Hedgehog pathway and its inhibitors in chronic obstructive pulmonary disease (COPD).

COPD affects millions of people and is now ranked as the third leading cause of death worldwide. This largely untreatable chronic airway disease results in irreversible destruction of lung architecture. The small lung hypothesis is now supported by epidemiological, physiological and clinical studies. Accordingly, the early and severe COPD phenotype carries the most dreadful prognosis and finds its roots during lung growth. Pathophysiological mechanisms remain poorly understood and implicate individual susceptibility (genetics), a large part of environmental factors (viral infections, tobacco consumption, air pollution) and the combined effects of those triggers on gene expression. Genetic susceptibility is most likely involved as the disease is severe and starts early in life. The latter observation led to the identification of Mendelian inheritance via disease-causing variants of SERPINA1 - known as the basis for alpha-1 anti-trypsin deficiency, and TERT. In the last two decades multiple genome wide association studies (GWAS) identified many single nucleotide polymorphisms (SNPs) associated with COPD. High significance SNPs are located in 4q31 near HHIP which encodes an evolutionarily highly conserved physiological inhibitor of the Hedgehog signaling pathway (HH). HHIP is critical to several in utero developmental lung processes. It is also implicated in homeostasis, injury response, epithelial-mesenchymal transition and tumor resistance to apoptosis. A few studies have reported decreased HHIP RNA and protein levels in human adult COPD lungs. HHIP+/- murine models led to emphysema. HH pathway inhibitors, such as vismodegib and sonidegib, are already validated in oncology, whereas other drugs have evidenced in vitro effects. Targeting the Hedgehog pathway could lead to a new therapeutic avenue in COPD. In this review, we focused on the early and severe COPD phenotype and the small lung hypothesis by exploring genetic susceptibility traits that are potentially treatable, thus summarizing promising therapeutics for the future.

[Modelling the bronchial epithelium in chronic obstructive pulmonary disease using human induced pluripotential stem cells]. / Modélisation de l'épithélium bronchique dans la bronchopneumopathie chronique obstructive par les cellules souches pluripotentes induites humaines.

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease leading to irreversible destruction of the terminal bronchioles. Although the precise patho-physiological mechanisms remain to be elucidated, the bronchial epithelium seems to play a pivotal role in the disease. Recent studies have highlighted a great heterogeneity among COPD patients, with various disease courses including, in about half the cases, an origin in childhood. Modelling of COPD is a major goal but currently available models are imperfect. Our work aims to create a new in vitro cellular model to study the pathology of the disease. The differentiation of human induced pluripotential stem cells (hiPSCs) in bronchial epithelium is a step towards a better understanding of the developmental origin and the identification of new therapeutic targets.

Influence of lane departure warnings onset and reliability on car drivers' behaviors.

Lane departures represent an important cause of road crashes. The objective of the present study was to assess the effects of an auditory Lane Departure Warning System (LDWS) for partial and full lane departures (onset manipulation) combined with missed warnings (reliability manipulation: 100% reliable, 83% reliable and 66% reliable) on drivers' performances and acceptance. Several studies indicate that LDWS improves drivers' performances during lane departure episodes. However, little is known about the effects of the warning onset and reliability of LDWS. Results of studies which looked at forward collision warning systems show that early warnings tend to improve drivers' performances and receive a better trust judgement from the drivers when compared to later warnings. These studies also suggest that reliable assistances are more effective and trusted than unreliable ones. In the present study, lane departures were brought about by means of a distraction task whilst drivers simulated driving in a fixed-base simulator with or without an auditory LDWS. Results revealed steering behaviors improvements with LDWS. More effective recovery maneuvers were found with partial lane departure warnings than with full lane departure warnings and assistance unreliability did not impair significantly drivers' behaviors. Regarding missed lane departure episodes, drivers were found to react later and spend more time out of the driving lane when compared to properly warned lane departures, as if driving without assistance. Subjectively, LDWS did not reduce mental workload and partial lane departure warnings were judged more trustworthy than full lane departure ones. Data suggests the use of partial lane departure warnings when designing LDWS and that even unreliable LDWS may draw benefits compared to no assistance.

