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The present work was done to elucidate whether hemichannels of a cell line derived from endothelial cells are affected by pro-inflammatory conditions (high glucose and IL-1β/TNF-α) known to lead to vascular dysfunction. We used EAhy 926 cells treated with high glucose and IL-1β/TNF-α. The hemichannel activity was evaluated with the dye uptake method and was abrogated with selective inhibitors or knocking down of hemichannel protein subunits with siRNA. Western blot analysis, cell surface biotinylation, and confocal microscopy were used to evaluate total and plasma membrane amounts of specific proteins and their cellular distribution, respectively. Changes in intracellular Ca and nitric oxide (NO) signals were estimated by measuring FURA-2 and DAF-FM probes, respectively. High glucose concentration was found to elevate dye uptake, a response that was enhanced by IL-1β/TNF-α. High glucose plus IL-1β/TNF-α-induced dye uptake was abrogated by connexin 43 (Cx43) but not pannexin1 knockdown. Furthermore, Cx43 hemichannel activity was associated with enhanced ATP release and activation of p38 MAPK, inducible NO synthase, COX , PGE receptor EP , and P2X /P2Y receptors. Inhibition of the above pathways prevented completely the increase in Cx43 hemichannel activity of cells treated high glucose and IL-1β/TNF-α. Both synthetic and endogenous cannabinoids (CBs) also prevented the increment in Cx43 hemichannel opening, as well as the subsequent generation and release of ATP and NO induced by pro-inflammatory conditions. The counteracting action of CBs also was extended to other endothelial alterations evoked by IL-1β/TNF-α and high glucose, including increased ATP-dependent Ca dynamics and insulin-induced NO production. Finally, inhibition of Cx43 hemichannels also prevented the ATP release from endothelial cells treated with IL-1β/TNF-α and high glucose. Therefore, we propose that reduction of hemichannel activity could represent a strategy against the activation of deleterious pathways that lead to endothelial dysfunction and possibly cell damage evoked by high glucose and pro-inflammatory conditions during cardiovascular diseases.

Under physiological conditions, microglia adopt a resting phenotype associated with the production of anti-inflammatory and neurotrophic factors. In response to a wide variety of insults, these cells shift to an activated phenotype that is necessary for the proper restoration of brain homeostasis. However, when the intensity of a threat is relatively high, microglial activation worsens the progression of damage rather than providing protection, with potentially significant consequences for neuronal survival. Coordinated interactions among microglia and other brain cells, including astrocytes and neurons, are critical for the development of timely and optimal inflammatory responses in the brain parenchyma. Tissue synchronization is in part mediated by connexins and pannexins, which are protein families that form different plasma membrane channels to communicate with neighboring cells. Gap junction channels (which are exclusively formed by connexins in vertebrates) connect the cytoplasm of contacting cells to coordinate electrical and metabolic coupling. Hemichannels (HCs) and pannexons (which are formed by connexins and pannexins, respectively) communicate the intra- and extracellular compartments and serve as diffusion pathways for the exchange of ions and small molecules. In this review article, we discuss the available evidence concerning the functional expression and regulation of connexin- and pannexin-based channels in microglia and their contributions to microglial function and dysfunction. Specifically, we focus on the possible implications of these channels in microglia-to-microglia, microglia-to-astrocyte and neuron-to-microglia interactions in the inflamed brain.

A mounting body of evidence indicates that adolescents are specially more susceptible to alcohol influence than adults. However, the mechanisms underlying this phenomenon remain poorly understood. Astrocyte-mediated gliotransmission is crucial for hippocampal plasticity and recently, the opening of hemichannels and pannexons has been found to participate in both processes. Here, we evaluated whether adolescent rats exposed to ethanol exhibit changes in the activity of astrocyte hemichannels and pannexons in the hippocampus, as well as alterations in astrocyte arborization and cytokine levels. Adolescent rats were subjected to ethanol (3.0 g/kg) for two successive days at 48-h periods over 14 days. The opening of hemichannels and pannexons was examined in hippocampal slices by dye uptake, whereas hippocampal cytokine levels and astroglial arborization were determined by ELISA and Sholl analysis, respectively. We found that adolescent ethanol exposure increased the opening of connexin 43 (Cx43) hemichannels and pannexin-1 (Panx1) channels in astrocytes. Blockade of p38 mitogen-activated protein kinase (MAPK), inducible nitric oxide synthase (iNOS) and cyclooxygenases (COXs), as well as chelation of intracellular Ca , drastically reduced the ethanol-induced channel opening in astrocytes. Importantly, ethanol-induced Cx43 hemichannel and Panx1 channel activity was correlated with increased levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-6 in the hippocampus, as well as with profound alterations in astrocyte arbor complexity. Thus, we propose that uncontrolled opening of astrocyte hemichannels and pannexons may contribute not only to the glial dysfunction and neurotoxicity caused by adolescent alcohol consumption, but also to the pathogenesis of alcohol use disorders in the adulthood.

