Avoidable blindness and value based healthcare: More value with a population approach

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Dual Effect of Beta-Amyloid on α7 and α4β2 Nicotinic Receptors Controlling the Release of Glutamate, Aspartate and GABA in Rat Hippocampus

BACKGROUND: We previously showed that beta-amyloid (Aβ), a peptide considered as relevant to Alzheimer's Disease, is able to act as a neuromodulator affecting neurotransmitter release in absence of evident sign of neurotoxicity in two different rat brain areas. In this paper we focused on the hippocampus, a brain area which is sensitive to Alzheimer's Disease pathology, evaluating the effect of Aβ (at different concentrations) on the neurotransmitter release stimulated by the activation of pre-synaptic cholinergic nicotinic receptors (nAChRs, α4β2 and α7 subtypes). Particularly, we focused on some neurotransmitters that are usually involved in learning and memory: glutamate, aspartate and GABA. METHODOLOGY/FINDINGS: WE USED A DUAL APPROACH: in vivo experiments (microdialysis technique on freely moving rats) in parallel to in vitro experiments (isolated nerve endings derived from rat hippocampus). Both in vivo and in vitro the administration of nicotine stimulated an overflow of aspartate, glutamate and GABA. This effect was greatly inhibited by the highest concentrations of Aβ considered (10 µM in vivo and 100 nM in vitro). In vivo administration of 100 nM Aβ (the lowest concentration considered) potentiated the GABA overflow evoked by nicotine. All these effects were specific for Aβ and for nicotinic secretory stimuli. The in vitro administration of either choline or 5-Iodo-A-85380 dihydrochloride (α7 and α4β2 nAChRs selective agonists, respectively) elicited the hippocampal release of aspartate, glutamate, and GABA. High Aβ concentrations (100 nM) inhibited the overflow of all three neurotransmitters evoked by both choline and 5-Iodo-A-85380 dihydrochloride. On the contrary, low Aβ concentrations (1 nM and 100 pM) selectively acted on α7 subtypes potentiating the choline-induced release of both aspartate and glutamate, but not the one of GABA. CONCLUSIONS/SIGNIFICANCE: The results reinforce the concept that Aβ has relevant neuromodulatory effects, which may span from facilitation to inhibition of stimulated release depending upon the concentration used

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

Rationale Most habitual smokers find it difficult to quit smoking because they are dependent upon the nicotine present in tobacco smoke. Tobacco dependence is commonly treated pharmacologically using nicotine replacement therapy or drugs, such as varenicline, that target the nicotinic receptor. Relapse rates, however, remain high and there remains a need to develop novel non-nicotinic pharmacotherapies for the dependence that are more effective than existing treatments. Objective The purpose of this paper is to review the evidence from preclinical and clinical studies that drugs that antagonise the metabotropic glutamate receptor 5 (mGluR5) in the brain are likely to be efficacious as treatments for tobacco dependence. Results Imaging studies reveal that chronic exposure to tobacco smoke reduces the density of mGluR5s in human brain. Preclinical results demonstrate that negative allosteric modulators (NAMs) at mGluR5 attenuate both nicotine self-administration and the reinstatement of responding evoked by exposure to conditioned cues paired with nicotine delivery. They also attenuate the effects of nicotine on brain dopamine pathways implicated in addiction. Conclusions Although mGluR5 NAMs attenuate most of the key facets of nicotine dependence they potentiate the symptoms of nicotine withdrawal. This may limit their value as smoking cessation aids. The NAMs that have been employed most widely in preclinical studies of nicotine dependence have too many \u201coff target\u201d effects to be used clinically. However newer mGluR5 NAMs have been developed for clinical use in other indications. Future studies will determine if these agents can also be used effectively and safely to treat tobacco dependence

Estimación integral de emisiones por motores de combustión en el Aeropuerto Internacional Rosario y de la dispersión en su entorno

Resumen: Sobre la base del tipo de motores que participan en movimientos aéreos y terrestres en el área del Aeropuerto Internacional Islas Malvinas de la ciudad de Rosario, Argentina, del tiempo y régimen de actividad, y de sus emisiones típicas conocidas a partir de los correspondientes manuales de emisión, se analiza la estadística de 9.484 vuelos y de 407.302 movimientos vehiculares terrestres durante el año 2016 para estimar sus emisiones netas y su alcance. Se ha cuantificado una emisión total anual de 111.372 t de dióxido de carbono (CO2 ), 5.799 t de monóxido de carbono (CO), 3.070 t de óxidos de nitrógeno (NOx ), y 990 t de hidrocarburos. Para cada uno de ellos se realiza un análisis estacional. La dispersión de los contaminantes se analiza mediante el software ALOHA haciendo uso de la rosa de los vientos característica de la zona. Las direcciones NO, O y SO predominan en la dispersión. Dentro de las simplificaciones asumidas, en estado puro el óxido nítrico (NO) es el contaminante potencialmente con mayor alcance, de hasta un par de kilómetros, seguido por dióxido de nitrógeno (NO2 ) y el monóxido de carbono (CO). Se contextualiza con la contaminación típica de la ciudad de Rosario, con la proyección hacia años futuros, y con la bibliografía disponible de estudios similares en otros aeropuertos.Abstract: Based on the type of engines involved in air and land movements in the area of the Islas Malvinas International Airport in the city of Rosario, Argentina, their time and activity regime, and their typical emissions known from the corresponding emission manuals, the statistics of 9,484 flights and 407,302 land vehicle movements during 2016 are analyzed to estimate their net emissions and scope. A total annual emission of 111,372 t of carbon dioxide (CO2 ), 5,799 t of carbon monoxide (CO), 3,069 t of nitrogen oxides (NOx ), and 990 t of hydrocarbons has been quantified. A seasonal analysis is carried out for each of them. The dispersion of the pollutants is analyzed using the ALOHA software making use of the wind rose characteristic of the area. The NW, W and SW directions predominate in the dispersion. Within the simplifications assumed, in its pure state nitric oxide (NO) is potentially the pollutant with the longest range, up to a couple of kilometers, followed by nitrogen dioxide (NO2 ) and carbon monoxide (CO). Results are contextualized with the typical pollution of the city of Rosario, with the projection towards future years, and with the available bibliography of similar studies in other airports