Posicionamiento del Comité Español Interdisciplinario de Prevención Cardiovascular y la Sociedad Española de Cardiología en el tratamiento de las dislipemias: divergencia entre las guías europea y estadounidense / Spanish Interdisciplinary Committee for Cardiovascular Disease Prevention and the Spanish Society of Cardiology Position Statement on Dyslipidemia Management. Differences Between the European and American Guidelines

La publicación en EE. UU. de la guía de 2013 de American College of Cardiology/American Heart Association para el tratamiento del colesterol elevado ha tenido gran impacto por el cambio de paradigma que supone. El Comité Español Interdisciplinario de Prevención Cardiovascular y la Sociedad Española de Cardiología han revisado esa guía, en comparación con la vigente guía europea de prevención cardiovascular y de dislipemias. El aspecto más destacable de la guía estadounidense es el abandono de los objetivos de colesterol unido a lipoproteínas de baja densidad, de modo que proponen el tratamiento con estatinas en cuatro grupos de riesgo aumentado. En pacientes con enfermedad cardiovascular establecida, ambas guías conducen a una estrategia terapéutica similar (estatinas potentes, dosis altas). Sin embargo, en prevención primaria, la aplicación de la guía estadounidense supondría tratar con estatinas a un número de personas excesivo, particularmente de edades avanzadas. Abandonar la estrategia según objetivos de colesterol, fuertemente arraigada en la comunidad científica, podría tener un impacto negativo en la práctica clínica y crear cierta confusión e inseguridad entre los profesionales y quizá menos seguimiento y adherencia de los pacientes. Por todo ello, el presente documento reafirma las recomendaciones de la guía europea. Ambas guías tienen aspectos positivos pero, en general y mientras no se resuelvan las dudas planteadas, la guía europea, además de utilizar tablas basadas en la población autóctona, ofrece mensajes más apropiados para el entorno español y previene del posible riesgo de sobretratamiento con estatinas en prevención primaria (AU)

The publication of the 2013 American College of Cardiology/American Heart Association guidelines on the treatment of high blood cholesterol has had a strong impact due to the paradigm shift in its recommendations. The Spanish Interdisciplinary Committee for Cardiovascular Disease Prevention and the Spanish Society of Cardiology reviewed this guideline and compared it with current European guidelines on cardiovascular prevention and dyslipidemia management. The most striking aspect of the American guideline is the elimination of the low-density lipoprotein cholesterol treat-to-target strategy and the adoption of a risk reduction strategy in 4 major statin benefit groups. In patients with established cardiovascular disease, both guidelines recommend a similar therapeutic strategy (high-dose potent statins). However, in primary prevention, the application of the American guidelines would substantially increase the number of persons, particularly older people, receiving statin therapy. The elimination of the cholesterol treat-to-target strategy, so strongly rooted in the scientific community, could have a negative impact on clinical practice, create a certain amount of confusion and uncertainty among professionals, and decrease follow-up and patient adherence. Thus, this article reaffirms the recommendations of the European guidelines. Although both guidelines have positive aspects, doubt remains regarding the concerns outlined above. In addition to using risk charts based on the native population, the messages of the European guideline are more appropriate to the Spanish setting and avoid the possible risk of overtreatment with statins in primary prevention (AU)

In vitro rescue of FGA deletion by lentiviral transduction of an afibrinogenemic patient's hepatocytes.

