Neuropathic pain induced alterations in the opioidergic modulation of a descending pain facilitatory area of the brain

Opioids play a major role at descending pain modulation but the effects of neuropathic pain on the brain opioidergic system remain understudied. Since descending facilitation is enhanced during neuropathic pain, we studied the opioidergic modulation of the dorsal reticular nucleus (DRt), a medullary pain facilitatory area, in the spared nerve injury (SNI) model of neuropathic pain. We first performed a series of behavioral experiments in naïve-animals to establish the role of µ-opioid receptor (MOR) in the effects of endogenous and exogenous opioids at the DRt. Specifically, we showed that lentiviral-mediated MOR-knockdown at the DRt increased sensitivity to thermal and mechanical stimuli while the MOR agonist DAMGO induced the opposite effects. Additionally, we showed that MOR-knockdown and the pharmacological blockade of MOR by CTAP at the DRt decreased and inhibited, respectively, the analgesic effects of systemic morphine. Then, we performed in vivo microdialysis to measure enkephalin peptides in the DRt and evaluated MOR expression in the DRt at mRNA, protein and phosphorylated form levels by quantitative real-time PCR and immunohistochemistry, respectively. SNI-animals, compared to sham control, showed higher levels of enkephalin peptides, lower MOR-labeled cells without alterations in MOR mRNA levels, and higher phosphorylated MOR-labeled cells. Finally, we performed behavioral studies in SNI animals to determine the potency of systemic morphine and the effects of the pharmacologic and genetic manipulation of MOR at the DRt. We showed a reduced potency of the antiallodynic effects of systemic morphine in SNI-animals compared to the antinociceptive effects in sham animals. Increasing MOR-cells at the DRt of SNI-animals by lentiviral-mediated MOR-overexpression produced no effects on mechanical allodynia. DAMGO induced anti-allodynia only after MOR-overexpression. These results show that MOR inhibits DRt pain facilitatory actions and that this action contributes to the analgesic effects of systemic opioids. We further show that the inhibitory function of MOR is impaired during neuropathic pain. This is likely due to desensitization and degradation of MOR which are adaptations of the receptor that can be triggered by MOR phosphorylation. Skipping counter-regulatory pathways involved in MOR adaptations might restore the opioidergic inhibition at pain facilitatory areas.This work was supported by the FCT (PTCD/SAU-NSC/110954/2009 FEDER/COMPETE) and ESF (NORTE-08-5369-FSE-000026)

Usefulness of neck ultrasonography in the follow-up of patients with differentiated thyroid cancer

Neck ultrasonography (US) is recommended for the assessment of all patients with thyroid carcinoma after initial therapy, since even low-risk patients with undetectable stimulated thyroglobulin (Tg) may present cervical metastases. In the case of these metastases, US is the most sensitive method and is superior to whole-body 131I scanning. Cervical lymph nodes with a diameter > 5 mm presenting thin calcifications and/or cystic degeneration have almost always a malignant etiology. In the absence of these characteristics, a round shape and the absence of an echogenic hilum are suspicious findings, whereas elongated lymph nodes with a visible echogenic hilum are considered benign. Doppler flow analysis helps with the differential diagnosis, usually revealing peripheral or mixed hypervascularization in malignant cases. In the presence of suspicious lymph nodes upon US, fine-needle aspiration cytology and measurement of Tg in the needle lavage fluid are useful and complementary exams for the definition of the etiology, with the combination of the two methods showing elevated sensitivity and 100% specificity. US is also useful before thyroidectomy, even contributing in some cases to modify the surgical planning, and before ablation for the measurement of thyroid remnants and detection of persistent lymph node metastases. Another application of this imaging method is to guide the injection of ethanol (sclerotherapy) or the introduction of electrodes for radiofrequency ablation in selected cases of isolated lymph node metastases as an alternative to traditional therapies.A ultra-sonografia (US) cervical é recomendada na avaliação de todos pacientes com carcinoma de tireóide após a terapia inicial, pois mesmo indivíduos de baixo risco com tireoglobulina (Tg) estimulada indetectável podem apresentar metástases cervicais. Para estas metástases, a US é o método mais sensível, superior à pesquisa de corpo inteiro (PCI) com 131I. Linfonodos cervicais com diâmetro > 5 mm com calcificações finas e/ou degeneração cística quase sempre são de etiologia maligna. Na ausência destas características, o formato arredondado e a ausência do hilo ecogênico são achados suspeitos, enquanto linfonodos alongados e com hilo ecogênico visível são considerados benignos. A avaliação do fluxo, através do doppler, auxilia no diagnóstico diferencial, usualmente revelando hipervascularização periférica ou mista nos casos malignos. Na presença de linfonodos suspeitos na US, a avaliação citológica do material obtido através da punção aspirativa por agulha fina (PAAF) e a dosagem da Tg, obtida do lavado da agulha, são testes úteis e complementares para definir a etiologia, com elevada sensibilidade quando combinados e especificidade de 100%. A US também é útil antes da tiroidectomia, auxiliando e até, em alguns casos, modificando o planejamento cirúrgico; e antes da ablação, para mensuração dos remanescentes tireoidianos e pesquisa de metástases linfonodais persistentes. Outra aplicação desse método de imagem é guiar a injeção de etanol (escleroterapia) ou a introdução de eletrodos para ablação com radiofreqüência em casos selecionados de metástases linfonodais isoladas, como alternativa às terapias convencionais.Santa Casa de Belo Horizonte Serviço de EndocrinologiaInstituto Alpha de GastroenterologiaUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de MedicinaUNIFESP, EPM, Depto. de MedicinaSciEL

