndrome characterized by, among other symptoms, chronic widespread pain, remains to be elucidated (Abeles et al., 2007). The fact that, when subjected to the same amount of stimulation, patients show enhanced brain responses as compared to controls provides evidence of central pain augmentation in this syndrome. We aimed to characterize brain response differences when stimulation is adjusted to elicit similar subjective levels of pain in both groups.

Trust-ware: A Methodology to Analyze, Design, and Secure Trust and Reputation Systems

Entendemos por inteligencia colectiva una forma de inteligencia que surge de la colaboración y la participación de varios individuos o, siendo más estrictos, varias entidades. En base a esta sencilla definición podemos observar que este concepto es campo de estudio de las más diversas disciplinas como pueden ser la sociología, las tecnologías de la información o la biología, atendiendo cada una de ellas a un tipo de entidades diferentes: seres humanos, elementos de computación o animales. Como elemento común podríamos indicar que la inteligencia colectiva ha tenido como objetivo el ser capaz de fomentar una inteligencia de grupo que supere a la inteligencia individual de las entidades que lo forman a través de mecanismos de coordinación, cooperación, competencia, integración, diferenciación, etc. Sin embargo, aunque históricamente la inteligencia colectiva se ha podido desarrollar de forma paralela e independiente en las distintas disciplinas que la tratan, en la actualidad, los avances en las tecnologías de la información han provocado que esto ya no sea suficiente. Hoy en día seres humanos y máquinas a través de todo tipo de redes de comunicación e interfaces, conviven en un entorno en el que la inteligencia colectiva ha cobrado una nueva dimensión: ya no sólo puede intentar obtener un comportamiento superior al de sus entidades constituyentes sino que ahora, además, estas inteligencias individuales son completamente diferentes unas de otras y aparece por lo tanto el doble reto de ser capaces de gestionar esta gran heterogeneidad y al mismo tiempo ser capaces de obtener comportamientos aún más inteligentes gracias a las sinergias que los distintos tipos de inteligencias pueden generar. Dentro de las áreas de trabajo de la inteligencia colectiva existen varios campos abiertos en los que siempre se intenta obtener unas prestaciones superiores a las de los individuos. Por ejemplo: consciencia colectiva, memoria colectiva o sabiduría colectiva. Entre todos estos campos nosotros nos centraremos en uno que tiene presencia en la práctica totalidad de posibles comportamientos inteligentes: la toma de decisiones. El campo de estudio de la toma de decisiones es realmente amplio y dentro del mismo la evolución ha sido completamente paralela a la que citábamos anteriormente en referencia a la inteligencia colectiva. En primer lugar se centró en el individuo como entidad decisoria para posteriormente desarrollarse desde un punto de vista social, institucional, etc. La primera fase dentro del estudio de la toma de decisiones se basó en la utilización de paradigmas muy sencillos: análisis de ventajas e inconvenientes, priorización basada en la maximización de algún parámetro del resultado, capacidad para satisfacer los requisitos de forma mínima por parte de las alternativas, consultas a expertos o entidades autorizadas o incluso el azar. Sin embargo, al igual que el paso del estudio del individuo al grupo supone una nueva dimensión dentro la inteligencia colectiva la toma de decisiones colectiva supone un nuevo reto en todas las disciplinas relacionadas. Además, dentro de la decisión colectiva aparecen dos nuevos frentes: los sistemas de decisión centralizados y descentralizados. En el presente proyecto de tesis nos centraremos en este segundo, que es el que supone una mayor atractivo tanto por las posibilidades de generar nuevo conocimiento y trabajar con problemas abiertos actualmente así como en lo que respecta a la aplicabilidad de los resultados que puedan obtenerse. Ya por último, dentro del campo de los sistemas de decisión descentralizados existen varios mecanismos fundamentales que dan lugar a distintas aproximaciones a la problemática propia de este campo. Por ejemplo el liderazgo, la imitación, la prescripción o el miedo. Nosotros nos centraremos en uno de los más multidisciplinares y con mayor capacidad de aplicación en todo tipo de disciplinas y que, históricamente, ha demostrado que puede dar lugar a prestaciones muy superiores a otros tipos de mecanismos de decisión descentralizados: la confianza y la reputación. Resumidamente podríamos indicar que confianza es la creencia por parte de una entidad que otra va a realizar una determinada actividad de una forma concreta. En principio es algo subjetivo, ya que la confianza de dos entidades diferentes sobre una tercera no tiene porqué ser la misma. Por otro lado, la reputación es la idea colectiva (o evaluación social) que distintas entidades de un sistema tiene sobre otra entidad del mismo en lo que respecta a un determinado criterio. Es por tanto una información de carácter colectivo pero única dentro de un sistema, no asociada a cada una de las entidades del sistema sino por igual a todas ellas. En estas dos sencillas definiciones se basan la inmensa mayoría de sistemas colectivos. De hecho muchas disertaciones indican que ningún tipo de organización podría ser viable de no ser por la existencia y la utilización de los conceptos de confianza y reputación. A partir de ahora, a todo sistema que utilice de una u otra forma estos conceptos lo denominaremos como sistema de confianza y reputación (o TRS, Trust and Reputation System). Sin embargo, aunque los TRS son uno de los aspectos de nuestras vidas más cotidianos y con un mayor campo de aplicación, el conocimiento que existe actualmente sobre ellos no podría ser más disperso. Existen un gran número de trabajos científicos en todo tipo de áreas de conocimiento: filosofía, psicología, sociología, economía, política, tecnologías de la información, etc. Pero el principal problema es que no existe una visión completa de la confianza y reputación en su sentido más amplio. Cada disciplina focaliza sus estudios en unos aspectos u otros dentro de los TRS, pero ninguna de ellas trata de explotar el conocimiento generado en el resto para mejorar sus prestaciones en su campo de aplicación concreto. Aspectos muy detallados en algunas áreas de conocimiento son completamente obviados por otras, o incluso aspectos tratados por distintas disciplinas, al ser estudiados desde distintos puntos de vista arrojan resultados complementarios que, sin embargo, no son aprovechados fuera de dichas áreas de conocimiento. Esto nos lleva a una dispersión de conocimiento muy elevada y a una falta de reutilización de metodologías, políticas de actuación y técnicas de una disciplina a otra. Debido su vital importancia, esta alta dispersión de conocimiento se trata de uno de los principales problemas que se pretenden resolver con el presente trabajo de tesis. Por otro lado, cuando se trabaja con TRS, todos los aspectos relacionados con la seguridad están muy presentes ya que muy este es un tema vital dentro del campo de la toma de decisiones. Además también es habitual que los TRS se utilicen para desempeñar responsabilidades que aportan algún tipo de funcionalidad relacionada con el mundo de la seguridad. Por último no podemos olvidar que el acto de confiar está indefectiblemente unido al de delegar una determinada responsabilidad, y que al tratar estos conceptos siempre aparece la idea de riesgo, riesgo de que las expectativas generadas por el acto de la delegación no se cumplan o se cumplan de forma diferente. Podemos ver por lo tanto que cualquier sistema que utiliza la confianza