Nicotine inside neurons

The crucial effects of chronic nicotine exposure are intracellular and include a cell-specific influence on the assembly and stoichiometry of the nAChRs exported to the plasma membrane, that affects the function of surface nAChRs and cholinergic transmission. In this context, it is worthwhile to consider extraneuronal tissues, especially where nicotine may reach much higher concentrations such as the lung epithelia. Many peripheral cell types and tissues express nAChR subunit transcripts, that may play crucial roles in signal transduction underlying tumor initiation or growt

Evidence for a protective effect of the loss of α4-containing nicotinic acetylcholine receptors on Aβ-related neuropathology in Tg2576 mice

International audienceIntroduction Loss of cholinergic neurons as well as α4β2* (* = containing) nicotinic acetylcholine receptors (nAChRs) is a prominent feature of Alzheimer’s disease (AD). Specifically, amyloid β (Aβ), the principal pathogenic factor of AD, is a high affinity ligand for nAChRs. Yet, the pathophysiological role of nAChRs in AD is not well established. Methods In the present study, we have investigated the effects of the loss of α4* nAChRs on the histological alterations of the Tg2576 mouse model of AD (APPswe) crossing hemizygous APPswe mice with mice carrying the genetic inactivation of α4 nAChR subunit (α4KO). Results A global decrease in Aβ plaque load was observed in the forebrain of APPswe/α4KO mice in comparison with APPswe mice, that was particularly marked in neocortex of 15 month-old mice. At the same age, several alterations in synaptophysin immunoreactivity were observed in cortico-hippocampal regions of APPswe mice that were partially counteracted by α4KO. The analysis of the immunoreactivity of specific astroglia (glial fibrillary acidic protein, GFAP) and microglia (ionized calcium-binding adapter molecule, Iba1) markers showed an increase in the number as well as in the area occupied by these cells in APPswe mice that were partially counteracted by α4KO. Conclusion Overall, the present histological study points to a detrimental role of α4* nAChRs that may be specific for Aβ-related neuropathology

Delirium in Older Adults: What a Surgeon Needs to Know

Delirium remains a challenging clinical problem in hospitalized older adults, especially for postoperative patients. This complication, with a high risk of postoperative mortality and an increased length of stay, frequently occurs in older adult patients. This brief narrative paper aims to review the recent literature regarding delirium and its most recent update. We also offer physicians a brief and essential clinical practice guide to managing this acute and common disease

Insights into different marine aquaculture infrastructures from a life cycle perspective

Aquaculture facilities represent an often-neglected process in environmental impact studies. This study focus on the environmental impact assessment of alternative net materials in Mediterranean marine aquaculture. A Life Cycle Assessment was conducted using primary and secondary data from specific databases and literature. Three baseline scenarios were compared: copper alloy net cages with 100 % of recycled material (CAN100), 75 % of recycled material (CAN75), and polyethylene net (PEN) System boundaries include manufacturing and disposal of cages, nets, and mooring system. The use and emissions of antifouling paints and CAN were considered. Sensitivity analysis of the most impacting sub-processes and Uncertainty analysis were also conducted. The use of CAN is advantageous in terms of environmental impact, but only considering a complete recyclability of the net at the end of its service life. Moreover, when considering a reduced service life of the PEN due to the detrimental effect of biofouling, the advantage of the CAN is even more evident. To counteract the negative effect of biofouling, copper-based antifouling paints are generally used in marine aquaculture. These products are a main environmental hotspot in PEN systems. Therefore, a higher consumption of such products could determine an environmental burden shifting from CAN to PEN ones. So far, CAN are not widespread in the aquaculture industry, mainly due to the high cost of initial investment compared to traditional PEN. Considering operational and environmental advantages, CAN cages could represent an affordable and resilient solution for aquaculture enhancing environmental, economic, and social performances of this industr

Whole organic electronic synapses for dopamine detection

A whole organic artificial synapse has been fabricated by patterning PEDOT:PSS electrodes on PDMS that are biased in frequency to yield a STP response. The timescale of the STP response is shown to be sensitive to the concentration of dopamine, DA, a neurotransmitter relevant for monitoring the development of Parkinson's disease and potential locoregional therapies. The sensitivity of the sensor towards DA has been validated comparing signal variation in the presence of DA and its principal interfering agent, ascorbic acid, AA. The whole organic synapse is biocompatible, soft and flexible, and is attractive for implantable devices aimed to real-time monitoring of DA concentration in bodily fluids. This may open applications in chronic neurodegenerative diseases such as Parkinson's disease