BACKGROUND: Congenital afibrinogenemia is a rare inherited autosomal recessive disorder in which a mutation in one of three genes coding for the fibrinogen polypeptide chains Aα, Bß and γ results in the absence of a functional coagulation protein. A patient with congenital afibrinogenemia, resulting from an FGA homozygous gene deletion, underwent an orthotopic liver transplant that resulted in complete restoration of normal hemostasis. The patient's explanted liver provided a unique opportunity to further investigate a potential novel treatment modality. OBJECTIVE: To explore a targeted gene therapy approach for patients with congenital afibrinogenemia. METHODS AND RESULTS: At the time of transplant, the patient's FGA-deficient hepatocytes were isolated and transduced with lentiviral vectors encoding the human fibrinogen Aα-chain. FGA-transduced hepatocytes produced fully functional fibrinogen in vitro. CONCLUSIONS: Orthotopic liver transplantation is a possible rescue treatment for failure of on-demand fibrinogen replacement therapy. In addition, we provide evidence that hepatocytes homozygous for a large FGA deletion can be genetically modified to restore Aα-chain protein expression and secrete a functional fibrinogen hexamer.

Photophysical, amplified spontaneous emission and charge transport properties of oligofluorene derivatives in thin films.

We investigate the photophysical and amplified spontaneous emission properties of a series of monodisperse solution-processable oligofluorenes functionalized with hexyl chains at the C9 position of each fluorene unit. Thin films of these oligofluorenes are then used in organic field-effect transistors and their charge transport properties are examined. We have particularly focused our attention on the influence of oligofluorene length on the absorption and steady-state fluorescence spectra, on the HOMO/LUMO energy levels, on the photoluminescence lifetime and quantum yield as well as on the amplified spontaneous emission properties and the charge carrier mobilities. Differential scanning calorimetry and X-ray diffraction measurements demonstrate that, among all oligofluorene derivatives used in this study, only the structure and morphology of the pentafluorene film is significantly modified by a thermal treatment above the glass transition temperature, resulting in a 9 nm blue-shift of the fluorescence spectrum without significant changes in the photoluminescence quantum yield and in the amplified spontaneous emission threshold. In parallel, hole field-effect mobility is significantly increased from 8.6 × 10(-7) to 3.8 × 10(-5) cm(2) V(-1) s(-1) upon thermal treatment, due to an increase of crystallinity. This study provides useful insights into the morphological control of oligofluorene thin films and how it affects their photophysical and charge transport properties. Moreover, we provide evidence that, because of the low threshold, the tunability of the amplified spontaneous emission and the photostability of the films, these oligofluorenes are promising candidates for organic solid-state laser applications.

[Molecular effects of new calcium antagonists: is the principle of parcimony out of place?]. / Effets moléculaires de nouveaux antagonistes calciques: le principe de parcimonie est-il toujours de mise ?

The calcium (Ca2+) channel antagonists (CCA) are used successfully in the treatment of hypertension and angina pectoris. Their mode of action is to decrease Ca2+ entry in the vascular smooth muscle cells. Their molecular targets are voltage activated Ca2+ channels (VACC), especially the L-type (VACC-L). This review examines the role of the VACC-L and of the T-type (VACC-T) in vascular physiology and hypertension. The molecular mechanisms at the base of the vascular selectivity of CCA are presented with, in filigree, the concern of trying to understand the effect of recently developed molecules. In particular, we will examine the ideas having recently emerged concerning the mode of action of last generation dihydropyridines (DHPs) stripped of some of the undesirable effects of prototypes AC considered as highly specific of the VACC-L. These properties could result, in particular, from their effects on the VACC-T, which could occur in addition to those classically observed on the VACC-L.

Prolonged islet allograft survival by alpha-1 antitrypsin: the role of humoral immunity.

Immunomodulatory properties have been recognized for human alpha-1 antitrypsin (hAAT). However, production of anti-hAAT antibodies in mice may inactivate the protein. In this study, we evaluated the effects of chronic hAAT administration on allogeneic islet graft survival. Chemically diabetic mice lacking an efficient humoral response due to the targeted disruption of the Ig mu-chain (muMT mice) or wild-type (WT) C57BL/6 mice received DBA/2 mouse islets under the kidney capsule. hAAT (Prolastin or Aralast) was given intraperitoneally on day 0 and every 3 days thereafter. Control animals received no treatment. hAAT administration in WT mice resulted in prolongation of islet allograft survival in a dose-dependent fashion in both hAAT-treated groups. Lack of Ig response (muMT mice) per se conferred a beneficial effect on graft survival that worsened in the Prolastin-treated groups but improved in the Aralast-treated group. Our data indicate that systemic administration of hAAT results in prolongation of islet allograft survival. Absence of mature B cells and Ig mu-chain resulted in improved graft survival, pointing to a role for B cells in the rejection process in this model. Treatment with Prolastin worsened graft survival in muMT mice, whereas Aralast did improve it, suggesting a different efficacy and possible actions of the two drug formulations.

