The conditioning of medical gases with hot water humidifiers

During invasive mechanical ventilation due to the dryness of medical gases is necessary to provide an adequate level of conditioning. The hot water humidifiers (HWH) heat the water, thus allowing the water vapor to heat and humidify the medical gases. In the common HWH there is a contact between the medical gases and the sterile water, thus increasing the risk of patient’s colonization and infection. Recently to avoid the condensation in the inspiratory limb of the ventilator circuit, new heated ventilator circuits have been developed. In this in vitro study we evaluated the efficiency (absolute/relative humidity) of three HWH: (1) a common HWH without a heated ventilator circuit (MR 730, Fisher&Paykel, New Zeland), (2) the same HWH with a heated ventilator circuit (Mallinckrodt Dar, Italy) and (3) a new HWH (DAR HC 2000, Mallinkckrodt Dar, Italy) with a heated ventilator circuit in which the water vapor reaches the medical gases through a gorotex membrane, avoiding any direct contact between the water and gases. At a temperature of 35°C and 37°C the HWH and heated tube were evaluated. The absolute humidity (AH) and relative humidity (RH) were measured by a psychometric method. The minute ventilation, tidal volume respiratory rate and oxygen fraction were: 5.8 ± 0.1 l/min, 740 ± 258 ml, 7.5 ± 2.6 bpm and 100%, respectively. Ventilator P2 Use of a bougie during percutaneous tracheostom

Centella asiatica l. Phytosome improves cognitive performance by promoting bdnf expression in rat prefrontal cortex

A wide range of people in the world use natural remedies as primary approaches against illnesses. Accordingly, understanding the mechanisms of action of phytochemicals has become of great interest. In this context, Centella asiatica L. is extensively used, not only as anti-inflammatory or antioxidant agent but also as brain tonic. On this basis, the purpose of this study was to evaluate whether the chronic administration of C. asiatica L. to adult male rats was able to improve the expression of Bdnf, one of the main mediators of brain plasticity. Moreover, we assessed whether the treatment could affect the cognitive performance in the novel object recognition (NOR) test. We confirmed the presence of the main compounds in the plasma. Furthermore, C. asiatica L. administration induced an increase of Bdnf in the prefrontal cortex, and the administration of the higher dose of the extract was able to improve cognitive performance. Finally, the increase in the preference index in the NOR test was paralleled by a further increase in Bdnf expression. Overall, we highlight the ability of C. asiatica L. to affect brain functions by increasing Bdnf expression and by enhancing the cognitive performance

PHARMACOLOGICAL APPROACHES TO SARS-CoV-2 INFECTION: FROM DRUG REPOSITIONING FOR COVID-19 TREATMENT TO DISEASE ARREST/PREVENTION WITH MoAbs AND NOVEL ANTIVIRALS

COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the major emergencies that have affected health care systems and society in recent decades. At the end of winter 2021-2022, the number of patients infected with SARS-CoV-2 and especially those suffering from severe COVID-19 is decreasing in Europe. This is due to the protective effect of anti-SARS-CoV-2 vaccines and the increasing number of people who had COVID-19, thus developing a certain immunity. However, vaccines to prevent the disease did not appear until more than one year after the emergence of SARS-CoV-2, so the initial medical approaches to control the disease focused on the existing drugs that were considered suitable for controlling the pathological events caused by the virus as far as was known at the time. Unfortunately, due in part to the limited initial knowledge of the molecular details of the pathology of COVID-19, many of the proposed drugs fell short of expectations and were abandoned. Over time, the challenge of understanding the mechanisms behind COVID-19 has generated a large body of knowledge about how this beta-coronavirus gains control of the host during infection, a knowledge that has been used to redefine treatment strategies by repurposing existing drugs and to explore new drugs. Here, we draw a picture of the major strategies and groups of drugs studied and provide a critical overview of their efficacy and safety based on the available literature data. The main topics covered are repurposed drugs, anticoagulants, anti-cytokine agents, monoclonal antibodies against SARS-CoV-2, and small antiviral molecules

