Endocannabinoids are released 'on-demand' on the basis of physiological need, and can be pharmacologically augmented by inhibiting their catabolic degradation. The endocannabinoid anandamide is ...degraded by the catabolic enzyme fatty acid amide hydrolase (FAAH). Anandamide is implicated in the mediation of fear behaviors, including fear extinction, suggesting that selectively elevating brain anandamide could modulate plastic changes in fear. Here we first tested this hypothesis with preclinical experiments employing a novel, potent and selective FAAH inhibitor, AM3506 (5-(4-hydroxyphenyl)pentanesulfonyl fluoride). Systemic AM3506 administration before extinction decreased fear during a retrieval test in a mouse model of impaired extinction. AM3506 had no effects on fear in the absence of extinction training, or on various non-fear-related measures. Anandamide levels in the basolateral amygdala were increased by extinction training and augmented by systemic AM3506, whereas application of AM3506 to amygdala slices promoted long-term depression of inhibitory transmission, a form of synaptic plasticity linked to extinction. Further supporting the amygdala as effect-locus, the fear-reducing effects of systemic AM3506 were blocked by intra-amygdala infusion of a CB1 receptor antagonist and were fully recapitulated by intra-amygdala infusion of AM3506. On the basis of these preclinical findings, we hypothesized that variation in the human FAAH gene would predict individual differences in amygdala threat-processing and stress-coping traits. Consistent with this, carriers of a low-expressing FAAH variant (385A allele; rs324420) exhibited quicker habituation of amygdala reactivity to threat, and had lower scores on the personality trait of stress-reactivity. Our findings show that augmenting amygdala anandamide enables extinction-driven reductions in fear in mouse and may promote stress-coping in humans.
Background: Tumour necrosis factor α (TNFα) may be an important mediator of insulin resistance. Infliximab is a chimeric monoclonal, high affinity antibody against the soluble and transmembrane TNFα, ...which can reduce markedly the biological activity of circulating and tissue TNFα and is used to treat various autoimmune disorders. Objective: To assess the effects of infliximab infusions on insulin sensitivity in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Methods: 45 patients (28 with RA, 17 with AS) aged 19–74 years were studied. All patients were treated with intravenous infliximab. A complete biochemical profile was obtained before and after 6 months’ treatment with infliximab. The Homoeostasis Model Assessment (HOMA) Index was used to measure insulin resistance and the Quantitative Insulin Sensitivity Check Index (QUICKI) to measure insulin sensitivity. Results: In the whole study group, no significant changes of the HOMA Index or QUICKI were seen. In the tertile of patients with the highest insulin resistance, a significant decrease of the HOMA Index and increase of the QUICKI was found (p<0.01 for both). Conclusions: The results suggest that infliximab treatment may have beneficial effects on insulin sensitivity in the most insulin resistant patients with RA and AS.
The paper presents a numerical investigation of the central collision of two equal-sized droplets in a gaseous phase. The investigation is based on the numerical solution of the Navier–Stokes ...equations in their axi-symmetric form using the finite volume technique. The Volume of Fluid Method (V.O.F) is employed for tracking the liquid–gas interface. An adaptive local grid refinement technique developed recently is used in order to increase the resolution around the interface. By using two V.O.F indicator functions the identity of each droplet is preserved and can be detected after droplet contact until coalescence. The results are compared with available experimental data and provide a very detailed picture of the collision process, the ligament formation and dimensions, the pinch off mechanism and the creation of the satellite droplet. The conversion of the droplet’s kinetic energy to the surface energy and vise versa, the energy viscous dissipation as well as the maximum deformation of the droplets are also evaluated.
This paper deals with the numerical three-dimensional prediction of the induced flow patterns around and inside a building, which is cross-ventilated in a natural way. The air change rate is ...controlled by two opposite openings on the building envelope, as a function of wind velocity and its incidence angle. The numerical methodology is based on the finite volume numerical solution of the Navier–Stokes equations, using the CFD commercial code FLUENT. The numerical results are compared with available experimental data regarding the refresh rate of the building's room and the relative velocity profiles at the window openings, indicating a good agreement. Furthermore, a detailed description of the natural ventilation process is provided, whilst additional information regarding the induced velocity and pressure field is presented; information which cannot be easily extrapolated by experimental methodologies. Finally, the impact of the inner topology of the building on the induced flow field is investigated.
The paper presents an extensive experimental and numerical study on a cross-ventilated building providing important features of the induced flow patterns at the two openings as a function of the free ...stream wind velocity's magnitude and its incidence angle. The experimental data are measured via anemometers across the openings, whilst the numerical methodology is based on the time-dependant solution of the governing Navier–Stokes equations. The experimental data are compared to the corresponding numerical results, revealing the unsteady character of the flow field especially at large incidence angles. Furthermore, additional information regarding the flow field near the opening edges, not easily extracted by experimental methods, provide an in depth sight in the main characteristics of the flow field both at the openings but also inside the building. Finally, a new methodology for the approximation of the volume flow rate aerating the building based on experimental measurements of the velocity field at the openings is presented.