para mejorar o posibilitar su funcionamiento, por su propia naturaleza, es especialmente vulnerable si las premisas en las que se basa son atacadas. En este sentido podemos comprobar (tal y como analizaremos en más detalle a lo largo del presente documento) que las aproximaciones que realizan las distintas disciplinas que tratan la violación de los sistemas de confianza es de lo más variado. únicamente dentro del área de las tecnologías de la información se ha intentado utilizar alguno de los enfoques de otras disciplinas de cara a afrontar problemas relacionados con la seguridad de TRS. Sin embargo se trata de una aproximación incompleta y, normalmente, realizada para cumplir requisitos de aplicaciones concretas y no con la idea de afianzar una base de conocimiento más general y reutilizable en otros entornos. Con todo esto en cuenta, podemos resumir contribuciones del presente trabajo de tesis en las siguientes. • La realización de un completo análisis del estado del arte dentro del mundo de la confianza y la reputación que nos permite comparar las ventajas e inconvenientes de las diferentes aproximación que se realizan a estos conceptos en distintas áreas de conocimiento. • La definición de una arquitectura de referencia para TRS que contempla todas las entidades y procesos que intervienen en este tipo de sistemas. • La definición de un marco de referencia para analizar la seguridad de TRS. Esto implica tanto identificar los principales activos de un TRS en lo que respecta a la seguridad, así como el crear una tipología de posibles ataques y contramedidas en base a dichos activos. • La propuesta de una metodología para el análisis, el diseño, el aseguramiento y el despliegue de un TRS en entornos reales. Adicionalmente se exponen los principales tipos de aplicaciones que pueden obtenerse de los TRS y los medios para maximizar sus prestaciones en cada una de ellas. • La generación de un software que permite simular cualquier tipo de TRS en base a la arquitectura propuesta previamente. Esto permite evaluar las prestaciones de un TRS bajo una determinada configuración en un entorno controlado previamente a su despliegue en un entorno real. Igualmente es de gran utilidad para evaluar la resistencia a distintos tipos de ataques o mal-funcionamientos del sistema. Además de las contribuciones realizadas directamente en el campo de los TRS, hemos realizado aportaciones originales a distintas áreas de conocimiento gracias a la aplicación de las metodologías de análisis y diseño citadas con anterioridad. • Detección de anomalías térmicas en Data Centers. Hemos implementado con éxito un sistema de deteción de anomalías térmicas basado en un TRS. Comparamos la detección de prestaciones de algoritmos de tipo Self-Organized Maps (SOM) y Growing Neural Gas (GNG). Mostramos como SOM ofrece mejores resultados para anomalías en los sistemas de refrigeración de la sala mientras que GNG es una opción más adecuada debido a sus tasas de detección y aislamiento para casos de anomalías provocadas por una carga de trabajo excesiva. • Mejora de las prestaciones de recolección de un sistema basado en swarm computing y odometría social. Gracias a la implementación de un TRS conseguimos mejorar las capacidades de coordinación de una red de robots autónomos distribuidos. La principal contribución reside en el análisis y la validación de las mejoras increméntales que pueden conseguirse con la utilización apropiada de la información existente en el sistema y que puede ser relevante desde el punto de vista de un TRS, y con la implementación de algoritmos de cálculo de confianza basados en dicha información. • Mejora de la seguridad de Wireless Mesh Networks contra ataques contra la integridad, la confidencialidad o la disponibilidad de los datos y / o comunicaciones soportadas por dichas redes. • Mejora de la seguridad de Wireless Sensor Networks contra ataques avanzamos, como insider attacks, ataques desconocidos, etc. Gracias a las metodologías presentadas implementamos contramedidas contra este tipo de ataques en entornos complejos. En base a los experimentos realizados, hemos demostrado que nuestra aproximación es capaz de detectar y confinar varios tipos de ataques que afectan a los protocoles esenciales de la red. La propuesta ofrece unas velocidades de detección muy altas así como demuestra que la inclusión de estos mecanismos de actuación temprana incrementa significativamente el esfuerzo que un atacante tiene que introducir para comprometer la red. Finalmente podríamos concluir que el presente trabajo de tesis supone la generación de un conocimiento útil y aplicable a entornos reales, que nos permite la maximización de las prestaciones resultantes de la utilización de TRS en cualquier tipo de campo de aplicación. De esta forma cubrimos la principal carencia existente actualmente en este campo, que es la falta de una base de conocimiento común y agregada y la inexistencia de una metodología para el desarrollo de TRS que nos permita analizar, diseñar, asegurar y desplegar TRS de una forma sistemática y no artesanal y ad-hoc como se hace en la actualidad. ABSTRACT By collective intelligence we understand a form of intelligence that emerges from the collaboration and competition of many individuals, or strictly speaking, many entities. Based on this simple definition, we can see how this concept is the field of study of a wide range of disciplines, such as sociology, information science or biology, each of them focused in different kinds of entities: human beings, computational resources, or animals. As a common factor, we can point that collective intelligence has always had the goal of being able of promoting a group intelligence that overcomes the individual intelligence of the basic entities that constitute it. This can be accomplished through different mechanisms such as coordination, cooperation, competence, integration, differentiation, etc. Collective intelligence has historically been developed in a parallel and independent way among the different disciplines that deal with it. However, this is not enough anymore due to the advances in information technologies. Nowadays, human beings and machines coexist in environments where collective intelligence has taken a new dimension: we yet have to achieve a better collective behavior than the individual one, but now we also have to deal with completely different kinds of individual intelligences. Therefore, we have a double goal: being able to deal with this heterogeneity and being able to get even more intelligent behaviors thanks to the synergies that the different kinds of intelligence can generate. Within the areas of collective intelligence there are several open topics where they always try to get better performances from groups than from the individuals. For example: collective consciousness, collective memory, or collective wisdom. Among all these topics we will focus on collective decision making, that has influence in most of the collective intelligent behaviors. The field of study of decision making is really wide, and its evolution has been completely parallel to the aforementioned collective intelligence. Firstly, it was focused on the individual as the main decision-making entity, but later it became involved in studying social and institutional groups as basic decision-making entities. The first studies within the decision-making discipline were based on simple paradigms, such as pros and cons analysis, criteria prioritization, fulfillment, following orders, or even chance. However, in the same way that studying the community instead of the individual meant a paradigm shift within collective intelligence, collective decision-making means a new challenge for all the related disciplines. Besides, two new main topics come up when dealing