Seaweed Secondary Metabolites with Beneficial Health Effects : An Overview of Successes in In Vivo Studies and Clinical Trials

Macroalgae are increasingly viewed as a source of secondary metabolites with great potential for the development of new drugs. In this development, in vitro studies are only the first step in a long process, while in vivo studies and clinical trials are the most revealing stages of the true potential and limitations that a given metabolite may have as a new drug. This literature review aims to give a critical overview of the secondary metabolites that reveal the most interesting results in these two steps. Phlorotannins show great pharmaceutical potential in in vivo models and, among the several examples, the anti-dyslipidemia activity of dieckol must be highlighted because it was more effective than lovastatin in an in vivo model. The IRLIIVLMPILMA tridecapeptide that exhibits an in vivo level of activity similar to the hypotensive clinical drug captopril should still be stressed, as well as griffithsin which showed such stunning results over a variety of animal models and which will probably move onto clinical trials soon. Regarding clinical trials, studies with pure algal metabolites are scarce, limited to those carried out with kahalalide F and fucoxanthin. The majority of clinical trials currently aim to ascertain the effect of algae consumption, as extracts or fractions, on obesity and diabetes.This research was funded by project MACBIOBLUE (MAC/1.1b/086), program Interreg MAC 2014–2020 co-financed by DRCT (Azores Regional Government), supporting G.P. Rosa’s grant, as well as by FCT—Fundação para a Ciência e a Tecnologia, the European Union, QREN, FEDER, and COMPETE, through funding the cE3c center (FCT UID/BIA/00329/2013, 2015–2018 and UID/BIA/00329/2019) and the QOPNA research unit (FCT UID/QUI/00062/2019)info:eu-repo/semantics/publishedVersio

Criticality in strongly correlated fluids

In this brief review I will discuss criticality in strongly correlated fluids. Unlike simple fluids, molecules of which interact through short ranged isotropic potential, particles of strongly correlated fluids usually interact through long ranged forces of Coulomb or dipolar form. While for simple fluids mechanism of phase separation into liquid and gas was elucidated by van der Waals more than a century ago, the universality class of strongly correlated fluids, or in some cases even existence of liquid-gas phase separation remains uncertain.Comment: Proceedings of Scaling Concepts and Complex Systems, Merida, Mexic

Discrimination, Crypticity, and Incipient Taxa in Entamoeba

Persistent difficulties in resolving clear lineages in diverging populations of prokaryotes or unicellular eukaryotes (protistan polyphyletic groups) are challenging the classical species concept. Although multiple integrated approaches would render holistic taxonomies, most phylogenetic studies are still based on single-gene or morphological traits. Such methodologies conceal natural lineages, which are considered “cryptic.” The concept of species is considered artificial and inadequate to define natural populations. Social organisms display differential behaviors toward kin than to nonrelated individuals. In “social” microbes, kin discrimination has been used to help resolve crypticity. Aggregative behavior could be explored in a nonsocial protist to define phylogenetic varieties that are considered “cryptic.” Two Entamoeba invadens strains, IP-1 and VK-1:NS are considered close populations of the same “species.” This study demonstrates that IP-1 and VK-1:NS trophozoites aggregate only with alike members and discriminate members of different strains based on behavioral and chemical signals. Combined morphological, behavioral/chemical, and ecological studies could improve Archamoebae phylogenies and define cryptic varieties. Evolutionary processes in which selection acted continuously and cumulatively on ancestors of Entamoeba populations gave rise to chemical and behavioral signals that allowed individuals to discriminate nonpopulation members and, gradually, to the emergence of new lineages; alternative views that claim a “Designer” or “Creator” as responsible for protistan diversity are unfounded

Integrating complementary and alternative medicine into academic medical centers: Experience and perceptions of nine leading centers in North America