[Prevalence of metabolic syndrome and association with ischemic heart disease in cardiological outpatients]. / Prevalencia de síndrome metabólico y asociación con la cardiopatía isquémica en pacientes cardiológicos ambulatorios.

INTRODUCTION: The metabolic syndrome (MS) is a cluster of cardiovascular risk factors with a common pathological link: insulin resistance. We analyzed its prevalence and its impact for the presence of ischemic heart disease (IHD). METHODS: We recorded data from 1,000 consecutive patients that attended the outpatient clinic of the Department of Cardiology from a tertiary hospital for the first time. The assessment of the metabolic syndrome was made according to the ATP-III. RESULTS: The global prevalence of the MS was 27.3% (95% CI: 25.6-28.9), and increased parallel to age. The highest prevalence of MS was found in patients with diabetes or impaired fasting glucose (70.1%) followed by patients with obesity (58.6%) or hypertension (4.3%). MS conferred higher risk for IHD (OR: 5.5) as compared to diabetes (OR: 3.8). Half of the patients with IHD had MS as well as 90% of the diabetics with ischemic heart disease. MS conferred the highest risk for IHD in patients with obesity (OR: 8.6), hypertriglyceridemia (OR: 6.5), family history of IHD (OR: 5.6), overweight (OR: 5.5) or hypertension (OR: 4.6). CONCLUSIONS: MS is highly prevalent in the patients from a Cardiological outpatient clinic and is an important risk factor for IHD, especially in subjects with obesity.

Prevalencia de síndrome metabólico y asociación con la cardiopatía isquémica en pacientes cardiológicos ambulatorios / Prevalence of metabolic syndrome and association with ischemic heart disease in cardiological outpatients

Introducción. El síndrome metabólico (SM) es una asociación de factores de riesgo cardiovascular con un nexo fisiopatológico común: la resistencia insulínica. Analizamos su prevalencia y su impacto para la presencia de cardiopatía isquémica (CI). Métodos. Se registraron los datos de 1.000 pacientes consecutivos que acudieron por primera vez a la consulta externa de un Servicio de Cardiología de un hospital terciario. El diagnóstico del SM se realizó según los criterios del Adult Treatment Pannel (ATP-III). Resultados. La prevalencia global de SM fue del 27,3% (IC al 95%: 25,6-29,0) y aumentó de forma paralela a la edad. La mayor prevalencia se encontró entre los pacientes con diabetes mellitus o intolerancia hidrocarbonada (70,1%) seguidos de los que tienen obesidad (58,6%) o hipertensión (48,3%). El SM confirió mayor riesgo de CI (odds ratio [OR]: 5,5) que la diabetes (OR: 3,8). La mitad de los pacientes con CI presentaron síndrome metabólico y el 90% de los diabéticos con CI. El SM confiere el mayor riesgo de tener CI en los pacientes con obesidad (OR: 8,6), hipertrigliceridemia (OR: 6,5), antecedentes familiares de CI (OR: 5,6), sobrepeso (OR: 5,5) o hipertensión arterial (OR: 4,6). Conclusiones. El SM es altamente prevalente en los pacientes atendidos en una consulta de Cardiología y es un importante factor de riesgo para la CI, especialmente en los pacientes que tienen obesidad