with collective decision-making: centralized and decentralized decision-making systems. In this thesis project we focus in the second one, because it is the most interesting based on the opportunities to generate new knowledge and deal with open issues in this area, as well as these results can be put into practice in a wider set of real-life environments. Finally, within the decentralized collective decision-making systems discipline, there are several basic mechanisms that lead to different approaches to the specific problems of this field, for example: leadership, imitation, prescription, or fear. We will focus on trust and reputation. They are one of the most multidisciplinary concepts and with more potential for applying them in every kind of environments. Besides, they have historically shown that they can generate better performance than other decentralized decision-making mechanisms. Shortly, we say trust is the belief of one entity that the outcome of other entities’ actions is going to be in a specific way. It is a subjective concept because the trust of two different entities in another one does not have to be the same. Reputation is the collective idea (or social evaluation) that a group of entities within a system have about another entity based on a specific criterion. Thus, it is a collective concept in its origin. It is important to say that the behavior of most of the collective systems are based on these two simple definitions. In fact, a lot of articles and essays describe how any organization would not be viable if the ideas of trust and reputation did not exist. From now on, we call Trust an Reputation System (TRS) to any kind of system that uses these concepts. Even though TRSs are one of the most common everyday aspects in our lives, the existing knowledge about them could not be more dispersed. There are thousands of scientific works in every field of study related to trust and reputation: philosophy, psychology, sociology, economics, politics, information sciences, etc. But the main issue is that a comprehensive vision of trust and reputation for all these disciplines does not exist. Every discipline focuses its studies on a specific set of topics but none of them tries to take advantage of the knowledge generated in the other disciplines to improve its behavior or performance. Detailed topics in some fields are completely obviated in others, and even though the study of some topics within several disciplines produces complementary results, these results are not used outside the discipline where they were generated. This leads us to a very high knowledge dispersion and to a lack in the reuse of methodologies, policies and techniques among disciplines. Due to its great importance, this high dispersion of trust and reputation knowledge is one of the main problems this thesis contributes to solve. When we work with TRSs, all the aspects related to security are a constant since it is a vital aspect within the decision-making systems. Besides, TRS are often used to perform some responsibilities related to security. Finally, we cannot forget that the act of trusting is invariably attached to the act of delegating a specific responsibility and, when we deal with these concepts, the idea of risk is always present. This refers to the risk of generated expectations not being accomplished or being accomplished in a different way we anticipated. Thus, we can see that any system using trust to improve or enable its behavior, because of its own nature, is especially vulnerable if the premises it is based on are attacked. Related to this topic, we can see that the approaches of the different disciplines that study attacks of trust and reputation are very diverse. Some attempts of using approaches of other disciplines have been made within the information science area of knowledge, but these approaches are usually incomplete, not systematic and oriented to achieve specific requirements of specific applications. They never try to consolidate a common base of knowledge that could be reusable in other context. Based on all these ideas, this work makes the following direct contributions to the field of TRS: • The compilation of the most relevant existing knowledge related to trust and reputation management systems focusing on their advantages and disadvantages. • We define a generic architecture for TRS, identifying the main entities and processes involved. • We define a generic security framework for TRS. We identify the main security assets and propose a complete taxonomy of attacks for TRS. • We propose and validate a methodology to analyze, design, secure and deploy TRS in real-life environments. Additionally we identify the principal kind of applications we can implement with TRS and how TRS can provide a specific functionality. • We develop a software component to validate and optimize the behavior of a TRS in order to achieve a specific functionality or performance. In addition to the contributions made directly to the field of the TRS, we have made original contributions to different areas of knowledge thanks to the application of the analysis, design and security methodologies previously presented: • Detection of thermal anomalies in Data Centers. Thanks to the application of the TRS analysis and design methodologies, we successfully implemented a thermal anomaly detection system based on a TRS.We compare the detection performance of Self-Organized- Maps and Growing Neural Gas algorithms. We show how SOM provides better results for Computer Room Air Conditioning anomaly detection, yielding detection rates of 100%, in training data with malfunctioning sensors. We also show that GNG yields better detection and isolation rates for workload anomaly detection, reducing the false positive rate when compared to SOM. • Improving the performance of a harvesting system based on swarm computing and social odometry. Through the implementation of a TRS, we achieved to improve the ability of coordinating a distributed network of autonomous robots. The main contribution lies in the analysis and validation of the incremental improvements that can be achieved with proper use information that exist in the system and that are relevant for the TRS, and the implementation of the appropriated trust algorithms based on such information. • Improving Wireless Mesh Networks security against attacks against the integrity, confidentiality or availability of data and communications supported by these networks. Thanks to the implementation of a TRS we improved the detection time rate against these kind of attacks and we limited their potential impact over the system. • We improved the security of Wireless Sensor Networks against advanced attacks, such as insider attacks, unknown attacks, etc. Thanks to the TRS analysis and design methodologies previously described, we implemented countermeasures against such attacks in a complex environment. In our experiments we have demonstrated that our system is capable of detecting and confining various attacks that affect the core network protocols. We have also demonstrated that our approach is capable of rapid attack detection. Also, it has been proven that the inclusion of the proposed detection mechanisms significantly increases the effort the attacker has to introduce in order to compromise the network. Finally we can conclude that, to all intents and purposes, this thesis offers a useful and applicable knowledge in real-life environments that allows us to maximize the performance of any system based on a TRS. Thus, we deal with the main deficiency of this discipline: the lack of a common and complete base of knowledge and the lack of a methodology for the development of TRS that allow us to analyze, design, secure and deploy TRS in a systematic way.