Peroxynitrite Inhibits Glutamate Transporter Subtypes

The reuptake of glutamate in neurons and astrocytes terminates excitatory signals and prevents the persistence of excitotoxic levels of glutamate in the synaptic cleft. This process is inhibited by oxygen radicals and hydrogen peroxide (H2O2). Here we show that another biological oxidant, peroxynitrite (ONOO-), formed by combination of superoxide (O2-) and nitric oxide (NO), potently inhibits glutamate uptake by purified or recombinant high affinity glutamate transporters reconstituted in liposomes. ONOO- reduces selectively the Vmax of transport; its action is fast (reachingor = 90% within 20 s), dose-dependent (50% inhibition at 50 microM), persistent upon ONOO- (or by product) removal, and insensitive to the presence of the lipid antioxidant vitamin E in the liposomal membranes. Therefore, it likely depends on direct interaction of ONOO- with the glutamate transporters. Three distinct recombinant glutamate transporters from the rat brain, GLT1, GLAST, and EAAC1, exhibit identical sensitivity to ONOO . H2O2 also inhibits reconstituted transport, and its action matches that of ONOO- on all respects; however, this is observed only with 5-10 mM H202 and after prolonged exposure (10 min) in highly oxygenated buffer. NO, released from NO donors (up to 10 mM), does not modify reconstituted glutamate uptake, although in parallel conditions it promotes cGMP formation in synaptosomal cytosolic fraction. Overall, our results suggest that the glutamate transporters contain conserved sites in their structures conferring vulnerability to ONOO- and other oxidants

Synaptoproteomic analysis of a rat gene-environment model of depression reveals involvement of energy metabolism and cellular remodeling pathways

Major depression is a severe mental illness that causes heavy social and economic burden worldwide. A number of studies have shown that interaction between individual genetic vulnerability and environmental risk factors, such as stress, is crucial in psychiatric pathophysiology. In particular, the experience of stressful events in childhood, such as neglect, abuse or parent loss, was found to increase the risk for development of depression in adult life. Here, to reproduce the gene x environment interaction, we employed an animal model that combines genetic vulnerability with early-life stress

The activation of the immune/inflammatory system is associated with the stress-induced anhedonia in rats: effect of pharmacological intervention

Despite the increased knowledge of depression neurobiology, an effective improvement in the overall impact of pharmacotherapy is still lacking, possibly because a number of systems that are affected in mood disorders may not be adequately modulated by pharmacological treatments. Indeed, it is known that this complex disorder is characterized by the interaction of many factors of different nature -i.e. genetic, biological, social and environmental- that act in concert to lead to the development of the illness. Currently, there is strong evidence that depression involves alterations of the immune/inflammatory systems, thus pointing to the importance to characterize this association as well as evaluate the potential impact of pharmacological intervention to interfere with such alterations. On these bases, the purpose of our study was to analyze the cerebral expression of several mediators of the immune/inflammatory system in an animal model of depression based on the environmental component of the disease. Specifically, we used the well-established chronic mild stress (CMS) paradigm to develop a validated rat model of depression in order to elucidate the role of inflammation on the generation of the pathological anhedonic phenotype. Moreover, to evaluate the ability of the pharmacological treatment in modulating the behavioral-associated inflammatory alterations, rats exposed to CMS were also chronically treated with the antidepressants imipramine and with the antipsychotic lurasidone. Our findings indicate that the stress-induced anhedonic phenotype is associated to altered expression of specific mediators of immune/inflammatory system and that pharmacological treatment is not only able to normalize the anhedonic phenotype but also the inflammatory changes. These data suggest that immune/inflammatory alteration may contribute to the subject\u2019s vulnerability of depression and support the idea that immune/inflammatory may serve as viable therapeutic target for more effective antidepressant drugs

Long-term abstinence from developmental cocaine exposure alters Arc/Arg3.1 modulation in the rat medial prefrontal cortex

Cocaine is a psychostimulant whose abuse causes a social and economic burden for our society. Most of the published literature deals with acute effects of cocaine or short-term abstinence in adult animals but much less information exists on neuroplastic changes following long-term abstinence. We have recently shown that the long-term abstinence following developmental exposure to cocaine results in increased Activity-Regulated Cytoskeletal- associated protein (Arc/Arg3.1) expression in the crude synaptosomal fraction (Giannotti et al. Int J Neuropsychopharmacology 7(4):625-634, 2014). Given that Arc/Arg3.1 localizes not only at active synapse but also in the nucleus (Okuno et al. Cell 149:886-898, 2012; Korb et al. Nat Neurosci 16:874-883 2013; Bloomer et al. Brain Res 1153:20-33 2007), we investigated Arc/Arg3.1 protein levels in the whole homogenate and the nuclear fraction of animals exposed to cocaine during adolescence. We observed the increased expression of Arc/Arg3.1 in both the fractions, suggesting that up-regulation of Arc/Arg3.1 protein may be partly due to the increased nuclear expression of Arc/Arg3.1 in the medial prefrontal cortex (mPFC) of rats sacrificed at postnatal day 90, following 48 days of abstinence. This effect seems to cause reduced Gria1 transcription. We also found reduced expression of fragile X mental retardation gene (FMR1) which normally inhibits Arc/Arg3.1 translation together with reduced expression of Ubiquitin-protein ligase E3A (Ube3a) that normally causes Arc/Arg3.1 protein degradation via ubiquitination. Further, we found increased expression of metabotropic glutamate receptor 5 (GRM5) which is also involved in the regulation of Arc/Arg3.1 expression. Taken together, our findings show that abstinence from developmental exposure to cocaine is associated with alterations in the finely tuned mechanisms that regulate Arc/Arg3.1 expression