Introduction. The metabolic syndrome (MS) is a cluster of cardiovascular risk factors with a common pathological link: insulin resistance. We analyzed its prevalence and its impact for the presence of ischemic heart disease (IHD). Methods. We recorded data from 1,000 consecutive patients that attended the outpatient clinic of the Department of Cardiology from a tertiary hospital for the first time. The assessment of the metabolic syndrome was made according to the ATP-III. Results. The global prevalence of the MS was 27.3% (95% CI: 25.6-28.9), and increased parallel to age. The highest prevalence of MS was found in patients with diabetes or impaired fasting glucose (70.1%) followed by patients with obesity (58.6%) or hypertension (4.3%). MS conferred higher risk for IHD (OR: 5.5) as compared to diabetes (OR: 3.8). Half of the patients with IHD had MS as well as 90% of the diabetics with ischemic heart disease. MS conferred the highest risk for IHD in patients with obesity (OR: 8.6), hypertriglyceridemia (OR: 6.5), family history of IHD (OR: 5.6), overweight (OR: 5.5) or hypertension (OR: 4.6). Conclusions. MS is highly prevalent in the patients from a Cardiological outpatient clinic and is an important risk factor for IHD, especially in subjects with obesity

Hipertensión arterial y síndrome metabólico / Hypertension and metabolic syndrome

Las interrelaciones existentes entre hipertensión arterial y el síndrome metabólico obedecen a nexos fisiopatológicos comunes y tienen importantes implicaciones terapéuticas y pronósticas. La obesidad, la resistencia insulínica y las alteraciones de la función renal se encuentran en el centro del sustrato fisiopatológico y deben ser el objetivo al que dirigir todas las estrategias preventivas y terapéuticas

The interrelations between hypertension and the metabolic syndrome are due to common physiopathologic links and have important therapeutic and prognostic implications. Obesity, insulin resistance, and renal dysfunction are in the core of the physiopathologic substrate and must be the main objective for preventive and therapeutical measures

Factores predictores de mortalidad de una cohorte clínica de pacientes ancianos / Mortality predictive factors of a clinical cohort of elderly patients

Objetivo. Estudiar la asociación entre las principales variables recogidas en la valoración geriátrica exhaustiva (VGE) y la mortalidad en una cohorte clínica de ancianos remitidos desde atención primaria, según criterios protocolizados, a una unidad de geriatría. Diseño. Estudio de cohorte clínica histórica. Emplazamiento. Consulta de la unidad de valoración geriátrica de un hospital de Madrid. Participantes. Un total de 140 pacientes > 65 años seguidos durante 70 meses. Mediciones principales. Se recogieron variables demogáficas, clínicas, funcionales y sociales durante la VGE realizada por un equipo multidisciplinario. Al cabo de 70 meses se valororó la supervivencia de esta cohorte y se analizaron los factores pronósticos de mortalidad mediante la técnica de riesgos proporcionales de Cox. Resultados. El 45% (n = 63) de los pacientes había fallecido tras los 70 meses del estudio, con una mediana de seguimiento de 37 meses. En el análisis univariable, la edad, el sexo masculino, el diagnóstico de neoplasia o enfermedad pulmonar obstructiva crónica, los índices de Katz y de Lawton y el Mini-Examen Cognoscitivo (MEC-35) se asociaron significativamente con mortalidad. En el análisis multivariable se mantuvieron como variables pronósticas de mortalidad: el MEC-35 (hazard ratio [HR] = 0,965; intervalo de confianza [IC] del 95%, 0,934-0,998; p = 0,037), el sexo masculino (HR = 2,75; IC del 95%, 1,6-4,74; p = 0,001), el índice de Katz (HR = 1,22; IC del 95%, 1,04-1,43; p = 0,017) y el índice de Lawton (HR = 0,93; IC del 95%, 0,82-1,07; p = 0,30). Conclusión. El deterioro cognitivo es un factor predictor de mortalidad (HR = 0,965), de manera que por cada punto de disminución del MEC-35 el riesgo de mortalidad a los 70 meses, ajustado por el sexo y los índices de Katz y Lawton, aumentará un 3,5% (1 ­ HR)

