A homing procedure for studying spatial memory in immature and adult rodents

In this procedure, subjects learn the spatial position of one hole out of many, that allows them to escape from a large open-field into their home cage. The arena is circular and can be rotated between trials so that no proximal landmark is permanently associated with the target hole. This task is thus similar to the Morris water maze procedure, since subjects must remember the position of the escape hole relative to extra-arena cues only. In addition it allows studying the importance of olfactory cues such as scent marks in or around a hole. Since the motivation is to reach home and the motor requirement is low, this task provides a useful alternative to the Morris place navigation task for studying spatial orientation in weanling or senescent rats. Examples are given showing that various behavioural parameters provide a good estimation as how subjects learn this task.

Normal glucagon signaling and β-cell function after near-total α-cell ablation in adult mice.

OBJECTIVEEvaluate whether healthy or diabetic adult mice can tolerate an extreme loss of pancreatic α-cells and how this sudden massive depletion affects β-cell function and blood glucose homeostasis.RESEARCH DESIGN AND METHODSWe generated a new transgenic model allowing near-total α-cell removal specifically in adult mice. Massive α-cell ablation was triggered in normally grown and healthy adult animals upon diphtheria toxin (DT) administration. The metabolic status of these mice was assessed in 1) physiologic conditions, 2) a situation requiring glucagon action, and 3) after β-cell loss.RESULTSAdult transgenic mice enduring extreme (98%) α-cell removal remained healthy and did not display major defects in insulin counter-regulatory response. We observed that 2% of the normal α-cell mass produced enough glucagon to ensure near-normal glucagonemia. β-Cell function and blood glucose homeostasis remained unaltered after α-cell loss, indicating that direct local intraislet signaling between α- and β-cells is dispensable. Escaping α-cells increased their glucagon content during subsequent months, but there was no significant α-cell regeneration. Near-total α-cell ablation did not prevent hyperglycemia in mice having also undergone massive β-cell loss, indicating that a minimal amount of α-cells can still guarantee normal glucagon signaling in diabetic conditions.CONCLUSIONSAn extremely low amount of α-cells is sufficient to prevent a major counter-regulatory deregulation, both under physiologic and diabetic conditions. We previously reported that α-cells reprogram to insulin production after extreme β-cell loss and now conjecture that the low α-cell requirement could be exploited in future diabetic therapies aimed at regenerating β-cells by reprogramming adult α-cells.

Scepticism Revisited

Liberalism claims that for a subject S to be justified in believing p, a proposition about the external world, on the basis of his senses it is not necessary to be antecedently justified in believing propositions as there is an external world. On the other hand, conservatism claims that to be justified in believing that p on the basis of one’s perception, one must have antecedent justification to believe that p. Intuitively, we are inclined to think that liberalism about the structure of perceptual justification fits better with our epistemic practices. We acknowledge that, although we cannot produce warrant for the background belief in the external world, our empirical beliefs can be perceptually justified. However, I am interested in arguing that conservatism is theoretically better supported than liberalism. The first reason to defend this is based on the fact that in embracing liberalism dogmatism is affected by pervasive problems. The second one comes from recognizing the strength of the argument based on the thesis that experience is theory-laden. But not all are advantages for conservatism. Conservatism is presupposed in contemporary formulations of scepticism through the requirement of prior justification for background assumptions, and this fact compels anti-sceptical conservatives to conceive a non-evidential form of warrant, entitlement, to contest the sceptical threat My main worry is that, although the path of entitlement has some prospects to succeed, this new notion of justification seems to be posed ad hoc for conservatives to solve the sceptical problem. These contents are organized along the three chapters. The result of chapter 1 is a pattern of sceptical argument formed by two premises: P1*, a conservative principle, and P2*. In chapter 2 and chapter 3 two anti-sceptical proposals against the argument sketched in chapter 1 are described. Chapter 2 is devoted to explain and assess a first anti-sceptical proposal that denies P1*: dogmatism. Moreover, in chapter 3, another anti-sceptical strategy is described (the route of entitlement) that contests scepticism denying the plausibility of P2*.

The effect of ethanol on fat storage in healthy subjects.