Signal changes in the spinal cord of the rat after injection of formalin into the hindpaw: Characterization using functional magnetic resonance imaging

Changes in metabolism and local circulation occur in the spinal cord during peripheral noxious stimulation. Evidence is presented that this stimulation also causes signal intensity alterations in functional magnetic resonance images of the spinal cord during formalin-induced pain. These results indicate the potential of functional magnetic resonance imaging in assessing noninvasively the extent and intensity of spinal cord excitation in this well characterized pain model. Therefore, the aim of this study was to establish functional magnetic resonance imaging as a noninvasive method to characterize temporal changes in the spinal cord after a single injection of 50 μl of formalin subcutaneously into the hindpaw of the anesthetized rat. This challenge produced a biphasic licking activity in the freely moving conscious animal. Images of the spinal cord were acquired within 2 min, enabling monitoring of the site and the temporal evolution of the signal changes during the development of formalin-induced hyperalgesia without the need of any surgical procedure. The time course of changes in the spinal cord functional image in the isoflurane-anesthetized animal was similar to that obtained from behavioral experiments. Also, comparable physiological data, control experiments, and the inhibition of a response through application of the local anesthetic agent lidocaine indicate that the signal changes observed after formalin injection were specifically related to excitability changes in the relevant segments of the lumbar spinal cord. This approach could be useful to characterize different models of pain and hyperalgesia and, more importantly, to evaluate effects of analgesic drugs.

