Stress-induced neuroinflammation: mechanisms and new pharmacological targets

Stress is triggered by numerous unexpected environmental, social or pathological stimuli occurring during the life of animals, including humans, which determine changes in all of their systems. Although acute stress is essential for survival, chronic, long-lasting stress can be detrimental. In this review, we present data supporting the hypothesis that stress-related events are characterized by modifications of oxidative/nitrosative pathways in the brain in response to the activation of inflammatory mediators. Recent findings indicate a key role for nitric oxide (NO) and an excess of pro-oxidants in various brain areas as responsible for both neuronal functional impairment and structural damage. Similarly, cyclooxygenase-2 (COX-2), another known source of oxidants, may account for stress-induced brain damage. Interestingly, some of the COX-2-derived mediators, such as the prostaglandin 15d-PGJ2 and its peroxisome proliferator-activated nuclear receptor PPARγ, are activated in the brain in response to stress, constituting a possible endogenous anti-inflammatory mechanism of defense against excessive inflammation. The stress-induced activation of both biochemical pathways depends on the activation of the N-methyl-D-aspartate (NMDA) glutamate receptor and on the activation of the transcription factor nuclear factor kappa B (NFκB). In the case of inducible NO synthase (iNOS), release of the cytokine TNF-α also accounts for its expression. Different pharmacological strategies directed towards different sites in iNOS or COX-2 pathways have been shown to be neuroprotective in stress-induced brain damage: NMDA receptor blockers, inhibitors of TNF-α activation and release, inhibitors of NFκB, specific inhibitors of iNOS and COX-2 activities and PPARγ agonists. This article reviews recent contributions to this area addressing possible new pharmacological targets for the treatment of stress-induced neuropsychiatric disorders.Spanish Ministries of HealthEducationFAPESPCNP

Scientific Evidence: Impact on a jury

The goal of this qualitative study was to better understand the impact of scientific evidence ‘s influence on a jury’s verdict. The presence of scientific evidence has the potential to convict the defendant or overturn a guilty verdict as seen in cases involving the innocence project. The theoretical framework for this qualitative study was Gerbner’s Cultivation Theory which postulates heavy exposure to television has the potential to influence the individual’s perception of the world. The researcher implemented an exploratory research design using purposive sampling. A total of 68 participants (prior jurors) applied for the study, 66 from an advertisement placed on Facebook, and 2 from Walden’s participant pool. Ten participants (N=10) followed through to the end of study. A semi structured interview using open ended format (questions) was conducted and recorded online via Zoom. The recordings were transcribed using Microsoft Word. The researcher used the qualitative software NVivo14 for organization and graphing of said data. Based on the generated codes and themes, the researcher’s findings indicated most participants felt apprehensive and had a sense of civic duty during the trial proceedings. Most trials associated with this study contained both hard and soft evidence. The individuals affected by scientific evidence were among most study participants. Providing this information to the prosecution and defense attorneys, understanding how the jurors felt during the trial and the potential influence scientific evidence has on a jury’s verdict can contribute to positive social change by aiding in preventing the conviction of innocent individuals

What determines auditory similarity? The effect of stimulus group and methodology.

Two experiments on the internal representation of auditory stimuli compared the pairwise and grouping methodologies as means of deriving similarity judgements. A total of 45 undergraduate students participated in each experiment, judging the similarity of short auditory stimuli, using one of the methodologies. The experiments support and extend Bonebright's (1996) findings, using a further 60 stimuli. Results from both methodologies highlight the importance of category information and acoustic features, such as root mean square (RMS) power and pitch, in similarity judgements. Results showed that the grouping task is a viable alternative to the pairwise task with N > 20 sounds whilst highlighting subtle differences, such as cluster tightness, between the different task results. The grouping task is more likely to yield category information as underlying similarity judgements

Idealized digital models for conical reed instruments, with focus on the internal pressure waveform

International audienceTwo models for the generation of self-oscillations of reed conical woodwinds are presented. They use the fewest parameters (of either the resonator or the ex-citer), whose influence can be quickly explored. The formulation extends iterated maps obtained for loss-less cylindrical pipes without reed dynamics. It uses spherical wave variables in idealized resonators, with one parameter more than for cylinders: the missing length of the cone. The mouthpiece volume equals that of the missing part of the cone, and is implemented as either a cylindrical pipe (first model) or a lumped element (second model). Only the first model adds a length parameter for the mouthpiece and leads to the solving of an implicit equation. For the second model, any shape of nonlinear characteristic can be directly considered. The complex characteristics impedance for spherical waves requires sampling times smaller than a round trip in the resonator. The convergence of the two models is shown when the length of the cylindrical mouthpiece tends to zero. The waveform is in semi-quantitative agreement with experiment. It is concluded that the oscillations of the positive episode of the mouthpiece pressure are related to the length of the missing part, not to the reed dynamics

