Can the dopaminergic-related effects of general anesthetics be linked to mechanisms involved in drug abuse and addiction?

BACKGROUND: General anesthetics (GA) are well known for the ability to induce a state of reversible loss of consciousness and unresponsiveness to painful stimuli. However, evidence from animal models and clinical studies show that GA exposure may induce behavioral changes beyond acute effects. Most research and concerns are focused on changes in cognition and memory. METHODS: We will look at effects of GA on behavior that is mediated by the dopaminergic system. RESULTS: Pharmacological resemblance of GA with drugs of abuse, and the complexity and importance of dopaminergic systems in both reward seeking and addictive illnesses make us believe that it deserves an overview about what is already known and what matters to us as healthcare workers and specifically as anesthesiologists. CONCLUSION: A review of available evidence strongly suggests that there may be a link between the effects of GA on the brain and substance abuse, partly explained by their influence on the dopaminergic system.

Biodegradable drug-eluting stents: Targeting urothelial tumors of upper urinary tract

INTRODUCTION & OBJECTIVES: Urothelial tumors of upper urinary tract are ranked among the most common types of cancers worldwide. The current standard therapy to prevent recurrence is intravesical Bacillus Calmetteâ Guerin (BCG) immunotherapy, but it presents several disadvantages such as BCG failure and intolerance. Another way is to use chemotherapy, which is generally better tolerated that BCG. In this case, drugs such as epirubicin, doxorubicin, paclitaxel and gemcitabine are used. Nevertheless, intravesical chemotherapy only prevents recurrence in the short-term. These failings can be partially attributed to the short residence time and low bioavailability of the drug within the upper urinary tract and the cancer cells, resulting in a need for frequent drug instillation. To avoid these problems, biodegradable ureteral stents impregnated by supercritical fluid CO2 (SCF) with each of the four anti-cancer drugs were produced. MATERIAL & METHODS: Four formulations with different concentrations of gelatin and alginate and crosslink agent were tested and bismuth was added to confer radiopaque properties to the stent. The preliminary in vivo validation studies in female domestic pigs was conducted at the University of Minho, Braga, after formal approval by the institutionâ s review board and in accordance with its internal ethical protocol for animal experiments. Paclitaxel, epirubicin, doxorubicin and gemcitabine were impregnated in the stents and the release kinetics was measured in artificial urine solution (AUS) for 9 days by UV spectroscopy in a microplate reader. The anti-tumoral effect of the developed stents in transitional cell carcinoma (TCC) and HUVEC primary cells, used as control, was evaluated. RESULTS: The in vivo validation of this second-generation of ureteral stents performed was herein demonstrated. Biodegradable ureteral stents were placed in the ureters of a female pigs, following the normal surgical procedure. The animals remained asymptomatic, with normal urine flow. The in vitro release study in AUS of the stent impregnated showed a higher release in the first 72h for the four anti-cancer drugs impregnated after this time the plateau was achieved and the stent degraded after 9 days. The direct and indirect contact of the anti-cancer biodegradable stents with the TCC and HUVEC cell lines confirm the anti-tumor effect of the stents impregnated with the four anti-cancer drugs, reducing around 75% of the viability of the TCC cell line after 72h and no killing effect in the HUVEC cells. CONCLUSIONS: The use of biodegradable ureteral stent in urology clinical practice not only reduce the stent-related symptoms but also open new treatment therapyâ s, like in urothelial tumors of upper urinary tract. Furthermore, we have demonstrated the clinical validation in vivo pig model. This study has thus shown the killing efficacy of the anti-cancer drug eluting biodegradable stents in vitro for the TCC cell line, with no toxicity observed in the control, non-cancerous cells.The direct and indirect contact of the anti-cancer biodegradable stents with the TCC and HUVEC cell lines confirm the anti-tumor effect of the stents impregnated with the four anti-cancer drugs, reducing around 75% of the viability of the TCC cell line after 72h and no killing effect in the HUVEC cells. This study has thus shown the killing efficacy of the anti-cancer drug eluting biodegradable stents in vitro for the TCC cell line, with no toxicity observed in the control, non-cancerous cells.