The activation of the immune/inflammatory system is associated with the stress-induced anhedonia in rats: effect of pharmacological intervention

Major depressive disorder (MDD) is a common disorder that represents a leading cause of disability in the world. It is thought originate from the interaction between susceptibility genes and environmental events, such as stress, to which an individual can be exposed in different moments of life. One of the major problems of depression is the relevant percentage of patients who do not show an adequate response to antidepressant therapy, as well as the high rate of relapse. Growing evidence suggest that the activation of the inflammatory/immune system contributes to the pathogenesis of depression. In particular, depression shows elevated comorbidity with cancer, arthritis rheumatoid, cardiovascular and neurodegenerative disease, characterized by inflammatory alteration. In addition, elevated blood levels of the pro-inflammatory cytokines including interleukin (IL)-1b, interleukin (IL)-6 and tumor necrosis factor (TNF)-a are commonly found in depressed patient. On these bases, it is important to characterize the changes of immune/inflammatory response in animal models of depression in order to establish their relationship with the depressive phenotype as well as the involvement in antidepressant response. Accordingly, the first aim of this study was to evaluate the inflammatory response of rats exposed to a chronic mild stress (CMS) paradigm, which represents a well-established animal model of depression. Next, a group of animals was treated with the antidepressant imipramine or the antipsychotic drug lurasidone, in order to evaluate the ability of the treatment to interfere with inflammatory alterations produced by the stress procedure

Remodelling by early-life stress of NMDA receptor-dependent synaptic plasticity in a gene-environment rat model of depression.

An animal model of depression combining genetic vulnerability and early-life stress (ELS) was prepared by submitting the Flinders Sensitive Line (FSL) rats to a standard paradigm of maternal separation. We analysed hippocampal synaptic transmission and plasticity in vivo and ionotropic receptors for glutamate in FSL rats, in their controls Flinders Resistant Line (FRL) rats, and in both lines subjected to ELS. A strong inhibition of long-term potentiation (LTP) and lower synaptic expression of NR1 subunit of the NMDA receptor were found in FSL rats. Remarkably, ELS induced a remodelling of synaptic plasticity only in FSL rats, reducing inhibition of LTP; this was accompanied by marked increase of synaptic NR1 subunit and GluR2/3 subunits of AMPA receptors. Chronic treatment with escitalopram inhibited LTP in FRL rats, but this effect was attenuated by prior ELS. The present results suggest that early gene-environment interactions cause lifelong synaptic changes affecting functional and molecular aspects of plasticity, partly reversed by antidepressant treatments

Lipopolysaccharide does not affect sucrose intake in stress-resilient rats: potential contribution of microglia

Stressful events during life may expose a subject to the development or the exacerbation of major depression, however even if this disease occurs in a significant percentage of stress-exposed subjects, most of them are able to successfully cope with the adverse situation and avoid such psychopathology. In addition, stress exposure strongly influences inflammatory events in the periphery and in the central nervous system (CNS), with an impact on behavioral alterations. In the CNS, microglia -brain tissue-resident macrophages- display stress-responsive properties; in particular, the detrimental effects caused by chronic stress may be driven by a dysregulation of this cellular population through the production of pro-inflammatory mediators. On these bases, the purpose of our study was to deepen our knowledge on the molecular mechanisms underpinning stress resilience. We exposed adult male rats to two weeks of chronic mild stress, before being challenged with Lipopolysaccharide (LPS, i.p. 250microg/kg) and sacrificed 24h or 6 days after the immune challenge. Behavioural alterations were monitored through the sucrose consumption test to evaluate the insurgence of anhedonic-like phenotype and to identify stress resilient rats. We measured the expression of pro-inflammatory cytokines (IL1beta, IL6, TNF-alpha), toll-like receptor 4 and markers of microglia activation (CD11b, Iba1, CX3CR1 and its ligand CX3CL1) in the rat prefrontal cortex, dorsal and ventral hippocampus (brain area involved in stress response and in the aetiology of depression). Interestingly, LPS worsened the sucrose intake in sham animals, but not in non-anhedonic rats; moreover, these behavioural effects seemed to be related to alterations in the expression of inflammatory mediators and markers of microglia activation, thus suggesting a potential role of these cells in the mechanisms of stress resilience