The central binary collision of two unequal sized droplets is numerically investigated using the volume of fluid (V.O.F.) methodology. The numerical method based on the solution of the continuity and ...momentum equations in axi-symmetric formulation is coupled with a recently developed adaptive local grid refinement technique, thus allowing an accurate representation of the interface between the liquid and gas phase. Mass transfer mechanisms are reproduced by solving a transport equation for a colour function representing the mass of one of the colliding droplets before and after collision and mixing. The investigation is performed assuming either constant relative velocity of the colliding droplets or constant total energy of the system, thus creating a combination of the standard non-dimensional parameters affecting the collision process, i.e. Weber (We) and Ohnesorge (Oh) numbers as also droplet diameter ratio (Δ). The reliability of the procedure is first established by comparing predictions with available experimental data. The effect of the above mentioned parameters on ligament’s formation, maximum deformation of the two droplets, the penetration of one droplet into the other and satellite droplet formation is quantified.
BACKGROUND AND PURPOSE Gastrointestinal (GI) motility is regulated in part by fatty acid ethanolamides (FAEs), including the endocannabinoid (EC) anandamide (AEA). The actions of FAEs are terminated ...by fatty acid amide hydrolase (FAAH). We investigated the actions of the novel FAAH inhibitor AM3506 on normal and enhanced GI motility.
EXPERIMENTAL APPROACH We examined the effect of AM3506 on electrically‐evoked contractility in vitro and GI transit and colonic faecal output in vivo, in normal and FAAH‐deficient mice treated with saline or LPS (100 µg·kg−1, i.p.), in the presence and absence of cannabinoid (CB) receptor antagonists. mRNA expression was measured by quantitative real time‐PCR, EC levels by liquid chromatography‐MS and FAAH activity by the conversion of 3H‐AEA to 3H‐ethanolamine in intestinal extracts. FAAH expression was examined by immunohistochemistry.
KEY RESULTS FAAH was dominantly expressed in the enteric nervous system; its mRNA levels were higher in the ileum than the colon. LPS enhanced ileal contractility in the absence of overt inflammation. AM3506 reversed the enhanced electrically‐evoked contractions of the ileum through CB1 and CB2 receptors. LPS increased the rate of upper GI transit and faecal output. AM3506 normalized the enhanced GI transit through CB1 and CB2 receptors and faecal output through CB1 receptors. LPS did not increase GI transit in FAAH‐deficient mice.
CONCLUSIONS AND IMPLICATIONS Inhibiting FAAH normalizes various parameters of GI dysmotility in intestinal pathophysiology. Inhibition of FAAH represents a new approach to the treatment of disordered intestinal motility.
The multinucleon transfer (MNT) reaction approach was successfully employed for the first time to measure the isomeric ratios (IRs) of 211Po isomer (25/2+) and its ground state (9/2+) at the IGISOL ...facility using a 945 MeV 136Xe beam impinged on 209Bi and natPb targets. The dominant production of isomers compared to the corresponding ground states was consistently revealed in the α-decay spectra. Deduced IR of 211Po populated through the 136Xe+natPb reaction was found to have an enhancement of ≈1.8-times than that observed for the 136Xe+209Bi. State-of-the-art Langevin-type model calculations have been utilized to estimate the spin distribution of an MNT residue. The computations qualitatively corroborate with the considerable increase in the IRs of 211Po produced from 136Xe+natPb compared to 136Xe+209Bi. Theoretical investigations indicate a weak dependence of target spin on the IRs. The enhancement of the 211Po isomer in the 136Xe+natPb over 136Xe+209Bi can be attributed to the different proton (p)-transfer production routes. Estimations demonstrate an increment in the angular momentum transfer, favorable for isomer production, with increasing projectile energy. Comparative analysis reveals the two entrance channel parameters, projectile mass and p-transfer channels, strongly influencing the population of the high-spin isomer of 211Po (25/2+). This letter reports the first experimental and theoretical study on the IRs of nuclei formed from two different p-transfer channels via two independent MNT reactions.
Objective: To describe the efficacy and safety of adalimumab in patients with rheumatoid arthritis (RA) who had previously discontinued infliximab treatment. Methods: 24 patients with RA who ...discontinued treatment with infliximab (switchers) were treated with adalimumab (40 mg every 2 weeks, subcutaneously) for 12 months. The results were compared with those for 25 patients with RA receiving adalimumab who had not previously used an anti-tumour necrosis factor α inhibitor (controls). Disease activity was measured with the 28 joint count Disease Activity Score (DAS28), and clinical response with the American College of Rheumatology (ACR) 20% response criteria. Results: At baseline there were no differences in demographic, clinical, and laboratory features between the two groups. After 12 months’ adalimumab treatment, clinical improvement was similar in both groups. More specifically, ACR 20% response criteria were achieved by 18/24 (75%) switchers and by 19/25 (76%) subjects in the control group. Four switchers discontinued the study—two because of adverse events and two because of lack of efficacy, while three control patients discontinued the study—one because of lack of efficacy and two owing to side effects. Conclusion: Adalimumab is a well tolerated and effective treatment for patients with RA, even when infliximab has been discontinued.
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