Ethanol-derived acetaldehyde: pleasure and pain of alcohol mechanism of action

Acetaldehyde (ACD), the first metabolite of ethanol (EtOH), has been implicated in several actions of alcohol, including its reinforcing effects. Previously considered an aversive compound, ACD was useful in alcoholic’s pharmacological treatment aimed at discouraging alcohol drinking. However, it has recently been shown that EtOH-derived ACD is necessary for EtOH-induced place preference and self-administration, thereby suggesting a possible involvement of ACD in EtOH motivational properties. In addition, EtOH-stimulating properties on DA neurons are prevented by pharmacological blockade of local catalase H2O2 system, the main metabolic step for biotransformation of EtOH into ACD within the central nervous system. It was further shown that pretreatment with thiol compounds, like L-Cysteine or D-Penicillamine, reduced EtOH and ACD-induced motivational effects, in fact preventing self-administration of both EtOH and ACD, thus suggesting a possible role for ACD as a biomarker useful in evaluating potential innovative treatments of alcohol abuse. These findings suggest a key role of ACD in the EtOH reinforcing effects. In the present paper we review the role of EtOH-derived ACD in the reinforcing effects of EtOH and the possibility that ACD may serve as a therapeutically targetable biomarker in the search for novel treatments in alcohol abuse and alcoholi

Long-acting combination of cabotegravir plus rilpivirine: A picture of potential eligible and ineligible HIV-positive individuals from the Italian ARCA cohort

Objectives: We aimed to evaluate the prevalence and characteristics of people living with HIV (PLWH) eligible for the long-acting injectable (LAI) regimen with cabotegravir (CAB) and rilpivirine (RPV), in comparison with ineligible individuals. Methods: This was an observational, cross-sectional study from the ARCA cohort, including virologically suppressed PLWH with at least one genotypic resistance testing (GRT) for reverse transcriptase and integrase from plasma and/or PBMCs. Eligibility criteria for LAI CAB+RPV were: negative HBsAg, absence of previous virological failures and/or resistance-associated mutations for non-nucleoside reverse transcriptase inhibitors (NNRTIs) and/or integrase strand transfer inhibitors. Potential differences between eligible and ineligible individuals were investigated by univariable and multivariable analyses. Results: A total of 514 individuals were included: 377 (73.3%) were male, median age was 51 (IQR: 43–58), on ART for 9 years (IQR: 4–17), virologically suppressed for 63 months (IQR: 35–105). Eligible individuals for CAB+RPV were 229 (44.5%, 95%CI: 40.8–48.8); compared with ineligible individuals, they received a lower number of previous regimens (aOR 0.76, 95% CI 0.71–0.83, P < 0.001) and were on current NNRTIs (aOR 2.16, 95% CI 1.38–3.37, P = 0.001). Conclusions: Less than half of virologically suppressed PLWH in the ARCA cohort were potentially eligible for CAB+RPV. They seem to be “less complicated” with shorter exposure to ART and preferably already on NNRTIs

Notulae to the Italian alien vascular flora: 11

In this contribution, new data concerning the distribution of vascular flora alien to Italy are presented. It includes new records, confirmations, exclusions, and status changes for Italy or for Italian administrative regions. Nomenclatural and distribution updates published elsewhere are provided as Suppl. material 1

Effect of L-cysteine on acetaldehyde self-administration

Acetaldehyde (ACD), the first metabolite of ethanol, has been implicated in several behavioural actions of alcohol, including its reinforcing effects. Recently, we reported that L-cysteine, a sequestrating agent of ACD, reduced oral ethanol self-administration and that ACD was orally self-administered. This study examined the effects of L-cysteine pre-treatment during the acquisition and maintenance phases of ACD (0.2%) self-administration as well as on the deprivation effect after ACD extinction and on a progressive ratio (PR) schedule of reinforcement. In a separate PR schedule of reinforcement, the effect of L-cysteine was assessed on the break-point produced by ethanol (10%). Furthermore, we tested the effect of L-cysteine on saccharin (0.2%) reinforcement. Wistar rats were trained to self-administer ACD by nose poking on a fixed ratio (FR1) schedule in 30-min daily sessions. Responses on an active nose-poke caused delivery of ACD solution, whereas responses on an inactive nose-poke had no consequences. L-cysteine reduced the acquisition (40 mg/kg), the maintenance and the deprivation effect (100 mg/kg) of ACD self-administration. Furthermore, at the same dose, L-cysteine (120 mg/kg) decreased both ACD and ethanol break point. In addition, L-cysteine was unable to suppress the different responses for saccharin, suggesting that its effect did not relate to an unspecific decrease in a general motivational state. Compared to saline, L-cysteine did not modify responses on inactive nose-pokes, suggesting an absence of a non-specific behavioural activation. Taken together, these results could support the hypotheses that ACD possesses reinforcing properties and L-cysteine reduces motivation to self-administer ACD