BACKGROUND: Ethanol can account for up to 10 percent of the energy intake of persons who consume moderate amounts of ethanol. Its effect on energy metabolism, however, is not known. METHODS: We studied the effect of ethanol on 24-hour substrate-oxidation rates in eight normal men during two 48-hour sessions in an indirect-calorimetry chamber. In each session, the first 24 hours served as the control period. On the second day of one session, an additional 25 percent of the total energy requirement was added as ethanol (mean [+/- SD], 96 +/- 4 g per day); during the other session, 25 percent of the total energy requirement was replaced by ethanol, which was isocalorically substituted for lipids and carbohydrates. RESULTS: Both the addition of ethanol and the isocaloric substitution of ethanol for other foods reduced 24-hour lipid oxidation. The respective mean (+/- SE) decreases were 49.4 +/- 6.7 and 44.1 +/- 9.3 g per day (i.e., reductions of 36 +/- 3 percent and 31 +/- 7 percent from the oxidation rate during the control day; P less than 0.001 and P less than 0.0025). This effect occurred only during the daytime period (8:30 a.m. to 11:30 p.m.), when ethanol was consumed and metabolized. Neither the addition of ethanol to the diet nor the isocaloric substitution of ethanol for other foods significantly altered the oxidation of carbohydrate or protein. Both regimens including ethanol produced an increase in 24-hour energy expenditure (7 +/- 1 percent with the addition of ethanol, P less than 0.001; 4 +/- 1 percent with the substitution of ethanol for other energy sources, P less than 0.025). CONCLUSIONS: Ethanol, either added to the diet or substituted for other foods, increases 24-hour energy expenditure and decreases lipid oxidation. Habitual consumption of ethanol in excess of energy needs probably favors lipid storage and weight gain.

Creació d’un programari per a l’avaluació de la qualitat dels resultats analítics generats al laboratori

La validació de mètodes és un dels pilars fonamentals de l’assegurament de la qualitat en els laboratoris d’anàlisi, tal i com queda reflectit en la norma ISO/IEC 17025. És, per tant, un aspecte que cal abordar en els plans d’estudis dels presents i dels futurs graus en Química. Existeix molta bibliografia relativa a la validació de mètodes, però molt sovint aquesta s’utilitza poc, degut a la dificultat manifesta de processar tota la informació disponible i aplicar-la al laboratori i als problemes concrets. Una altra de les limitacions en aquest camps és la manca de programaris adaptats a les necessitats del laboratori. Moltes de les rutines estadístiques que es fan servir en la validació de mètodes són adaptacions fetes amb Microsoft Excel o venen incorporades en paquets estadístics gegants, amb un alt grau de complexitat. És per aquest motiu que l’objectiu del projecte ha estat generar un programari per la validació de mètodes i l’assegurament de la qualitat dels resultats analítics, que incorporés únicament les rutines necessàries. Específicament, el programari incorpora les funcions estadístiques necessàries per a verificar l’exactitud i avaluar la precisió d’un mètode analític. El llenguatge de programació triat ha estat el Java en la seva versió 6. La part de creació del programari ha constat de les següents etapes: recollida de requisits, anàlisi dels requisits, disseny del programari en mòduls, programació d les funcions del programa i de la interfície gràfica, creació de tests d’integració i prova amb usuaris reals, i, finalment, la posada en funcionament del programari (creació de l’instal·lador i distribució del programari).

Novel function for interleukin-7 in dendritic cell development.

Interleukin-7 (IL-7) is crucial for the development of T and B lymphocytes from common lymphoid progenitors (CLPs) and for the maintenance of mature T lymphocytes. Its in vivo role for dendritic cells (DCs) has been poorly defined. Here, we investigated whether IL-7 is important for the development or maintenance of different DC types. Bone marrow-derived DCs expressed the IL-7 receptor (IL-7R) and survived significantly longer in the presence of IL-7. Migratory DCs (migDCs) isolated from lymph nodes also expressed IL-7R. Surprisingly, IL-7R was not required for their maintenance but indirectly for their development. Conventional DCs (cDCs) and plasmacytoid DCs (pDCs) resident in lymph nodes and spleen were IL-7R(-). Using mixed bone marrow chimeras, we observed an intrinsic requirement for IL-7R signals in their development. As the number of CLPs but not myeloid progenitors was reduced in the absence of IL-7 signals, we propose that a large fraction of cDCs and pDCs derives from CLPs and shares not only the lymphoid origin but also the IL-7 requirement with lymphocyte precursors.

Microtubule-depolymerizing agents used in antibody-drug conjugates induce antitumor immunity by stimulation of dendritic cells.