The formation of gap junctions was initially thought to be the central role of connexins, however, recent evidence had brought to light the high relevance of unopposed hemichannels as an independent mechanism for the selective release of biomolecules during physiological and pathological conditions. In the healthy brain, the physiological opening of astrocyte hemichannels modulates basal excitatory synaptic transmission. At the other end, the release of potentially neurotoxic compounds through astroglial hemichannels and pannexons has been insinuated as one of the functional alterations that negatively affect the progression of multiple brain diseases. Recent insights in this matter have suggested encannabinoids (eCBs) as molecules that could regulate the opening of these channels during diverse conditions. In this review, we discuss and hypothesize the possible interplay between the eCB system and the hemichannel/pannexon-mediated signaling in the inflamed brain and during event of synaptic plasticity. Most findings indicate that eCBs seem to counteract the activation of major neuroinflammatory pathways that lead to glia-mediated production of TNF-α and IL-1β, both well-known triggers of astroglial hemichannel opening. In contrast to the latter, in the normal brain, eCBs apparently elicit the Ca -activation of astrocyte hemichannels, which could have significant consequences on eCB-dependent synaptic plasticity.

At least half of human immunodeficiency virus (HIV)-infected individuals suffer from a wide range of cognitive, behavioral and motor deficits, collectively known as HIV-associated neurocognitive disorders (HAND). The molecular mechanisms that amplify damage within the brain of HIV-infected individuals are unknown. Recently, we described that HIV augments the opening of connexin-43 (Cx43) hemichannels in cultured human astrocytes, which result in the collapse of neuronal processes. Whether HIV soluble viral proteins such as gp120, can regulate hemichannel opening in astrocytes is still ignored. These channels communicate the cytosol with the extracellular space during pathological conditions. We found that gp120 enhances the function of both Cx43 hemichannels and pannexin-1 channels in mouse cortical astrocytes. These effects depended on the activation of IL-1β/TNF-α, p38 MAP kinase, iNOS, cytoplasmic Ca2+ and purinergic signaling. The gp120-induced channel opening resulted in alterations in Ca2+ dynamics, nitric oxide production and ATP release. Although the channel opening evoked by gp120 in astrocytes was reproduced in ex vivo brain preparations, these responses were heterogeneous depending on the CA1 region analyzed. We speculate that soluble gp120-induced activation of astroglial Cx43 hemichannels and pannexin-1 channels could be crucial for the pathogenesis of HAND.

This paper presents advanced computer simulation of rock cutting process typical for excavation works in civil engineering. Theoretical formulation of the hybrid discrete/finite element model has been presented. The discrete and finite element methods have been used in different subdomains of a rock sample according to expected material behaviour, the part which is fractured and damaged during cutting is discretized with the discrete elements while the other part is treated as a continuous body and it is modelled using the finite element method. In this way, an optimum model is created, enabling a proper representation of the physical phenomena during cutting and efficient numerical computation. The model has been applied to simulation of the laboratory test of rock cutting with a single TBM (tunnel boring machine) disc cutter. The micromechanical parameters have been determined using the dimensionless relationships between micro- and macroscopic parameters. A number of numerical simulations of the LCM test in the unrelieved and relieved cutting modes have been performed. Numerical results have been compared with available data from in-situ measurements in a real TBM as well as with the theoretical predictions showing quite a good agreement. The numerical model has provided a new insight into the cutting mechanism enabling us to investigate the stress and pressure distribution at the tool–rock interaction. Sensitivity analysis of rock cutting performed for different parameters including disc geometry, cutting velocity, disc penetration and spacing has shown that the presented numerical model is a suitable tool for the design and optimization of rock cutting process.