Abolition of morphine-immunosuppression in mice lacking the μ-opioid receptor gene

Opiates are potent analgesic and addictive compounds. They also act on immune responses, and morphine, the prototypic opiate, has been repeatedly described as an immunosuppressive drug. Pharmacological studies have suggested that the inhibitory action of opiates on immunity is mediated by multiple opioid receptor sites but molecular evidence has remained elusive. Recently, three genes encoding μ- (MOR), δ-, and κ-opioid receptors have been cloned. To investigate whether the μ-opioid receptor is functionally implicated in morphine immunosuppression in vivo, we have examined immune responses of mice with a genetic disruption of the MOR gene. In the absence of drug, there was no difference between wild-type and mutant mice with regard to a large number of immunological endpoints, suggesting that the lack of MOR-encoded protein has little consequence on immune status. Chronic morphine administration induced lymphoid organ atrophy, diminished the ratio of CD4+CD8+ cells in the thymus and strongly reduced natural killer activity in wild-type mice. None of these effects was observed in MOR-deficient mice after morphine treatment. This demonstrates that the MOR gene product represents a major molecular target for morphine action on the immune system. Because our previous studies of MOR-deficient mice have shown that this receptor protein is also responsible for morphine analgesia, reward, and physical dependence, the present results imply that MOR-targeted therapeutic drugs that are developed for the treatment of pain or opiate addiction may concomitantly influence immune responses.