Antibody-drug conjugates (ADC) are emerging as powerful treatment strategies with outstanding target-specificity and high therapeutic activity in patients with cancer. Brentuximab vedotin represents a first-in-class ADC directed against CD30(+) malignancies. We hypothesized that its sustained clinical responses could be related to the stimulation of an anticancer immune response. In this study, we demonstrate that the dolastatin family of microtubule inhibitors, from which the cytotoxic component of brentuximab vedotin is derived, comprises potent inducers of phenotypic and functional dendritic cell (DC) maturation. In addition to the direct cytotoxic effect on tumor cells, dolastatins efficiently promoted antigen uptake and migration of tumor-resident DCs to the tumor-draining lymph nodes. Exposure of murine and human DCs to dolastatins significantly increased their capacity to prime T cells. Underlining the requirement of an intact host immune system for the full therapeutic benefit of dolastatins, the antitumor effect was far less pronounced in immunocompromised mice. We observed substantial therapeutic synergies when combining dolastatins with tumor antigen-specific vaccination or blockade of the PD-1-PD-L1 and CTLA-4 coinhibitory pathways. Ultimately, treatment with ADCs using dolastatins induces DC homing and activates cellular antitumor immune responses in patients. Our data reveal a novel mechanism of action for dolastatins and provide a strong rationale for clinical treatment regimens combining dolastatin-based therapies, such as brentuximab vedotin, with immune-based therapies. Cancer Immunol Res; 2(8); 741-55. ©2014 AACR.

Patient satisfaction after biofeedback for constipation and pelvic floor dyssynergia.

Patients referred for chronic constipation frequently report symptoms of straining, feeling of incomplete evacuation, or the need to facilitate defecation digitally (dyschezia). When such patients show manometric evidence of inappropriate contraction or failure to relax the pelvic floor muscles during attempts to defecate, they are diagnosed as having pelvic floor dyssynergia (Rome I). To evaluate long-term satisfaction of patients with pelvic floor dyssynergia after biofeedback. Forty-one consecutive patients referred for chronic constipation at an outpatient gastrointestinal unit and diagnosed as having pelvic floor dyssynergia who completed a full course of biofeedback. Data have been collected using a standardised questionnaire. A questionnaire survey of patients' satisfaction rate and requirement of aperients was undertaken. Mean age and symptom duration were respectively 41 and 20 years. Half of patients reported fewer than 3 bowel motions per week. Patients were treated with a mean of 5 biofeedback sessions. At the end of the therapy pelvic floor dyssynergia was alleviated in 85% of patients and 49% were able to stop all aperients. Satisfaction was maintained at follow-up telephone interviews undertaken after a mean period of 2 years, as biofeedback was helpful for 79% of patients and 47% still abstained from intake of aperients. Satisfaction after biofeedback is high for patients referred for chronic constipation and diagnosed with pelvic floor dyssynergia. Biofeedback improves symptoms related to dyschezia and reduces use of aperients.

TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune reactions. While TREM-1-amplified responses likely aid an improved detection and elimination of pathogens, excessive production of cytokines and oxygen radicals can also severely harm the host. Studies addressing the pathogenic role of TREM-1 during endotoxin-induced shock or microbial sepsis have so far mostly relied on the administration of TREM-1 fusion proteins or peptides representing part of the extracellular domain of TREM-1. However, binding of these agents to the yet unidentified TREM-1 ligand could also impact signaling through alternative receptors. More importantly, controversial results have been obtained regarding the requirement of TREM-1 for microbial control. To unambiguously investigate the role of TREM-1 in homeostasis and disease, we have generated mice deficient in Trem1. Trem1(-/-) mice are viable, fertile and show no altered hematopoietic compartment. In CD4(+) T cell- and dextran sodium sulfate-induced models of colitis, Trem1(-/-) mice displayed significantly attenuated disease that was associated with reduced inflammatory infiltrates and diminished expression of pro-inflammatory cytokines. Trem1(-/-) mice also exhibited reduced neutrophilic infiltration and decreased lesion size upon infection with Leishmania major. Furthermore, reduced morbidity was observed for influenza virus-infected Trem1(-/-) mice. Importantly, while immune-associated pathologies were significantly reduced, Trem1(-/-) mice were equally capable of controlling infections with L. major, influenza virus, but also Legionella pneumophila as Trem1(+/+) controls. Our results not only demonstrate an unanticipated pathogenic impact of TREM-1 during a viral and parasitic infection, but also indicate that therapeutic blocking of TREM-1 in distinct inflammatory disorders holds considerable promise by blunting excessive inflammation while preserving the capacity for microbial control.

How to use the standard model with own data?