Effect of sodium chloride on solutesolvent interactions in aqueous polyethylene glycolsodium sulfate two-phase systems

Partition behavior of eight small organic compounds and six proteins was examined in poly(ethylene glycol)-8000sodium sulfate aqueous two-phase systems containing 0.215 M NaCl and 0.5 M osmolyte (sorbitol, sucrose, TMAO) and poly(ethylene glycol)-10000sodium sulfate0.215 M NaCl system, all in 0.01 M sodium phosphate buffer, pH 6.8. The differences between the solvent properties of the coexisting phases (solvent dipolarity/polarizability, hydrogen bond donor acidity, and hydrogen bond acceptor basicity) were characterized with solvatochromic dyes using the solvatochromic comparison method. Differences between the electrostatic properties of the phases were determined by analysis of partitioning of sodium salts of dinitrophenylated (DNP-) amino acids with aliphatic alkyl side-chain. The partition coefficients of all compounds examined (including proteins) were described in terms of solutesolvent interactions. The results obtained in the study show that solutesolvent interactions of nonionic organic compounds and proteins in polyethylene glycolsodium sulfate aqueous two-phase system change in the presence of NaCl additive.

A critical evaluation of methods for the reconstruction of tissue-specific models

Under the framework of constraint based modeling, genome-scale metabolic models (GSMMs) have been used for several tasks, such as metabolic engineering and phenotype prediction. More recently, their application in health related research has spanned drug discovery, biomarker identification and host-pathogen interactions, targeting diseases such as cancer, Alzheimer, obesity or diabetes. In the last years, the development of novel techniques for genome sequencing and other high-throughput methods, together with advances in Bioinformatics, allowed the reconstruction of GSMMs for human cells. Considering the diversity of cell types and tissues present in the human body, it is imperative to develop tissue-specific metabolic models. Methods to automatically generate these models, based on generic human metabolic models and a plethora of omics data, have been proposed. However, their results have not yet been adequately and critically evaluated and compared. This work presents a survey of the most important tissue or cell type specific metabolic model reconstruction methods, which use literature, transcriptomics, proteomics and metabolomics data, together with a global template model. As a case study, we analyzed the consistency between several omics data sources and reconstructed distinct metabolic models of hepatocytes using different methods and data sources as inputs. The results show that omics data sources have a poor overlapping and, in some cases, are even contradictory. Additionally, the hepatocyte metabolic models generated are in many cases not able to perform metabolic functions known to be present in the liver tissue. We conclude that reliable methods for a priori omics data integration are required to support the reconstruction of complex models of human cells.

Development of a poly(L-Lactic acid) based drug release system

Dissertação de mestrado em Biofísica e Bionanossistemas

Depressed mothers and infants are more relaxed during breastfeeding versus bottlefeeding interactions: brief report

Depressed and non-depressed mothers and their 3-month-old infants were videotaped during breastfeeding and bottlefeeding interactions. The videotapes were subsequently coded for a number of feeding interaction behaviors as well as being rated on the Interaction Rating Scales. No differences were noted between the depressed and non-depressed mothers. Several breastfeeding versus bottlefeeding group effects were observed. The breastfeeding mothers showed less burping and less intrusive behavior during the nipple-in periods as well as during the nipple-out periods. In addition, the breastfeeding mothers and their infants received better ratings on the Interaction Rating Scales. These data suggest that the depressed mothers and their infants not unlike the non-depressed mothers and their infants were benefited by breastfeeding.