DAT atypical inhibitors as novel antipsychotic drugs

Despite its classification as a psychiatric disease, schizophrenia is both a behavioral and a biological disorder resulting in neurocognitive dysfunction. Social and economic costs of schizophrenia are extremely high compared to its incidence and prevalence, however, due to a heterogeneous pattern of brain pathology and symptoms and to an unknown etiology, developing an effective treatment has been really challenging. Among the many neurochemical hypothesis, the dysregulation of dopaminergic neurotransmission has been considered as a central dogma of schizophrenia over the last few decades. In fact, patients with this pathology exhibit increased dopamine (DA) synthesis and release in the striatum which seems to correlate with positive symptoms and moreover, most of the effective antipsychotic drugs (APDs) are D2-receptor antagonists. Unfortunately, chronic treatment with APDs is associated with the induction of extrapyramidal side effects (EPS). In order to identify new possible APDs with a novel mechanism of action and potentially less EPS we tested 3 different compounds generated from the structural modification of vanoxerine (or GBR12909), a known atypical inhibitor of the presynaptic DA transporter (DAT) with cocaine-like activity but cardiotoxic properties that have precluded its clinical use. Preliminary in vitro studies showed that DAhLIs (DAT atypical inhibitors) are able to bind to DAT and inhibit DA reuptake. Additionally, our in vivo results showed that DAhLI i) have putative central effects, ii), unlike vanoxerine, reduce novelty-induced locomotor activity, and iii) counteract cocaine stimulating effects, suggesting that DAhLI may potentiate DA reuptake via DAT. These compounds may provide a way to reduce DA extracellular levels and DA neurotransmission with a selective action on active DA synapses, thus with reduced EPS typical of D2 antagonists, representing a new promising class of presynaptic APDs

A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants

Background: Cluster Headache (CH) is a severe primary headache, with a poorly understood pathophysiology. Complex genetic factors are likely to play a role in CH etiology; however, no confirmed gene associations have been identified. The aim of this study is to identify genetic variants influencing risk to CH and to explore the potential pathogenic mechanisms. Methods: We have performed a genome-wide association study (GWAS) in a clinically well-defined cohort of 99 Italian patients with CH and in a control sample of 360 age-matched sigarette smoking healthy individuals, using the Infinium PsychArray (Illumina), which combines common highly-informative genome-wide tag SNPs and exonic SNPs. Genotype data were used to carry out a genome-wide single marker case-control association analysis using common SNPs, and a gene-based association analysis focussing on rare protein altering variants in 745 candidate genes with a putative role in CH. Results: Although no single variant showed statistically significant association at the genome-wide threshold, we identified an interesting suggestive association (P = 9.1 7 10 126) with a common variant of the PACAP receptor gene (ADCYAP1R1). Furthermore, gene-based analysis provided significant evidence of association (P = 2.5 7 10 125) for a rare potentially damaging missense variant in the MME gene, encoding for the membrane metallo-endopeptidase neprilysin. Conclusions: Our study represents the first genome-wide association study of common SNPs and rare exonic variants influencing risk for CH. The most interesting results implicate ADCYAP1R1 and MME gene variants in CH susceptibility and point to a role for genes involved in pain processing. These findings provide new insights into the pathogenesis of CH that need further investigation and replication in larger CH samples

O015. Evaluation of the genetic polymorphism of the α3 (CHRNA3) and α5 (CHRNA5) nicotinic receptor subunits, in patients with cluster headache

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Proteomic research of proteins involved in pain expression in an animal model of chronic pain

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Serum protein changes in a rat model of chronic pain show a correlation between animal and humans

In previous works we showed the overexpression of some proteins in biological fluids from patients suffering chronic pain. In this proteomic study we analysed serum from a rat model of neuropathic pain obtained by the chronic constriction injury (CCI) of sciatic nerve, at two time intervals, 2 and 5 weeks after the insult, to find proteins involved in the expression or mediation of pain. Sham-operated and CCI rats were treated with saline or indomethacin. Two weeks after ligation, we identified three serum proteins overexpressed in CCI rats, two of which, alpha-1-macroglobulin and vitamin D-binding protein (VDBP), remained increased 5 weeks post-surgery; at this time interval, we found increased levels of further proteins, namely apolipoprotein A-I (APOA1), apolipoprotein E (APOE), prostaglandin-H2 D-isomerase (PTGDS) and transthyretin (TTR), that overlap the overexpressed proteins found in humans. Indomethacin treatment reversed the effects of ligation. The qPCR analysis showed that transcript levels of APOA1, APOE, PTGDS and VDBP were overexpressed in the lumbar spinal cord (origin of sciatic nerve), but not in the striatum (an unrelated brain region), of CCI rats treated with saline 5 weeks after surgery, demonstrating that the lumbar spinal cord is a possible source of these proteins