Efecto de la administración de dosis subletales de LPS por la vía oral, en la sobrevida y producción de citocinas durante el desarrollo de sepsis polimicrobiana inducida por ligadura y punción de ciego

El modelo de ligadura y punción de ciego (CLP) se utiliza para estudiar mecanismos fisiopatológicos de daño en sepsis. En el modelo de choque endotóxico , la administración de dosis subletales de lipopolisacárido (LPS), protege contra dosis letales posteriores; sin embargo, éste efecto se desconoce en el modelo de CLP. En este estudio se exploró el efecto de la administración de dosis subletales de LPS por la vía oral (O), en la sobrevida y producción de citocinas de animales con sepsis polimicrobiana. Durante la primera fase del estudio, ratones Balb/c machos fueron agrupados en a) sham, b) controles, c) tratados con 5 dosis subletales de LPS (50 µg/100 µl) dos veces por semana vía intraperitoneal (IP) o d) tratados vía O. Sólo los grupos control y tratados con LPS vías IP y O fueron retados con la CLP. Se evaluó superviviencia, positividad de hemocultivos, análisis microbiológico de heces, concentraciones séricas de TNF, IFN-γ, IL-6 e IL-10, expresión de TNF en hígado y pulmón, además del porcentaje de células de Kupffer en hígado y de edema en pulmón, y la presencia de inmunoglobulinas anti-LPS. En la segunda fase, ratones Balb/c fueron agrupados en a) sham, b) controles, tratados profilácticamente con c) 0.01, d) 0.1, e) 1 o f) 10 mg/kg de fragmentos F(ab)2 anti-TNF; éste mismo protocolo fue probado con fragmentos F(ab)2 anti-IFNγ. En estos grupos se evaluó la superviviencia y producción sérica de TNF, IL-1, IL-6, IFN-γ e IL-10. Una vez definida la dosis protectora para cada anticuerpo, su administración se inició en diferentes tiempos para definir su papel terapéutico. Los resultados de la primera fase mostraron que solo la CLP ocasionó una infección polimicrobiana, y que el tratamiento con LPS vía O protegió vs el grupo C (87% vs 50%)(p<0.05). La protección se asoció con reducción de IFN-γ vs C (p<0.05) y aumento de IL-10 4h después de la cirugía, reducción del tiempo de expresión de TNF hasta las 4h en hígado y retraso de la expresión a partir de las 4h en pulmón del grupo O vs la expresión observada en C (desde la 1.5-24h). El tratamiento con LPS vía O también redujo el porcentaje de células de Kupffer en hígado (27.5 vs 37.7) y % de edema en pulmón (12.51 vs 26.6) vs C (p<0.05). Finalmente en el grupo O se observó un predominio de IgM vs los grupos C e IP (p<0.05). En la segunda fase del estudio, el tratamiento con fragmentos F(ab)2 anti-TNF protegió en dosis de 1 mg/kg vs C (69% vs 29%; p<0.05). La protección se asoció a la coexistencia de IL-1β e IL-10 durante las primeras 24h de estudio, además de niveles elevados de IL-6 a las 48, disminuyó IL-1β y aumentó IL-10. Finalmente observó que el tratamiento con 1 mg/kg de anti- TNF, protegió solo cuando se inició -2h, -30min o 30min de la CLP. Por su parte, la administración de fragmentos F(ab)2 anti-IFN-γ aumentó la superviviencia en dosis de 0.01 mg/kg (78%) vs 33% documentado en C (p<0.05), lo que se asoció con la coexistencia de Il-1β e IL-10 durante las primeras 24h de estudio, 48h después disminuyó IL-1β y aumentó IL-10, en tanto que la IL-6 se mantuvo elevada durante todo el estudio. El efecto terapéutico del anti-IFN-γ pudo constatarse cuando se administró -2 o 24h después de la CLP, ya que aumentó la supervivencia en 88 y 94% respectivamente vs 54% observada en C (p<0.05). Se concluye que el tratamiento con dosis subletales de LPS vía oral protegió significativamente en el modelo murino de sepsis inducida por CLP. Palabras clave. CLP, sepsis, tolerancia, coexistencia.Cecal ligation and puncture model (CLP) is used to investigate mechanisms of tissue injury in sepsis. In endotoxic shoch model, administration of sublethal doses of lipopolysaccharide (LPS), protects against subsequent lethal doses; however, this effect is unknown in CLP model. This study was aimed to explore the effect of administration of sublethal doses of LPS by oral route (O), on the survival and cytokine milieu in animals with polymicrobian sepsis. In a first phase male mice Balb/c were grouped into a) sham, b) controls, c) treated with 5 sublethal doses of LPS (50 µg/100 µl) twice a week by intraperitonel route (IP) or d) treated by O route; the control group and those treated with LPS O and IP routes were challenged with CLP. We evaluated survival, positive blood cultures, microbiological testing of stool, serum concentrations of TNF, IFN-γ, IL-6 and IL-10, TNF expression in liver and lung, as well as percentage of Kupffer cells in liver and lung edema, and presence of anti-LPS immunoglobulins. In the second phase, Balb / c mice were divided into a) sham, b) controls, treated prophylactically with c) 0.01, d) 0.1, e) 1 of) 10 mg / kg of F (ab) 2 anti-TNF fragments, this protocol was also tested with F (ab) 2 anti-IFN-γ fragments. In these groups we evaluated the survival and production of serum TNF, IL-1, IL-6, IFN-γ and IL-10. After the protective dose for each antibody, was defined, its administration was initiated at different times. The results of the first phase showed that LPS treatment significantly protected via O in comparison with C group (87% vs 50%; p0.05). This protection was associated with reduced IFN-γ vs C (p <0.05) and increased IL-10 4h after surgery. The TNF expression was abolished at 4h in liver, while it initiates at 4h and continues until 48h in lung of group O vs expression observed in C (1.5- 24h). LPS treatment by O route also reduced the percentage of Kupffer cells in liver (27.5 vs. 37.7) and percentage of lung edema (12.51 vs 26.6) vs C (p <0.05). Finally, in the O group showed a predominance of IgM vs C and IP groups (p <0.05). In the second phase of the study, treatment with F (ab) 2 anti-TNF fragments protected in doses of 1 mg/kg vs C (69 vs 29%; p<0.05). This protection was associated with the coexistence of IL-1β and IL-10 during the first 24 hours of study, and high levels of IL-6; 48 after CLP, IL-1β decreased and IL-10 increased. Finally, we found that treatment with 1 mg /kg of anti-TNF protected only when it was began prior (-2h, -30min) or 30min after from the CLP. Administration of F (ab) 2 fragments anti-IFN-γ protected at doses of 0.01 mg/kg (78% survival) vs C (33%) (p <0.05), which was associated with coexistence of Il-1β and IL-10 during the first 24 hours of study, decreased IL-1β and increased IL-10 48h after of CLP, while IL-6 remained elevated throughout the study. Therapeutic effect of anti-IFN-γ was tested when his administration started -2 or 24h after CLP, increased survival at 88 and 94% respectively vs 54% observed in C (p <0.05). We conclude that the treatment with sublethal doses of LPS by oral route significantly protects in the sepsis murine model induced by CLP