Information and communications technology (ICT) could support ambient assisted living (AAL) based interventions to provide support to informal caregivers of people with dementia, especially when they need to cope with their feelings of overburden or isolation. An e-learning platform (understAID application) was tested by informal caregivers from Denmark, Poland, and Spain to explore the technical and the pedagogical specifications, as well as evaluating the impact of its use on the psychological status of the participants. 61 informal caregivers completed the study taking part in the experimental (n=30) or control (n=31) groups. 33.3% of the caregivers were satisfied with the application and around 50% of the participants assessed it as technically and pedagogically acceptable. After using understAID the caregivers in the experimental group significantly decreased their depressive symptomatology according to the Center for Epidemiologic Studies Depression scale, but a possible benefit on their feelings of competence and satisfaction with the caring experience was also observed. The low scores obtained for satisfaction were highlighting issues that need to be modified to meet the informal caregivers’ needs in national, social, and cultural context. Some possible biases are also considered and discussed to be taken into account in future improvements of understAID application.

Many patients with Alzheimer's disease will develop agitation at later stages of the disease, which constitutes one of the most challenging and distressing aspects of dementia. Recently, nonpharmacological therapies have become increasingly popular and have been proven to be effective in managing the behavioral symptoms (including agitation) that are common in the middle or later stages of dementia. These therapies seem to be a good alternative to pharmacological treatment to avoid unpleasant side effects. We present a systematic review of randomized controlled trials (RCTs) focused on the nonpharmacological management of agitation in Alzheimer's disease (AD) patients aged 65 years and above. Of the 754 studies found, eight met the inclusion criteria. This review suggests that music therapy is optimal for the management of agitation in institutionalized patients with moderately severe and severe AD, particularly when the intervention includes individualized and interactive music. Bright light therapy has little and possibly no clinically significant effects with respect to observational ratings of agitation but decreases caregiver ratings of physical and verbal agitation. Therapeutic touch is effective for reducing physical nonaggressive behaviors but is not superior to simulated therapeutic touch or usual care for reducing physically aggressive and verbally agitated behaviors. Melissa oil aromatherapy and behavioral management techniques are not superior to placebo or pharmacological therapies for managing agitation in AD. Further research in clinical trials is required to confirm the effectiveness and long-term effects of nonpharmacological interventions for managing agitation in AD. These types of studies may lead to the development of future intervention protocols to improve the well-being and daily functioning of these patients, thereby avoiding residential care placement.

BACKGROUND: Chronic foot pain (CFP) is a widespread condition worldwide; however, few studies that relate CFP and foot health-related quality of life have been reported. OBJECTIVE: The aim of this study was to describe the impact of foot health and health in general in a sample of adult people with CFP compared with a control group. STUDY DESIGN: This study was designed as a retrospective case-control study. SETTING: Podiatric section of a care center. METHODS: Two hundred adults were included in the study. Patients were divided into CFP patient (n = 100) and control groups (n = 100). All of them regularly attended a private podiatric clinic to take care of their foot health. Self-reported data and medical histories for people with and without CFP were evaluated. All findings were compared with quality of life (QoL) scores based on the Foot Health Status Questionnaire, Spanish version. RESULTS: Adults with CFP (compared to the control group) showed reductions in QoL linked to overall health and foot health in particular and were statistically significant with respect to several domains: (1) foot pain, (2) foot function, (3) general health, and (4) physical activity. These differ-ences were evaluated with a t-test for independent samples, and statistical significance was consid-ered a P value of P < 0.05. LIMITATIONS: The study was not a randomized controlled trial. Although primary outcome data were self-reported, the assessor was not blinded. CONCLUSIONS: CFP patients, regardless of gender, recorded a negative influence on QoL-related foot health that seems to be linked with the presence of this chronic condition.

This paper presents advanced computer simulation of rock cutting process typical for excavation works in civil engineering. Theoretical formulation of the hybrid discrete/finite element model has been presented. The discrete and finite element methods have been used in different subdomains of a rock sample according to expected material behaviour, the part which is fractured and damaged during cutting is discretized with the discrete elements while the other part is treated as a continuous body and it is modelled using the finite element method. In this way, an optimum model is created, enabling a proper representation of the physical phenomena during cutting and efficient numerical computation. The model has been applied to simulation of the laboratory test of rock cutting with a single TBM (tunnel boring machine) disc cutter. The micromechanical parameters have been determined using the dimensionless relationships between micro- and macroscopic parameters. A number of numerical simulations of the LCM test in the unrelieved and relieved cutting modes have been performed. Numerical results have been compared with available data from in-situ measurements in a real TBM as well as with the theoretical predictions showing quite a good agreement. The numerical model has provided a new insight into the cutting mechanism enabling us to investigate the stress and pressure distribution at the tool–rock interaction. Sensitivity analysis of rock cutting performed for different parameters including disc geometry, cutting velocity, disc penetration and spacing has shown that the presented numerical model is a suitable tool for the design and optimization of rock cutting process.