Influence of oxygen conditions on bacterial interactions within biofilms related with cystic fibrosis

Dissertação de mestrado em Bioengineering

Comparative study of the use of diltiazem as an antispasmodic drug in coronary angiography via the transradial approach

OBJECTIVE: To evaluate the impact of the use, prior to the procedure, of injectable diltiazem to prevent complications. METHODS: Between September 2000 and July 2001, 50 patients underwent transradial coronary angiography and were randomized to receive placebo (GI) or diltiazem (GII) through a catheter inserted into the radial artery. All patients received isosorbide mononitrate. Ultrasound analyses of the radial artery were performed before examination, 30 minutes afterwards, and 7 days afterwards to evaluate the flow, the diameter, and the artery output. RESULTS: The radial artery diameter of GI was 2.4± 0.5 mm before the procedure and 2.3±0.5 mm after 30 minutes (NS), whereas in GII the diameter was 2.2±0.3 mm before the examination and 2.5±0.4 mm 30 minutes after it (P<0.001). Radial artery output in group 1 was 7.3±5.l2 mL/min before the examination and 6.1±3.5 mL/min 30 minutes after the examination (NS), and GII had an increase of 5.9±2.5 mL/min before examination to 9.05± 7.78 mL/min after the examination (P=0.04). Complications (spasm, occlusion, and partial obstruction) occurred in 4 patients (17.4%) in GI and did not occur in GII (P=0.04). CONCLUSION: The study suggests a decrease in vascular complications through the transradial access for coronary angiography with the use of diltiazem as an antispasmodic drug, resulting in the significant increase in the diameter of the radial artery and radial artery output.

Interactions between fiscal and monetary policy

Mestrado em Economia Monetária e Financeira

Interacciones Transitorias de Proteínas Solubles con Membranas Lipídicas. Transient interactions of soluble proteins with lipid membranes.

La transferencia de proteínas solubles a la interfase de la membrana lipídica es un paso clave en varios procesos celulares. Esta traslocación resulta en un importante cambio en el ambiente de la proteína con consecuencias sobre su conformación, estabilidad y actividad biológica. En este proyecto estudiamos las condiciones que determinan la unión a la membrana, particularmente el balance entre interacciones electrostáticas e hidrofóbicas, y los factores que determinan la conformación, estabilidad y dinámica de la proteína en interfaces. Particularmente, estudiaremos la interacción con membranas de la proteína transportadora de ácido cólico de hígado de ave L-BABP, la proteína beta-2 glicoproteína humana y la proteína asociada a microtúbulos SL21. Hemos encontrado que el estado de fase del lípido determina la conformación y estabilidad de L-BABP unida periféricamente. En este proyecto estudiaremos la naturaleza de las interacciones que determinan esta dependencia. beta-2 glicoproteína humana se une a membranas aniónicas e induce cambios estructurales en el lípido cuando ocurre la transición al estado desplegado de la proteína. El proyecto contempla estudiar comparativamente las interacciones del estado nativo y parcialmente desplegado de beta-2 glicoproteína con membranas. Estudiaremos los cambios conformacionales de proteínas y lípidos utilizando espectroscopia infrarroja por transformada de Fourier (FTIR), espectroscopia de emisión de fluorescencia y espectroscopia de dicroísmo circular (CD). Utilizaremos calorimetría diferencial de barrido (DSC) para estudios de estabilidad y espectroscopia de fosforescencia para estudiar dinámica rotacional de proteínas en la membrana.

Desarrollos innovadores, estrategias de aprendizaje e interacciones de comunicación llevadas a cabo con Tecnologías de la Información y la Comunicación en el área de Ciencias Experimentales. Innovative developments, learning strategies and communication interactions carried out with CIT in experimental science.