Presence of antibodies against cyclic citrullinated peptides in patients with 'rhupus': a cross-sectional study

'Rhupus' is a rare condition sharing features of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). If rhupus is a distinctive entity, an overlap between RA and SLE or a subset of SLE is currently debated. This study was performed to explore the prevalence of antibodies against cyclic citrullinated peptides (anti-CCP antibodies) in rhupus. Patients meeting American College of Rheumatology criteria for RA, SLE, or both were included. Clinical and radiographic features were recorded and sera were searched for anti-CCP antibodies, rheumatoid factor, antinuclear antibodies, anti-extractable nuclear antigens, and antibodies against double-stranded DNA (anti-dsDNA antibodies). Seven patients for each group were included. Clinical and serological features for RA or SLE were similar between rhupus and RA patients, and between rhupus and SLE patients, respectively. Values for anti-CCP antibodies obtained were significantly (p < 0.05) higher in RA (6/7) and rhupus (4/7) than in SLE patients (0/7) and healthy subjects (0/7). Our data support the possibility that rhupus is an overlap between RA and SLE, because highly specific autoantibodies for RA (anti-CCP) and for SLE (anti-dsDNA and anti-Sm) are detected in coexistence

Search for new particles in events with energetic jets and large missing transverse momentum in proton-proton collisions at root s=13 TeV

A search is presented for new particles produced at the LHC in proton-proton collisions at root s = 13 TeV, using events with energetic jets and large missing transverse momentum. The analysis is based on a data sample corresponding to an integrated luminosity of 101 fb(-1), collected in 2017-2018 with the CMS detector. Machine learning techniques are used to define separate categories for events with narrow jets from initial-state radiation and events with large-radius jets consistent with a hadronic decay of a W or Z boson. A statistical combination is made with an earlier search based on a data sample of 36 fb(-1), collected in 2016. No significant excess of events is observed with respect to the standard model background expectation determined from control samples in data. The results are interpreted in terms of limits on the branching fraction of an invisible decay of the Higgs boson, as well as constraints on simplified models of dark matter, on first-generation scalar leptoquarks decaying to quarks and neutrinos, and on models with large extra dimensions. Several of the new limits, specifically for spin-1 dark matter mediators, pseudoscalar mediators, colored mediators, and leptoquarks, are the most restrictive to date.Peer reviewe