Recent Advances in Inflammation and Treatment of Small Airways in Asthma

Small airways were historically considered to be almost irrelevant in the development and control of pulmonary chronic diseases but, as a matter of fact, in the past few years we have learned that they are not so &#8220;silent&#8221;. Asthma is still a worldwide health issue due to the great share of patients being far from optimal management. Several studies have shown that the deeper lung inflammation plays a critical role in asthma pathogenesis, mostly in these not well-controlled subjects. Therefore, assessing the degree of small airways inflammation and impairment appears to be a pivotal step in the asthmatic patient&#8217;s management. It is now possible to evaluate them through direct and indirect measurements, even if some obstacles still affect their clinical application. The success of any treatment obviously depends on several factors but reaching the deeper lung has become a priority and, for inhaled drugs, this is strictly connected to the molecule&#8217;s size. The aim of the present review is to summarize the recent evidence concerning the small airway involvement in asthma, its physiopathological characteristics and how it can be evaluated in order to undertake a personalized pharmacological treatment and achieve a better disease control

Effect of opioid receptor blockade on acetaldehyde self-administration and ERK phosphorylation in the rat nucleus accumbens

We have previously shown that acetaldehyde (ACD), the first metabolite of ethanol, regulates its motivational properties and possesses reinforcing effects by itself. A large and still growing body of evidence indicates that the endogenous opioidergic system plays a critical role in the motivational effects of ethanol and suggests a role for extracellular signal-regulated kinase (ERK) in these effects of both ethanol and ACD. The present study was undertaken to examine if opioid-mediated mechanisms are involved in the reinforcing properties of ACD and in ACD-elicited ERK activation. To this end, Wistar rats were trained to orally self-administer ACD (0.2%) by nose poking. Responses on active nose poke caused delivery of ACD solution, whereas responses on inactive nose poke had no consequences. The effect of pretreatment with a nonselective opioid receptor antagonist, naltrexone (NTX), was evaluated during (1) maintenance of ACD self-administration, (2) deprivation effect after ACD extinction, and (3) ACD self-administration under a progressive-ratio schedule of reinforcement. Additionally, we tested the effect of NTX on saccharin (0.05%) reinforcement, as assessed by oral self-administration, and on ACD-elicited ERK phosphorylation in the nucleus accumbens (Acb), as assessed by immunohistochemistry. Finally, we examined the effect of a μ1-selective opioid receptor antagonist, naloxonazine (NLZ), on the maintenance phase of ACD and saccharin self-administration. The results indicate that NTX (0.4–0.8 mg/kg) reduced the maintenance, the deprivation effect, and the break points of ACD self-administration without suppressing saccharin self-administration. Moreover, NTX decreased ACD-elicited ERK activation in the Acb shell and core. NLZ (10–15 mg/kg) reduced the maintenance phase of ACD self-administration without interfering with saccharin self-administration, whereas both NTX and NLZ failed to modify responses on inactive nose poke indicating the lack of a nonspecific behavioral activation. Overall, these results indicate that the opioid system is implicated in the reinforcing properties of ACD and suggest an involvement of ERK. The finding that NTX and NLZ reduce ACD but not saccharin self-administration indicates that these effects are specific to ACD

Altered neuronal activity in the ventromedial prefrontal cortex drives nicotine intake escalation

International audienc

Fibronectin promotes elastin deposition, elasticity and mechanical strength in cellularised collagen-based scaffolds