Objective. To study the association between the main variables collected in the comprehensive geriatric assessment (CGA) and mortality, in a clinical cohort of elderly people referred from primary care, following standardised criteria, to a geriatric unit. Design. Retrospective cohort study. Setting. Outpatient department of a geriatric unit of a hospital in Madrid, Spain. Participants. A total of 140 patients older than 65 years were followed up for 70 months. Main measurements. We collected demographic, clinical, functional, and social variables during the CGA carried out by a multidisciplinary team. After 70 months we measured this cohort survival and we analysed the predictive factors for mortality using Cox hazard ratio analysis. Results. Sixty three patients died after the 70 months of the study, and the survival median was 37 months. In the univariate analysis, age, male gender, diagnosed cancer, COPD, the Katz and Lawton indices, and the Mini-Mental State Examination (MMSE) score of 35 items, were significantly associated with mortality. In the multivariate analysis we found, as predictive factors for mortality: MMSE-35 (HR=0.965; 95% CI, 0.934-0.998; P=.037); male gender (HR=2.75; 95% CI, 1.6-4.74; P=.001); Katz score (HR=1.22; 95% CI, 1.04-1.43; P=.017); Lawton score (HR=0.93; 95% CI, 0.82-1.07; P=.30). Conclusion. Cognitive impairment is a mortality predictive factor (HR=0.65), for each point less in the MMSE-35, we observed an increase in mortality risk of 3.5% (1­HR) at 70 months, after adjustment for Katz and Lawton index and gender

Control of the refractive index in photopolymerizable materials for (2+1)D solitary wave guide formation.

We report an experimental and theoretical study on the optimization of (2+1)D self-written waveguide formation inside a photopolymerizable material. The accurate control of the refractive index value inside the bulk of the material during the polymerization process gives us the opportunity to define a virtual core and a virtual cladding for the system. The V value which characterizes the guidance properties of a fiber can be applied to this propagation. The control of the V value allows us to propagate single mode or multimode waveguides on a few centimeters. Numerical simulations of these waveguides based on a paraxial model including both photopolymerization and Kerr effect give very good agreement with our experimental results.

Growth-suppressive function of human connexin32 in a conditional immortalized mouse hepatocyte cell line.

Mouse hepatocytes immortalized with a temperature-sensitive allele of the SV40 large T-antigen (CHST8 cells) were found to lack the high expression of the gap junction proteins Cx26 and Cx32 that characterizes normal mouse hepatocytes, expressing instead Cx43 and Cx45 at minimal levels. In order to examine the growth suppressive function of Cx32 on hepatocytes, we transfected these CHST8 cells with human Cx32 complementary deoxyribonucleic acid and measured the growth rates at 33, 37, and 39 degrees C. Expression of human Cx32 and its messenger ribonucleic acid in the stable cell lines was confirmed by immunocytochemistry and by Western and Northern blots analyses. Dye transfer following lucifer yellow injection into the transfectants was extensive; Cx32 channels displayed unitary conductances of about 70 pS and were moderately voltage sensitive. When cultured at 33 and 39 degrees C, growth rates of both parental cells and transfectants were of the same level. When examined at 37 degrees C, growth rate of the transfectant, which highly expressed Cx32 at the membranes, was significantly decreased compared to the parental cells. However, no changes in the expression of Cx32 protein in the transfectants were observed between 33 and 37 degrees C. These results suggest that Cx32 expression could inhibit hepatocyte growth in vitro using the conditional immortalized cells. Cx32 transfectants using a conditional immortalized mouse hepatocyte may be useful for examining the mechanisms of growth and differentiation in hepatocytes by gap junction expression.

Gap junction expression and cell proliferation in differentiating cultures of Cx43 KO mouse hepatocytes.