Las Tecnologías de la Información y la Comunicación (TIC) han alcanzando una fuerte expansión en la última década y se convierten en una estrategia clave para la educación científica y tecnológica. Actualmente se realizan significativas inversiones en computadoras e insumos acordes a esta tecnología lo que no garantiza que éstas mejores disponibilidades sean necesariamente conducentes a propuestas educativas aceptables, ya que la incorporación de las TIC en la educación científica no puede consistir en un mero cambio de soporte sin que esto se acompañe de una renovación constructivista del aprendizaje. También se observa un escaso desarrollo y aplicación de las TIC tanto en la formación de grado de las carreras científicas, como en la formación permanente de los docentes. A partir de lo expuesto, nos planteamos los siguientes problemas: ¿cómo generar cursos de formación docente con alternativas virtuales que garanticen la construcción, actualización y transferencia de conocimientos en las disciplinas científicas? ¿qué diseño de materiales se requiere para potenciar aprendizajes flexibles de calidad?, ¿qué dimensiones, variables e indicadores dan cuenta de procesos de comunicación en estos entornos?, ¿Cuáles son las principales estrategias que promueven los desarrollos tecnológicos? ¿De qué manera se lleva a cabo el seguimiento y evaluación de los desarrollos tecnológicos? Para dar respuesta a estos interrogantes nos planteamos este proyecto que tiene por objetivos: diseñar, desarrollar, implementar y evaluar materiales basados en un modelo constructivista que utiliza como soporte las TIC el marco de la "Enseñanza para la Comprensión". Analizar las relaciones que se establecen en el intercambio comunicativo a través de las TIC, ya sea de manera síncrona o asíncrona e identificar las estrategias de aprendizaje utilizadas por los estudiantes cuando trabajan con entornos virtuales. Se profundizará en los siguientes temas: "La materia y sus cambios", "Biotecnología" y "Dilemas investigativos a los que se enfrentan los científicos". Los dos primeros módulos estarán destinados a la formación de futuros docentes en Ciencias y a la formación permanente de docentes en ejercicio. Los usuarios del tercer módulo serán los estudiantes del ciclo de nivelacion. Se propone desarrollar instrumentos de evaluación, adaptando indicadores que sirvan para evaluar el modelo, el diseño de los materiales, el medio tecnológico, la eficiencia de estos programas con TIC. Se van a definir variables que permitan identificar las estrategias de aprendizaje utilizadas por los usuarios de estos desarrollos tecnológicos y las relaciones que se establecen en el intercambio comunicativo de los entornos virtuales, haciendo hincapié en la lecto-escritura científica. Se utilizará la plataforma Moodle que permite la administración de los estudiantes, las interacciones sociales necesarias para integrar una comunidad de aprendizaje a través de los foros y correo electrónico y la evaluación continua de los aprendizajes. El desarrollo de los contenidos específicos y las actividades de aprendizaje se hará en CD interactivos elaborados con diferentes programas de computación. En el desarrollo de los materiales se incluyen algunas simulaciones interactivas que permiten comprender conceptos que habitualmente requerían experimentación fáctica. El estudio se enmarca en la combinación de dos enfoques metodológicos que integran técnicas y procedimientos de análisis tanto cuantitativos como cualitativos. Consideramos que esta investigación es una contribución teórica importante ya que propone mejorar un modelo para la enseñanza de las Ciencias Naturales introduciendo las TIC. Se espera realizar un aporte novedoso al campo de la Didáctica de las Ciencias con la obtención de los resultados y acciones tendientes a establecer una red de comunicaciones entre los docentes participantes y los investigadores involucrados en el programa, instalada en forma progresiva.

Interacciones inmuno-endócrinas: participación de tlr-4 y citoquinas pro-inflamatorias en la regulación de la proliferación de células lactotropas. Immuno-endocrine interactions: Contribution of tlr-4 and pro-inflammatory cytokines in the regulation of lactotroph cell proliferation.