One of the tightest bottlenecks in vascular tissue engineering (vTE) is the lack of strength and elasticity of engineered vascular wall models caused by limited elastic fiber deposition. In this study, flat and tubular collagen gel-based scaffolds were cellularised with vascular smooth muscle cells (SMCs) and supplemented with human plasma fibronectin (FN), a known master organizer of several extracellular matrix (ECM) fiber systems. The consequences of FN on construct maturation was investigated in terms of geometrical contraction, viscoelastic mechanical properties and deposition of core elastic fiber proteins. FN was retained in the constructs and promoted deposition of elastin by SMCs as well as of several proteins required for elastogenesis such as fibrillin-1, lysyl oxidase, fibulin-4 and latent TGF-beta binding protein-4. Notably, gel contraction, tensile equilibrium elastic modulus and elasticity were strongly improved in tubular engineered tissues, approaching the behaviour of native arteries. In conclusion, this study demonstrates that FN exerts pivotal roles in directing SMC-mediated remodeling of scaffolds toward the production of a physiological-like, elastin-containing ECM with excellent mechanical properties. The developed FN-supplemented systems are promising for tissue engineering applications where the generation of mature elastic tissue is desired and represent valuable advanced in vitro models to investigate elastogenesis. (C) 2018 Elsevier Ltd. All rights reserved

Hampered long-term depression and thin spine loss in the nucleus accumbens of ethanol-dependent rats

Alcoholism involves long-term cognitive deficits, including memory impairment, resulting in substantial cost to society. Neuronal refinement and stabilization are hypothesized to confer resilience to poor decision making and addictive-like behaviors, such as excessive ethanol drinking and dependence. Accordingly, structural abnormalities are likely to contribute to synaptic dysfunctions that occur from suddenly ceasing the use of alcohol after chronic ingestion. Here we show that ethanol-dependent rats display a loss of dendritic spines in medium spiny neurons of the nucleus accumbens (Nacc) shell, accompanied by a reduction of tyrosine hydroxylase immunostaining and postsynaptic density 95-positive elements. Further analysis indicates that "long thin" but not "mushroom" spines are selectively affected. In addition, patch-clamp experiments from Nacc slices reveal that long-term depression (LTD) formation is hampered, with parallel changes in field potential recordings and reductions in NMDA-mediated synaptic currents. These changes are restricted to the withdrawal phase of ethanol dependence, suggesting their relevance in the genesis of signs and/or symptoms affecting ethanol withdrawal and thus the whole addictive cycle. Overall, these results highlight the key role of dynamic alterations in dendritic spines and their presynaptic afferents in the evolution of alcohol dependence. Furthermore, they suggest that the selective loss of long thin spines together with a reduced NMDA receptor function may affect learning. Disruption of this LTD could contribute to the rigid emotional and motivational state observed in alcohol dependence

Hampered long-term depression and thin spine loss in the nucleus accumbens of ethanol-dependent rats

Alcoholism involves long-term cognitive deficits, including memory impairment, resulting in substantial cost to society. Neuronal refinement and stabilization are hypothesized to confer resilience to poor decision making and addictive-like behaviors, such as excessive ethanol drinking and dependence. Accordingly, structural abnormalities are likely to contribute to synaptic dysfunctions that occur from suddenly ceasing the use of alcohol after chronic ingestion. Here we show that ethanol-dependent rats display a loss of dendritic spines in medium spiny neurons of the nucleus accumbens (Nacc) shell, accompanied by a reduction of tyrosine hydroxylase immunostaining and postsynaptic density 95-positive elements. Further analysis indicates that &#8220;long thin&#8221; but not &#8220;mushroom&#8221; spines are selectively affected. In addition, patch-clamp experiments from Nacc slices reveal that long-term depression (LTD) formation is hampered, with parallel changes in field potential recordings and reductions in NMDA-mediated synaptic currents. These changes are restricted to the withdrawal phase of ethanol dependence, suggesting their relevance in the genesis of signs and/or symptoms affecting ethanol withdrawal and thus the whole addictive cycle. Overall, these results highlight the key role of dynamic alterations in dendritic spines and their presynaptic afferents in the evolution of alcohol dependence. Furthermore, they suggest that the selective loss of long thin spines together with a reduced NMDA receptor function may affect learning. Disruption of this LTD could contribute to the rigid emotional and motivational state observed in alcohol dependence