BACKGROUND: Patients across North America are using complementary and alternative medicine (CAM) with increasing frequency as part of their management of many different health conditions. The objective of this study was to develop a guide for academic health sciences centers that may wish to consider starting an integrative medicine program. METHODS: We queried North American leaders in the field of integrative medicine to identify initial sites. Key stakeholders at each of the initial sites visited were then asked to identify additional potential study sites (snowball sampling), until no new sites were identified. We conducted structured interviews to identify critical factors associated with success and failure in each of four domains: research, education, clinical care, and administration. During the interviews, field notes were recorded independently by at least two investigators. Team meetings were held after each visit to reach consensus on the information recorded and to ensure that it was as complete as possible. Content analysis techniques were used to identify key themes that emerged from the field notes. RESULTS: We identified ten leading North American integrative medical centers, and visited nine during 2002–2003. The centers visited suggested that the initiation of an integrative medicine program requires a significant initial outlay of funding and a motivated "champion". The centers had important information to share regarding credentialing, medico-legal issues and billing for clinical programs; identifying researchers and research projects for a successful research program; and strategies for implementing flexible educational initiatives and establishing a functional administrative structure. CONCLUSION: Important lessons can be learned from academic integrative programs already in existence. Such initiatives are timely and feasible in a variety of different ways and in a variety of settings

Measurements of fiducial and differential cross sections for Higgs boson production in the diphoton decay channel at s√=8 TeV with ATLAS

Measurements of fiducial and differential cross sections are presented for Higgs boson production in proton-proton collisions at a centre-of-mass energy of s√=8 TeV. The analysis is performed in the H → γγ decay channel using 20.3 fb−1 of data recorded by the ATLAS experiment at the CERN Large Hadron Collider. The signal is extracted using a fit to the diphoton invariant mass spectrum assuming that the width of the resonance is much smaller than the experimental resolution. The signal yields are corrected for the effects of detector inefficiency and resolution. The pp → H → γγ fiducial cross section is measured to be 43.2 ±9.4(stat.) − 2.9 + 3.2 (syst.) ±1.2(lumi)fb for a Higgs boson of mass 125.4GeV decaying to two isolated photons that have transverse momentum greater than 35% and 25% of the diphoton invariant mass and each with absolute pseudorapidity less than 2.37. Four additional fiducial cross sections and two cross-section limits are presented in phase space regions that test the theoretical modelling of different Higgs boson production mechanisms, or are sensitive to physics beyond the Standard Model. Differential cross sections are also presented, as a function of variables related to the diphoton kinematics and the jet activity produced in the Higgs boson events. The observed spectra are statistically limited but broadly in line with the theoretical expectations

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

DNA microarray profiling of genes differentially regulated by the histone deacetylase inhibitors vorinostat and LBH589 in colon cancer cell lines

<p>Abstract</p> <p>Background</p> <p>Despite the significant progress made in colon cancer chemotherapy, advanced disease remains largely incurable and novel efficacious chemotherapies are urgently needed. Histone deacetylase inhibitors (HDACi) represent a novel class of agents which have demonstrated promising preclinical activity and are undergoing clinical evaluation in colon cancer. The goal of this study was to identify genes in colon cancer cells that are differentially regulated by two clinically advanced hydroxamic acid HDACi, vorinostat and LBH589 to provide rationale for novel drug combination partners and identify a core set of HDACi-regulated genes.</p> <p>Methods</p> <p>HCT116 and HT29 colon cancer cells were treated with LBH589 or vorinostat and growth inhibition, acetylation status and apoptosis were analyzed in response to treatment using MTS, Western blotting and flow cytometric analyses. In addition, gene expression was analyzed using the Illumina Human-6 V2 BeadChip array and Ingenuity^®Pathway Analysis.</p> <p>Results</p> <p>Treatment with either vorinostat or LBH589 rapidly induced histone acetylation, cell cycle arrest and inhibited the growth of both HCT116 and HT29 cells. Bioinformatic analysis of the microarray profiling revealed significant similarity in the genes altered in expression following treatment with the two HDACi tested within each cell line. However, analysis of genes that were altered in expression in the HCT116 and HT29 cells revealed cell-line-specific responses to HDACi treatment. In addition a core cassette of 11 genes modulated by both vorinostat and LBH589 were identified in both colon cancer cell lines analyzed.</p> <p>Conclusion</p> <p>This study identified HDACi-induced alterations in critical genes involved in nucleotide metabolism, angiogenesis, mitosis and cell survival which may represent potential intervention points for novel therapeutic combinations in colon cancer. This information will assist in the identification of novel pathways and targets that are modulated by HDACi, providing much-needed information on HDACi mechanism of action and providing rationale for novel drug combination partners. We identified a core signature of 11 genes which were modulated by both vorinostat and LBH589 in a similar manner in both cell lines. These core genes will assist in the development and validation of a common gene set which may represent a molecular signature of HDAC inhibition in colon cancer.</p