In this work discuss the use of the standard model for the calculation of the solvency capital requirement (SCR) when the company aims to use the specific parameters of the model on the basis of the experience of its portfolio. In particular, this analysis focuses on the formula presented in the latest quantitative impact study (2010 CEIOPS) for non-life underwriting premium and reserve risk. One of the keys of the standard model for premium and reserves risk is the correlation matrix between lines of business. In this work we present how the correlation matrix between lines of business could be estimated from a quantitative perspective, as well as the possibility of using a credibility model for the estimation of the matrix of correlation between lines of business that merge qualitative and quantitative perspective.

Elaboració de membranes de fibra buida modificades amb nanopartícules metàl·liques per aplicacions catalítiques

Investigación producida a partir de una estancia en la Université Paul Sabatier, Toulouse III - CNRS, entre 2007 y 2009. Durante los últimos años la investigación centrada en nuevos materiales de tamaño nanoscòpico (nanopartículas, quantum dots, nanotubos de carbono,...) ha experimentado un crecimiento considerable debido a las especiales propiedades de los "nanoobjetos" con respecto a magnetismo, catálisis, conductividad eléctrica, etc ... Sin embargo, hoy en día todavía existen pocas aplicaciones de las nanopartículas en temas medioambientales. Uno de los motivos de esta situación es la posible toxicidad de los nanoobjetos, pero existe también una dificultad tecnológica dado que las nanopartículas tienden a agregarse y es muy difícil manipularlas sin que pierdan sus propiedades especiales. Así, aunque la preparación de materiales catalíticos nanoestructurados es muy interesante, es necesario definir nuevas estrategias para prepararlos. Este proyecto de investigación tiene como objetivo principal la preparación de nuevas membranas catalíticas con nanopartículas metálicas en el interior para aplicaciones de tratamiento de agua. La innovación principal de este proyecto consiste en que las nanopartículas no son introducidas en la matriz polimérica una vez preformadas sino que se hacen crecer en el interior de la matriz polimérica mediante una síntesis intermatricial. El único requisito es que la matriz polimérica contenga grupos funcionales capaces de interaccionar con los precursores de las nanopartículas. Una vez finalizado el proyecto se puede afirmar que se han logrado parte de los objetivos planteados inicialmente. Concreamente ha quedado demostrado que se pueden sintetizar nanopartículas metálicas de metales nobles (platino y paladio) en membranas de fibra hueca de micro- y ultrafiltración siguiendo dos metodologías diferentes: modificación fotoquímica de polímeros y deposición de multicapas de polielectrolitos. Los nuevos materiales son efectivos en la catálisis de reducción de un compuesto modelo (4-nitrofenol con borohidruro de sodio) y, en general, los resultados han sido satisfactorios. Sin embargo, se ha puesto de manifiesto que el uso de un reactivo que genera hidrógeno gas en contacto con la solución acuosa dificulta enormemente la implementación de la reacción catalítica al ser el medio de la membrana una matriz porosa. Así, como conclusión principal se puede decir que se han encontrado las limitaciones de esta aproximación y se sugieren dos posibilidades de continuidad: la utilización de las membranas sintetizadas en contactores gas-líquido o bien el estudio y optimización del sistema de membrana en configuración de membranas planas, un objetivo más asequible dada su menor complejidad. Esta investigación se ha realizado en el seno del “Laboratoire de Génie Chimique” de Toulouse y del Departamento de Química de la Michigan State University y ha sido posible gracias a un proyecto financiado por la “Agence National pour la Recherce” y al programa PERMEANT entre el CNRS y la NSF.

Estrategies per la inversió tridimensional de dades magnetotel.lúriques:

Projecte de recerca elaborat a partir d’una estada a la Dublin Institute for Advanced Studies, Irlanda, entre setembre i desembre del 2009.En els últims anys s’ha realitzat un important avanç en la modelització tridimensional en magnetotel•lúrica (MT) gracies a l'augment d’algorismes d’inversió tridimensional disponibles. Aquests codis utilitzen diferents formulacions del problema (diferències finites, elements finits o equacions integrals), diverses orientacions del sistema de coordenades i, o bé en el conveni de signe, més o menys, en la dependència temporal. Tanmateix, les impedàncies resultants per a tots els valors d'aquests codis han de ser les mateixes una vegada que es converteixen a un conveni de signe comú i al mateix sistema de coordenades. Per comparar els resultats dels diferents codis hem dissenyat models diferents de resistivitats amb estructures tridimensional incrustades en un subsòl homogeni. Un requisit fonamental d’aquests models és que generin impedàncies amb valors importants en els elements de la diagonal, que no són menyspreables. A diferència dels casos del modelització de dades magnetotel.lúriques unidimensionals i bidimensionals, pel al cas tridimensional aquests elements de les diagonals del tensor d'impedància porten informació sobre l'estructura de la resistivitat. Un dels models de terreny s'utilitza per comparar els diferents algoritmes que és la base per posterior inversió dels diferents codis. Aquesta comparació va ser seguida de la inversió per recuperar el conjunt de dades d'una estructura coneguda.

