The effect of different formulas in children with cow ' s milk allergy on the occurrence of other allergic manifestations and the time of immune tolerance acquisition: The atopic march II study

Background : Recent data suggest that the use of extensively hydrolyzed casein formula containing the probiotic L.rhamnosus GG (LGG) (EHCF+LGG) reduces the incidence of other AMs and hastens the development of immune tolerance in children with IgE- mediated cow ' s milk allergy (CMA). To see whether formula choice for CMA treatment could impact the occurrence of other AMs and the time of immune tolerance acquisition. Method : Prospective open non- randomized trial on a cohort of children with a diagnosis of IgE- mediated CMA in the first year of life, already in follow- up. The patients were treated with one of the following formulas: EHCF+LGG, rice hydrolyzed formula (RHF), soy formula (SF), extensively hydrolyzed whey formula (EHWF) or amino- acid based formula (AAF). All subjects were evaluated during a 36 months follow- up. The occurence of AMs (atopic eczema, allergic urticaria, asthma and oculorhinitis) was diagnosed Immune tolerance acquisition was evaluated every 12 month by the result of oral food challenge. Results : A total of 365 subjects completed the study, 73 per group. All children were from families of middle socio- economic status and lived in urban areas. At enrollment, all subjects were in stable clinical conditions without symptoms related to CMA. Demographic and anamnestic features were similar comparing the study cohorts at enrolment. Binomial regression revealed that the estimates of the incidence of the AMs are: EHCF+LGG: 0.22 (Bonferroni corrected 95%CI: 0.09 to 0.34); RHF: 0.52 (Bonferroni corrected 95%CI: 0.37 to 0.67); SF: 0.58 (Bonferroni corrected 95%CI: 0.43 to 0.72); EHWF : 0.51 (Bonferroni corrected 95%CI: 0.36 to 0.66); AAF: 0.77 (Bonferroni corrected 95%CI: 0.64 to 0.89). The incidence of the main outcome in the RHF, SF, EHWF and AAF groups vs the EHCF+LGG group was always higher than the pre- specified absolute difference of 0.25 and significantly higher at the pre- specified alphalevel of 0.0125 ( P - value <= 0.001 in all cases). The acquisition of immune tolerance was significantly higher in the EHCF+LGG group comparing to the other groups. The rate of immune tolerance acquisition for EHCF+LGG groups was (95%CI): at 12 months = 0.41 (0.30 to 0.52); at 24 months = 0.64 (0.53 to 0.75); at 36 months = 0.81 (0.72 to 0.90). Conclusion : The results of the study suggest that EHCF+LGG is superior to other formulas for the prevention of AMs and for the acquisition of immune tolerance in children with CMA

EP1 receptor within the ventrolateral periaqueductal grey controls thermonociception and rostral ventromedial medulla cell activity in healthy and neuropathic rat

The aim of this study was to investigate the expression of prostaglandin EP1 receptor within the ventrolateral periaqueductal grey (VL PAG). The role of VL PAG EP1 receptor in controlling thermonociception and rostral ventromedial medulla (RVM) activity in healthy and neuropathic rats was also examined. EP1 receptor was indeed found to be expressed within the VL PAG and co-localized with vesicular GABA transporter. Intra-VL PAG microinjection of ONO-DI-004, a selective EP1 receptor agonist, dose-dependently reduced tail flick latency as well as respectively increasing and decreasing the spontaneous activity of ON and OFF cells. Furthermore, it increased the ON cell burst and OFF cell pause. Intra-VL PAG prostaglandin E2 (PGE2) behaved similarly to ONO-DI-004. The effects of ONO-DI-004 and PGE2 were antagonized by intra-VL PAG L335677, a selective EP1 receptor antagonist. L335677 dose-dependently increased the tail flick latency and ongoing activity of the OFF cells, while reducing the ongoing ON cell activity. It also decreased the ON cell burst and OFF cell pause. In neuropathic rats using spare nerve injury (SNI) of the sciatic nerve model, EP1 receptor expression decreased in the VL PAG. However, ONO-DI-004 and L335677 were able to alter pain responses and ON and OFF cell activity, as they did in healthy animals. Collectively, these data show that within the VL PAG, EP1 receptor has a facilitatory effect on the nociceptive response and consistently affects RVM neuron activity. Thus, the blockade of EP1 receptor in the VL PAG leads to antinociception in neuropathic pain conditions, despite its down-regulation. The expression of EP1 receptor on GABAergic neurons is consistent with an EP1 receptor blockade-induced disinhibition of the antinociceptive descending pathway at VL PAG level

2-Pentadecyl-2-oxazoline ameliorates memory impairment and depression-like behaviour in neuropathic mice: possible role of adrenergic alpha2- and H3 histamine autoreceptors