El presente proyecto tiene como objetivo estudiar, a nivel celular y molecular, los mecanismos inmuno-endócrinos que participan en la proliferación de células lactotropas normales y tumorales frente a procesos inflamatorios inducidos experimentalmente. Una particular atención se pondrá al evaluar la contribución de IL-6 como citoquina intrahipofisaria durante el desarrollo tumoral y su rol como señal paracrina/autocrina en la senescencia hipofisaria. Debido a que agentes inflamatorios y anti-inflamatorios pueden inducir alteraciones en el crecimiento y la función hipofisaria, no se descartaría que, en el curso de una inflamación, como la inducida por el lipopolisacárido bacteriano LPS, puedan ocurrir modificaciones en el índice proliferativo de las células lactotropas y/o en la secreción de su producto hormonal, la prolactina. Dado el auge en las investigaciones referidas al campo de la modulación inmuno-endócrina, es que planteamos investigar la participación de TLR4, componente crucial del complejo proteico que inicia la señal LPS, en hipófisis normales y tumorales inducidas por estrógeno así como también en la línea celular somatolactotrópica GH3B6. Dentro de las vías de transducción de señales involucradas se determinará la participación de MAPK-ERK1/2 y de PI3K asi como la contribución de NF-kB en la regulación del crecimiento celular inducido por IL-6/LPS mediante el uso de inhibidores específicos. La microscopía electrónica y confocal, resultarán de fundamental importancia para valorar los procesos de translocación nuclear de NF-kB como así también para definir la localización ultraestructural de los mediadores mencionados. Además, se valorará el mecanismo de senescencia celular hipofisaria mediante parámetros morfológicos, bioquímicos y ultraestructurales durante el desarrollo de prolactinomas inducidos experimentalmente. Finalmente dilucidar las posibles vías de transducción de señales que se desencadenan frente a estímulos inflamatorios/proliferativos podría explicar algunos aspectos moleculares sobre la función de control del ciclo celular y las limitaciones de crecimiento en adenomas hipofisarios que subyacen en la falta de progresión de estos tumores a la malignidad. The aim of the present project is to study the immuno-endocrine mechanisms involved in the proliferation of normal and tumoral lactotrophs experimentally induced by inflammatory factors. Also, the contribution of IL-6 as a paracrine / autocrine signal in the pituitary senescence will be assessed along tumor development induced by estrogen treatment. Considering that both, inflammatory and anti-inflammatory agents can modify the pituitary function, it is possible that in the course of inflammation, as induced by bacterial lipopolysaccharide LPS, some alteration may occur in the proliferative index of lactotrophs and / or in the PRL secretion. Our main objective is to investigate the cellular and molecular mechanisms involved by the activation of TLR4, a crucial component of the protein complex initiated by LPS, in normal and pathological pituitaries induced by estrogen as well as in the GH3B6 cell line. The participation of MAPK-ERK1 / 2 and PI3K signaling pathway and the contribution of NF-kB in the proliferative responses triggered by IL-6/LPS will be analyzed by using specific inhibitors. Confocal microscopy analysis is essential to assess the process of nuclear translocation of NF-kB as well as the use of electron microscopy to define the ultrastructural localization of the above mentioned mediators. In addition, the mechanisms of pituitary cell senescence will be evaluated through morphological, biochemical and ultrastructural approaches during the development of experimental prolactinomas. Finally, the elucidation of possible signal transduction pathways which are triggered by inflammatory / proliferative stimuli, would explain some molecular aspects of cell cycle control and limitations in pituitary tumor growth that underlie the lack of progress in these pituitary tumors to malignancy.