Effect of epinephrine on oxygen consumption and delivery during progressive hemorrhage.

OBJECTIVE: To determine whether, during hemorrhagic shock, the effect of epinephrine on energy metabolism could be deleterious, by enhancing the oxygen requirement at a given level of oxygen delivery (DO2). DESIGN: Prospective, randomized, control trial. SETTING: Experimental laboratory. SUBJECTS: Two groups of seven mongrel dogs were studied. The epinephrine group received a continuous infusion of epinephrine (1 microgram/min/kg) while the control group received saline. INTERVENTION: Dogs were anesthetized with pentobarbital, and shock was produced by stepwise hemorrhage. MEASUREMENTS AND MAIN RESULTS: Oxygen consumption (VO2) was continuously measured by the gas exchange technique, while DO2 was independently calculated from cardiac output (measured by thermodilution) and blood oxygen content. A dual-lines regression fit was applied to the DO2 vs. VO2 plot. The intersection of the two regression lines defined the critical value of DO2. Values above critical DO2 belonged to phase 1, while phase 2 occurred below critical DO2. In the control group, VO2 was independent of DO2 during phase 1; VO2 was dependent on DO2 during phase 2. In the epinephrine group, the expected increase in VO2 (+19%) and DO2 (+50%) occurred under normovolemic conditions. During hemorrhage, VO2 immediately decreased, and the slope of phase 1 was significantly (p < .01) different from zero, and was significantly (p < .05) steeper than in the control group (0.025 +/- 0.005 vs. 0.005 +/- 0.010). However, the critical DO2 (8.7 +/- 1.7 vs. 9.7 +/- 2.4 mL/min/kg), the critical VO2 (5.6 +/- 0.5 vs. 5.5 +/- 0.9 mL/min/kg), and the slope of phase 2 (0.487 +/- 0.080 vs. 0.441 +/- 0.130) were not different from control values. CONCLUSIONS: The administration of pharmacologic doses of epinephrine significantly increased VO2 under normovolemic conditions due to the epinephrine-induced thermogenic effect. This effect progressively decreased during hemorrhage. The critical DO2 and the relationship between DO2 and VO2 in the supply-dependent phase of shock were unaffected by epinephrine infusion. These results suggest that during hemorrhagic shock, epinephrine administration did not exert a detrimental effect on the relationship between DO2 and VO2.

Estudi per la implantació de un ERP en una empresa de muntatges elèctrics

Aquest projecte presenta un estudi per a la implantació d’un Enterprise Resource Planning (ERP) en una empresa de muntatges elèctrics. Per a això es mostra una primera part teòrica on es dóna a conèixer tot el que comporta el terme ERP i el seu procés d'implantació. A continuació s'estudien els requeriments i necessitats de l'empresa objecte de l'estudi. Per a finalitzar, s'estudien tres solucions existents el mercat actual de ERP’s i es selecciona la que millor s'adapta a les necessitats i requeriments en vistes a una hipotètica implantació.

Solid phase microextraction as a short-term sampling technique for BTEX occupational exposure

Solid phase microextraction (SPME) has been widely used for many years in various applications, such as environmental and water samples, food and fragrance analysis, or biological fluids. The aim of this study was to suggest the SPME method as an alternative to conventional techniques used in the evaluation of worker exposure to benzene, toluene, ethylbenzene, and xylene (BTEX). Polymethylsiloxane-carboxen (PDMS/CAR) showed as the most effective stationary phase material for sorbing BTEX among other materials (polyacrylate, PDMS, PDMS/divinylbenzene, Carbowax/divinylbenzene). Various experimental conditions were studied to apply SPME to BTEX quantitation in field situations. The uptake rate of the selected fiber (75 microm PDMS/CAR) was determined for each analyte at various concentrations, relative humidities, and airflow velocities from static (calm air) to dynamic (> 200 cm/s) conditions. The SPME method also was compared with the National Institute of Occupational Safety and Health method 1501. Unlike the latter, the SPME approach fulfills the new requirement for the threshold limit value-short term exposure limit (TLV-STEL) of 2.5 ppm for benzene (8 mg/m(3))