Neuropathic pain (NP) remains an untreatable disease due to the complex pathophysiology that involves the whole pain neuraxis including the forebrain. Sensory dysfunctions such as allodynia and hyperalgesia are only part of the symptoms associated with neuropathic pain that extend to memory and affectivity deficits. The development of multi-target molecules might be a promising therapeutic strategy against the symptoms associated with NP. 2-pentadecyl-2-oxazoline (PEA-OXA) is a plant-derived agent, which has shown effectiveness against chronic pain and associated neuropsychiatric disorders. The molecular mechanisms by which PEA-OXA exerts its effects are, however, only partially known. In the current study, we show that PEA-OXA, besides being an alpha2 adrenergic receptor antagonist, also acts as a modulator at histamine H3 receptors, and report data on its effects on sensory, affective and cognitive symptoms associated with the spared nerve injury (SNI) model of neuropathic pain in mice. Treatment for 14&nbsp;days with PEA-OXA after the onset of the symptoms associated with neuropathic pain resulted in the following effects: (i) allodynia was decreased; (ii) affective/cognitive impairment associated with SNI (depression, spatial, and working memories) was counteracted; (iii) long-term potentiation in vivo in the lateral entorhinal cortex-dentate gyrus (perforant pathway, LPP) was ameliorated, (iv) hippocampal glutamate, GABA, histamine, norepinephrine and dopamine level alterations after peripheral nerve injury were reversed, (v) expression level of the TH positive neurons in the Locus Coeruleus were normalized. Thus, a 16-day treatment with PEA-OXA alleviates the sensory, emotional, cognitive, electrophysiological and neurochemical alterations associated with SNI-induced neuropathic pain

DijetGAN:A Generative-Adversarial Network Approach for the Simulation of QCD Dijet Events at the LHC

A Generative-Adversarial Network (GAN) based on convolutional neural networks is used to simulate the production of pairs of jets at the LHC. The GAN is trained on events generated using MadGraph5 + Pythia8, and Delphes3 fast detector simulation. We demonstrate that a number of kinematic distributions both at Monte Carlo truth level and after the detector simulation can be reproduced by the generator network with a very good level of agreement. The code can be checked out or forked from the publicly accessible online repository https://gitlab.cern.ch/disipio/DiJetGAN .Comment: 17 pages, 8 figure

The blockade of the transient receptor potential vanilloid type 1 and fatty acid amide hydrolase decreases symptoms and central sequelae in the medial prefrontal cortex of neuropathic rats

<p>Abstract</p> <p>Background</p> <p>Neuropathic pain is a chronic disease resulting from dysfunction within the "pain matrix". The basolateral amygdala (BLA) can modulate cortical functions and interactions between this structure and the medial prefrontal cortex (mPFC) are important for integrating emotionally salient information. In this study, we have investigated the involvement of the transient receptor potential vanilloid type 1 (TRPV1) and the catabolic enzyme fatty acid amide hydrolase (FAAH) in the morphofunctional changes occurring in the pre-limbic/infra-limbic (PL/IL) cortex in neuropathic rats.</p> <p>Results</p> <p>The effect of <it>N</it>-arachidonoyl-serotonin (AA-5-HT), a hybrid FAAH inhibitor and TPRV1 channel antagonist, was tested on nociceptive behaviour associated with neuropathic pain as well as on some phenotypic changes occurring on PL/IL cortex pyramidal neurons. Those neurons were identified as belonging to the BLA-mPFC pathway by electrical stimulation of the BLA followed by hind-paw pressoceptive stimulus application. Changes in their spontaneous and evoked activity were studied in sham or spared nerve injury (SNI) rats before or after repeated treatment with AA-5-HT. Consistently with the SNI-induced changes in PL/IL cortex neurons which underwent profound phenotypic reorganization, suggesting a profound imbalance between excitatory and inhibitory responses in the mPFC neurons, we found an increase in extracellular glutamate levels, as well as the up-regulation of FAAH and TRPV1 in the PL/IL cortex of SNI rats. Daily treatment with AA-5-HT restored cortical neuronal activity, normalizing the electrophysiological changes associated with the peripheral injury of the sciatic nerve. Finally, a single acute intra-PL/IL cortex microinjection of AA-5-HT transiently decreased allodynia more effectively than URB597 or I-RTX, a selective FAAH inhibitor or a TRPV1 blocker, respectively.</p> <p>Conclusion</p> <p>These data suggest a possible involvement of endovanilloids in the cortical plastic changes associated with peripheral nerve injury and indicate that therapies able to normalize endovanilloid transmission may prove useful in ameliorating the symptoms and central sequelae associated with neuropathic pain.</p

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

How the First Year of the COVID-19 Pandemic Impacted Patients’ Care in the Vascular Surgery Divisions of the Southern Regions of the Italian Peninsula

Background: To investigate the effects of the COVID-19 lockdowns on the vasculopathic population. Methods: The Divisions of Vascular Surgery of the southern Italian peninsula joined this multicenter retrospective study conducted through cross-sectional survey. Each received a 13- point questionnaire, investigating the hospitalization rate of vascular patients in the first 11 months of the COVID-19 pandemic and in the preceding 11 months. Results: 27 out of 29 Centers were enrolled. April-December 2020 (7092 patients) vs 2019 (9161 patients): post-EVAR surveillance, treatment for Rutherford category 3 peripheral arterial disease, and asymptomatic carotid stenosis revascularization significantly decreased [1484 (16.2%) vs 1014 (14.3%), p=0.0009; 1401 (15.29%) vs 959 (13.52%), p=0.0006; and 1558 (17.01%) vs 934 (13.17%), p&lt;0.0001, respectively]; while revascularization or major amputations for chronic limb-threatening ischemia, and urgent revascularization for symptomatic carotid stenosis significantly increased [1204 (16.98%) vs 1245 (13.59%), p&lt;0.0001; 355 (5.01%) vs 358 (3.91%), p=0.0007; and 153 (2.16%) vs 140 (1.53%), p=0.0009, respectively. Conclusions: The suspension of elective activities during the COVID-19 pandemic caused a significant reduction in asymptomatic carotid stenosis revascularization, treatment for Rutherford 3 peripheral arterial disease, post-EVAR surveillance. Contestually, we observed a significant increase in urgent revascularization for symptomatic carotid stenosis, and revascularization or major amputations for chronic limb-threatening ischemia