HGF Mediates the Anti-inflammatory Effects of PRP on Injured Tendons

Platelet-rich plasma (PRP) containing hepatocyte growth factor (HGF) and other growth factors are widely used in orthopaedic/sports medicine to repair injured tendons. While PRP treatment is reported to decrease pain in patients with tendon injury, the mechanism of this effect is not clear. Tendon pain is often associated with tendon inflammation, and HGF is known to protect tissues from inflammatory damages. Therefore, we hypothesized that HGF in PRP causes the anti-inflammatory effects. To test this hypothesis, we performed in vitro experiments on rabbit tendon cells and in vivo experiments on a mouse Achilles tendon injury model. We found that addition of PRP or HGF decreased gene expression of COX-1, COX-2, and mPGES-1, induced by the treatment of tendon cells in vitro with IL-1β. Further, the treatment of tendon cell cultures with HGF antibodies reduced the suppressive effects of PRP or HGF on IL-1β-induced COX-1, COX-2, and mPGES-1 gene expressions. Treatment with PRP or HGF almost completely blocked the cellular production of PGE2 and the expression of COX proteins. Finally, injection of PRP or HGF into wounded mouse Achilles tendons in vivo decreased PGE2 production in the tendinous tissues. Injection of platelet-poor plasma (PPP) however, did not reduce PGE2 levels in the wounded tendons, but the injection of HGF antibody inhibited the effects of PRP and HGF. Further, injection of PRP or HGF also decreased COX-1 and COX-2 proteins. These results indicate that PRP exerts anti-inflammatory effects on injured tendons through HGF. This study provides basic scientific evidence to support the use of PRP to treat injured tendons because PRP can reduce inflammation and thereby reduce the associated pain caused by high levels of PGE2. © 2013 Zhang et al

A caveolin-binding domain in the HCN4 channels mediates functional interaction with caveolin proteins

Pacemaker (HCN) channels have a key role in the generation and modulation of spontaneous activity of sinoatrial node myocytes. Previous work has shown that compartmentation of HCN4 pacemaker channels within caveolae regulates important functions, but the molecular mechanism responsible is still unknown. HCN channels have a conserved caveolin-binding domain (CBD) composed of three aromatic amino acids at the N-terminus; we sought to evaluate the role of this CBD in channel-protein interaction by mutational analysis. We generated two HCN4 mutants with a disrupted CBD (Y259S, F262V) and two with conservative mutations (Y259F, F262Y). In CHO cells expressing endogenous caveolin-1 (cav-1), alteration of the CBD shifted channels activation to more positive potentials, slowed deactivation and made Y259S and F262V mutants insensitive to cholesterol depletion-induced caveolar disorganization. CBD alteration also caused a significant decrease of current density, due to a weaker HCN4-cav-1 interaction and accumulation of cytoplasmic channels. These effects were absent in mutants with a preserved CBD. In caveolin-1-free fibroblasts, HCN4 trafficking was impaired and current density reduced with all constructs; the activation curve of F262V was not altered relative to wt, and that of Y259S displayed only half the shift than in CHO cells. The conserved CBD present in all HCN isoforms mediates their functional interaction with caveolins. The elucidation of the molecular details of HCN4-cav-1 interaction can provide novel information to understand the basis of cardiac phenotypes associated with some forms of caveolinopathies

Comparison of protein carbonyl (Pco), paraoxonase-1 (pon1) and c-reactive protein (crp) as diagnostic and prognostic markers of septic inflammation in dogs

Reliable diagnostic and prognostic markers of sepsis are lacking, but essential in veterinary medicine. We aimed to assess the accuracy of C-Reactive Protein (CRP), protein carbonyls (PCO) and paraoxonase-1 (PON1) in differentiating dogs with sepsis from those with sterile inflammation and healthy ones, and predict the outcome in septic dogs. These analytes were retrospectively evaluated at admission in 92 dogs classified into healthy, septic and polytraumatized. Groups were compared using the Kruskal–Wallis test, followed by a Mann–Whitney U test to assess differences between survivors and non-survivors. Correlation between analytes was assessed using the Spearman’s test, and their discriminating power was assessed through a Receiver Operating Characteristic (ROC) curve. PON1 and CRP were, respectively, significantly lower and higher in dogs with sepsis compared with polytraumatized and clinically healthy dogs (p < 0.001 for both the analytes), and also in dogs with trauma compared with healthy dogs (p = 0.011 and p = 0.017, respectively). PCO were significantly increased in septic (p < 0.001) and polytraumatized (p < 0.005) as compared with healthy dogs. PON1 and CRP were, respectively, significantly lower and higher in dogs that died compared with survivors (p < 0.001 for both analytes). Ultimately, evaluation of CRP and PON1 at admission seems a reliable support to diagnose sepsis and predict outcomes

Childhood Vaccinations and Type 1 Diabetes.