Primary cultures of adult mouse hepatocytes are shown here to reexpress differentiated hepatocyte features following treatment with 2% DMSO and 10(-7) M glucagon. To examine the roles of gap junctional communication during hepatocyte growth and differentiation, we have compared treated and untreated hepatocytes from connexin (Cx)32-deficient [Cx32 knockout (KO)] and wild-type mice. In untreated cultures, DNA replication of Cx32 KO hepatocytes was markedly higher than of wild types. Although Cx26 mRNA levels remained high at all time points in wild-type and Cx32 KO hepatocytes, Cx32 mRNA and protein in wild-type hepatocytes underwent a marked decline, which recovered in 10-day treated cultures. Increased levels of Cx26 protein and junctional conductance were observed in Cx32 KO hepatocytes at 96 h in culture, a time when cell growth rate was high. Treatment with DMSO/glucagon highly reinduced Cx26 expression in Cx32 KO hepatocytes, and such treatment reinduced expression of both Cx32 and Cx26 expression in wild types. Dye transfer was not observed following Lucifer yellow injection into DMSO/glucagon-treated Cx32 KO hepatocytes, whereas the spread was extensive in wild types. Nevertheless, high junctional conductance values were observed in treated cells from both genotypes. These studies provide a method by which the differentiated phenotype can be obtained in cultured mouse hepatocytes and provide in vitro evidence that expression of gap junctions formed of Cx32 are involved in the regulation of growth of mouse hepatocytes.

Olfactory learning induces differential long-lasting changes in rat central olfactory pathways.

In the present work, we investigated lasting changes induced by olfactory learning at different levels of the olfactory pathways. For this, evoked field potentials induced by electrical stimulation of the olfactory bulb were recorded simultaneously in the anterior piriform cortex, the posterior piriform cortex, the lateral entorhinal cortex and the dentate gyrus. The amplitude of the evoked field potential's main component was measured in each site before, immediately after, and 20 days after completion of associative learning. Evoked field potential recordings were carried out under two experimental conditions in the same animals: awake and anesthetized. In the learning task, rats were trained to associate electrical stimulation of one olfactory bulb electrode with the delivery of sucrose (positive reward), and stimulation of a second olfactory bulb electrode with the delivery of quinine (negative reward). In this way, stimulation of the same olfactory bulb electrodes used for inducing field potentials served as a discriminative cue in the learning paradigm. The data showed that positively reinforced learning resulted in a lasting increase in evoked field potential amplitude restricted to posterior piriform cortex and lateral entorhinal cortex. In contrast, negatively reinforced learning was mainly accompanied by a decrease in evoked field potential amplitude in the dentate gyrus. Moreover, the expression of these learning-related changes occurred to be modulated by the animals arousal state. Indeed, the comparison between anesthetized versus awake animals showed that although globally similar, the changes were expressed earlier with respect to learning, under anesthesia than in the awake state. From these data we suggest that associative olfactory learning involves different neural circuits depending on the acquired value of the stimulus. Furthermore, they show the existence of a functional dissociation between anterior and posterior piriform cortex in mnesic processes, and stress the importance of the animal's arousal state on the expression of learning-induced plasticity.

Neurophysiological mechanisms of auditory selective attention in humans.

This chapter reviews the main data on the physiological substrates of auditory selective attention and their contribution to theoretical models of cognitive psychology. While event-related potentials, magnetoencephalography, and more recently neuroimaging techniques have provided fundamental information on the neural correlates of attention in the central cortical system, measurements of the frequency-following responses in the brainstem and evoked otoacoustic emissions at the cochlea strongly suggest attentional phenomena at the auditory periphery. We propose an adaptive filtering mechanism for selective auditory attention that can be flexibly and dynamically tuned depending on the attentional demand.

A real-time two-dimensional pulsed-wave Doppler system.

An experimental system was developed to acquire and visualise in real-time two-dimensional (2-D) velocity maps. Data acquisition is performed by using a modified commercial echograph based on a 5-MHz, 128-element linear-array transducer with electronic focussing and beam steering. Additional electronics were integrated into the echograph to implement a 2-D Doppler system capable of measuring the velocity component on the scanning plane. Suitable axial and lateral scanning methods were studied to obtain Doppler measurements over a scanning area. A colour image of the estimated velocity field is presented in real time on a personal computer using different visualisation techniques. The system performance was tested experimentally both in vitro and in vivo on a human carotid artery.