A nutrient balance model for typical Irish farming systems

The twin objectives of the work described were to construct nutrient balance models (NBM) for a range of Irish animal production systems and to evaluate their potential as a means of estimating the nutrient composition of farm wastes. The NBM has three components. The first is the intake of nutrients in the animal's diet. The second is retention or the nutrients the animal retains for the production of milk, meat or eggs. The third is the balance or the difference between the nutrient intake and retention. Data on the intake levels and their nutrient value for dairy cows, beef cattle, pigs and poultry systems were assembled. Literature searches and interviews with National experts were the primary sources of information. NBMs were then constructed for each production system. Summary tables of the nutrient values for the common diet constituents used in Irish animal production systems, the nutrient composition of the animal products and the NBMs (nutrient intake, retention and excretion) for a range of production systems were assembled. These represent the first comprehensive data set of this type for Irish animal production systems. There was generally good agreement between the derived NBMs values and those published in the literature. The NBMs were validated on a number of farms. Data on animal numbers, fertiliser use, concentrates inputs and production output were recorded on seven farms. Using the data a nutrient input/output balance was constructed for each farm. This was compared with the NBM estimate of the farm nutrient balance. The results showed good agreement between the measured balance and the NBM estimate particularly for the pig and poultry farms. However, the validation emphasised the inherent risks associated with NBMs. The average values used for feed intake and production parameters in the NEMs may result in the under or over estimate of actual nutrient balances on individual farms where these variables are substantially different. On the grassland farms there was a poor correlation between the input/output estimate and the NBM. This possibly results from the omission of the soil's contribution to the nutrient balance. However, the results indicate that the NBMs developed are a potentially useful tool for estimating nutrient balances. They also will serve to highlight the significant fraction of the nutrient inputs into farming systems that are retained on the farm. The potential of the NBM as a means of estimating the nutrient composition of farm wastes was evaluated on two farms. Feed intake and composition, animal production, slurry production was monitored during the indoor winter feeding period. Slurry samples were taken for analysis. The appropriates NBMs were used to estimate the nutrient balance for each farm. The nutrient content of the slurry produced was calculated. There was a good agreement between the NBM estimate and the measured values. This preliminary evaluation suggests that the NBM has a potential to provide the farmer with a simple means of estimating the nutrient value of his slurry.

Approved Drug Products with Theurapeutic Equivalence Evaluation - 34th edition

The publication, Approved Drug Products with Therapeutic Equivalence Evaluations (the List, commonly known as the Orange Book), identifies drug products approved on the basis of safety and effectiveness by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act (the Act). Drugs on the market approved only on the basis of safety (covered by the ongoing Drug Efficacy Study Implementation [DESI] review [e.g., Donnatal® Tablets and Librax® Capsules] or pre-1938 drugs [e.g., Phenobarbital Tablets]) are not included in this publication. The main criterion for the inclusion of any product is that the product is the subject of an application with an effective approval that has not been withdrawn for safety or efficacy reasons. Inclusion of products on the List is independent of any current regulatory action through administrative or judicial means against a drug product. In addition, the List contains therapeutic equivalence evaluations for approved multisource prescription drug products. These evaluations have been prepared to serve as public information and advice to state health agencies, prescribers, and pharmacists to promote public education in the area of drug product selection and to foster containment of health care costs. Therapeutic equivalence evaluations in this publication are not official FDA actions affecting the legal status of products under the Act.

Long-term Outcomes of Drug-eluting versus Bare-metal stent for ST-elevation Myocardial Infarction

Background:Long-term outcomes of drug-eluting stents (DES) versus bare-metal stents (BMS) in patients with ST-segment elevation myocardial infarction (STEMI) remain uncertain.Objective:To investigate long-term outcomes of drug-eluting stents (DES) versus bare-metal stents (BMS) in patients with ST-segment elevation myocardial infarction (STEMI).Methods:We performed search of MEDLINE, EMBASE, the Cochrane library, and ISI Web of Science (until February 2013) for randomized trials comparing more than 12-month efficacy or safety of DES with BMS in patients with STEMI. Pooled estimate was presented with risk ratio (RR) and its 95% confidence interval (CI) using random-effects model.Results:Ten trials with 7,592 participants with STEMI were included. The overall results showed that there was no significant difference in the incidence of all-cause death and definite/probable stent thrombosis between DES and BMS at long-term follow-up. Patients receiving DES implantation appeared to have a lower 1-year incidence of recurrent myocardial infarction than those receiving BMS (RR = 0.75, 95% CI 0.56 to 1.00, p= 0.05). Moreover, the risk of target vessel revascularization (TVR) after receiving DES was consistently lowered during long-term observation (all p< 0.01). In subgroup analysis, the use of everolimus-eluting stents (EES) was associated with reduced risk of stent thrombosis in STEMI patients (RR = 0.37, p=0.02).Conclusions:DES did not increase the risk of stent thrombosis in patients with STEMI compared with BMS. Moreover, the use of DES did lower long-term risk of repeat revascularization and might decrease the occurrence of reinfarction.