Preferential synaptic relationships between substance P-immunoreactive boutons and neurokinin 1 receptor sites in the rat spinal cord

Substance P plays an important role in the transmission of pain-related information in the dorsal horn of the spinal cord. Recent immunocytochemical studies have shown a mismatch between the distribution of substance P and its receptor in the superficial laminae of the dorsal horn. Because such a mismatch was not observed by using classical radioligand binding studies, we decided to investigate further the issue of the relationship between substance P and its receptor by using an antibody raised against a portion of the carboxyl terminal of the neurokinin 1 receptor and a bispecific monoclonal antibodies against substance P and horseradish peroxidase. Light microscopy revealed a good correlation between the distributions of substance P and the neurokinin 1 receptor, both being localized with highest densities in lamina I and outer lamina II of the spinal dorsal horn. An ultrastructural double-labeling study, combining preembedding immunogold with enzyme-based immunocytochemistry, showed that most neurokinin 1 receptor immunoreactive dendrites were apposed by substance P containing boutons. A detailed quantitative analysis revealed that neurokinin 1 receptor immunoreactive dendrites received more appositions and synapses from substance P immunoreactive terminals than those not expressing the neurokinin 1 receptor. Such preferential innervation by substance P occurred in all superficial dorsal horn laminae even though neurokinin 1 receptor immunoreactive dendrites were a minority of the total number of dendritic profiles in the above laminae. These results suggest that, contrary to the belief that neuropeptides act in a diffuse manner at a considerable distance from their sites of release, substance P should act on profiles expressing the neurokinin 1 receptor at a short distance from its site of release.

Sodium channels and pain

Although it is well established that hyperexcitability and/or increased baseline sensitivity of primary sensory neurons can lead to abnormal burst activity associated with pain, the underlying molecular mechanisms are not fully understood. Early studies demonstrated that, after injury to their axons, neurons can display changes in excitability, suggesting increased sodium channel expression, and, in fact, abnormal sodium channel accumulation has been observed at the tips of injured axons. We have used an ensemble of molecular, electrophysiological, and pharmacological techniques to ask: what types of sodium channels underlie hyperexcitability of primary sensory neurons after injury? Our studies demonstrate that multiple sodium channels, with distinct electrophysiological properties, are encoded by distinct mRNAs within small dorsal root ganglion (DRG) neurons, which include nociceptive cells. Moreover, several DRG neuron-specific sodium channels now have been cloned and sequenced. After injury to the axons of DRG neurons, there is a dramatic change in sodium channel expression in these cells, with down-regulation of some sodium channel genes and up-regulation of another, previously silent sodium channel gene. This plasticity in sodium channel gene expression is accompanied by electrophysiological changes that poise these cells to fire spontaneously or at inappropriate high frequencies. Changes in sodium channel gene expression also are observed in experimental models of inflammatory pain. Thus, sodium channel expression in DRG neurons is dynamic, changing significantly after injury. Sodium channels within primary sensory neurons may play an important role in the pathophysiology of pain.

Causalgia, pathological pain, and adrenergic receptors

Control of expression of molecular receptors for chemical messengers and modulation of these receptors’ activity are now established as ways to alter cellular reaction. This paper extends these mechanisms to the arena of pathological pain by presenting the hypothesis that increased expression of α-adrenergic receptors in primary afferent neurons is part of the etiology of pain in classical causalgia. It is argued that partial denervation by lesion of peripheral nerve or by tissue destruction induces a change in peripheral nociceptors, making them excitable by sympathetic activity and adrenergic substances. This excitation is mediated by α-adrenergic receptors and has a time course reminiscent of experimental denervation supersensitivity. The change in neuronal phenotype is demonstrable after lesions of mixed nerves or of the sympathetic postganglionic supply. Similar partial denervations also produce a substantial increase in the number of dorsal root ganglion neurons evidencing the presence of α-adrenergic receptors. The hypothesis proposes the increased presence of α-adrenergic receptors in primary afferent neurons to result from an altered gene expression triggered by cytokines/growth factors produced by disconnection of peripheral nerve fibers from their cell bodies. These additional adrenergic receptors are suggested to make nociceptors and other primary afferent neurons excitable by local or circulating norepinephrine and epinephrine. For central pathways, the adrenergic excitation would be equivalent to that produced by noxious events and would consequently evoke pain. In support, evidence is cited for a form of denervation supersensitivity in causalgia and for increased expression of human α-adrenergic receptors after loss of sympathetic activity.