Type 1 diabetes (T1D) is the most common paediatric endocrine disease, and its frequency has been found to increase worldwide. Similar to all conditions associated with poorly regulated glucose metabolism, T1D carries an increased risk of infection. Consequently, careful compliance by T1D children with schedules officially approved for child immunization is strongly recommended. However, because patients with T1D show persistent and profound limitations in immune function, vaccines may evoke a less efficient immune response, with corresponding lower protection. Moreover, T1D is an autoimmune condition that develops in genetically susceptible individuals and some data regarding T1D triggering factors appear to indicate that infections, mainly those due to viruses, play a major role. Accordingly, the use of viral live attenuated vaccines is being debated. In this narrative review, we discussed the most effective and safe use of vaccines in patients at risk of or with overt T1D. Literature analysis showed that several problems related to the use of vaccines in children with T1D have not been completely resolved. There are few studies regarding the immunogenicity and efficacy of vaccines in T1D children, and the need for different immunization schedules has not been precisely established. Fortunately, the previous presumed relationship between vaccine administration and T1D appears to have been debunked, though some doubts regarding rotavirus vaccines remain. Further studies are needed to completely resolve the problems related to vaccine administration in T1D patients. In the meantime, the use of vaccines remains extensively recommended in children with this disease

Influence of the dopaminergic system, CREB, and transcription factor-κB on cocaine neurotoxicity

Cocaine is a widely used drug and its abuse is associated with physical, psychiatric and social problems. Abnormalities in newborns have been demonstrated to be due to the toxic effects of cocaine during fetal development. The mechanism by which cocaine causes neurological damage is complex and involves interactions of the drug with several neurotransmitter systems, such as the increase of extracellular levels of dopamine and free radicals, and modulation of transcription factors. The aim of this review was to evaluate the importance of the dopaminergic system and the participation of inflammatory signaling in cocaine neurotoxicity. Our study showed that cocaine activates the transcription factors NF-κB and CREB, which regulate genes involved in cellular death. GBR 12909 (an inhibitor of dopamine reuptake), lidocaine (a local anesthetic), and dopamine did not activate NF-κB in the same way as cocaine. However, the attenuation of NF-κB activity after the pretreatment of the cells with SCH 23390, a D1 receptor antagonist, suggests that the activation of NF-κB by cocaine is, at least partially, due to activation of D1 receptors. NF-κB seems to have a protective role in these cells because its inhibition increased cellular death caused by cocaine. The increase in BDNF (brain-derived neurotrophic factor) mRNA can also be related to the protective role of both CREB and NF-κB transcription factors. An understanding of the mechanisms by which cocaine induces cell death in the brain will contribute to the development of new therapies for drug abusers, which can help to slow down the progress of degenerative processes.FAPESP, 2006/50105-0CAPESCNPqUniversity of São Paulo, #2011.1.9333.1.

J-Integral characterization of the nozzle steels from intermediate test vessels IV-5 and IV-9

Reported here are the results of elastic-plastic fracture toughness tests performed on low alloy steels from the nozzles of the intermediate test vessels IV-5 and IV-9 from the Heavy Steel Section Technology Program at Oak Ridge National Laboratory. These vessels had been given prototypic nozzle corner flaw tests prior to the development of the ASTM E-813 standard test procedure for J-integral testing. The objective of this work is to provide J-integral material test support for future elastic-plastic fracture mechanics analysis of the nozzles. J-integral tests at 88{degrees}C (190{degrees}F) of the IV-5 nozzle material produced stable ductile tearing. The tearing resistance data are expected to support analysis of the observed similar stable tearing response of the nozzle corner flaw. J-integral tests at 24{degrees}C (75{degrees}F) of the IV-9 nozzle produced elastic-plastic fracture instability preceded by stable tearing. A similar response was observed in the IV-9 nozzle corner flaw test. It will be a major and important challenge to develop a fracture mechanics rationale that reconciles these small specimen and nozzle corner flaw test results. These test results are being made available to allow their use by a wide variety of organizations in developing such a rationale, which would be a significant contribution to quantifying the flaw tolerance of reactor pressure vessels