Combined searches for the production of supersymmetric top quark partners in proton-proton collisions at root s=13 TeV

A combination of searches for top squark pair production using proton-proton collision data at a center-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 137 fb(-1) collected by the CMS experiment, is presented. Signatures with at least 2 jets and large missing transverse momentum are categorized into events with 0, 1, or 2 leptons. New results for regions of parameter space where the kinematical properties of top squark pair production and top quark pair production are very similar are presented. Depending on themodel, the combined result excludes a top squarkmass up to 1325 GeV for amassless neutralino, and a neutralinomass up to 700 GeV for a top squarkmass of 1150 GeV. Top squarks with masses from 145 to 295 GeV, for neutralino masses from 0 to 100 GeV, with a mass difference between the top squark and the neutralino in a window of 30 GeV around the mass of the top quark, are excluded for the first time with CMS data. The results of theses searches are also interpreted in an alternative signal model of dark matter production via a spin-0 mediator in association with a top quark pair. Upper limits are set on the cross section for mediator particle masses of up to 420 GeV

Probing effective field theory operators in the associated production of top quarks with a Z boson in multilepton final states at root s=13 TeV

Peer reviewe

Measurements of the Electroweak Diboson Production Cross Sections in Proton-Proton Collisions at root s=5.02 TeV Using Leptonic Decays

The first measurements of diboson production cross sections in proton-proton interactions at a center-of-mass energy of 5.02 TeV are reported. They are based on data collected with the CMS detector at the LHC, corresponding to an integrated luminosity of 302 pb(-1). Events with two, three, or four charged light leptons (electrons or muons) in the final state are analyzed. The WW, WZ, and ZZ total cross sections are measured as sigma(WW) = 37:0(-5.2)(+5.5) (stat)(-2.6)(+2.7) (syst) pb, sigma(WZ) = 6.4(-2.1)(+2.5) (stat)(-0.3)(+0.5)(syst) pb, and sigma(ZZ) = 5.3(-2.1)(+2.5)(stat)(-0.4)(+0.5) (syst) pb. All measurements are in good agreement with theoretical calculations at combined next-to-next-to-leading order quantum chromodynamics and next-to-leading order electroweak accuracy

Observation of tW production in the single-lepton channel in pp collisions at root s=13 TeV

A measurement of the cross section of the associated production of a single top quark and a W boson in final states with a muon or electron and jets in proton-proton collisions at root s = 13 TeV is presented. The data correspond to an integrated luminosity of 36 fb(-1) collected with the CMS detector at the CERN LHC in 2016. A boosted decision tree is used to separate the tW signal from the dominant t (t) over bar background, whilst the subleading W+jets and multijet backgrounds are constrained using data-based estimates. This result is the first observation of the tW process in final states containing a muon or electron and jets, with a significance exceeding 5 standard deviations. The cross section is determined to be 89 +/- 4 (stat) +/- 12 (syst) pb, consistent with the standard model.Peer reviewe

Measurement of the top quark mass using events with a single reconstructed top quark in pp collisions at root s=13 TeV

Abstract:A measurement of the top quark mass is performed using a data sample en-riched with single top quark events produced in thetchannel. The study is based on proton-proton collision data, corresponding to an integrated luminosity of 35.9 fb−1, recorded at√s= 13TeV by the CMS experiment at the LHC in 2016. Candidate events are selectedby requiring an isolated high-momentum lepton (muon or electron) and exactly two jets,of which one is identified as originating from a bottom quark. Multivariate discriminantsare designed to separate the signal from the background. Optimized thresholds are placedon the discriminant outputs to obtain an event sample with high signal purity. The topquark mass is found to be172.13+0.76−0.77GeV, where the uncertainty includes both the sta-tistical and systematic components, reaching sub-GeV precision for the first time in thisevent topology. The masses of the top quark and antiquark are also determined separatelyusing the lepton charge in the final state, from which the mass ratio and difference aredetermined to be0.9952+0.0079−0.0104and0.83+1.79−1.35GeV, respectively. The results are consistentwithCPTinvariance

Search for invisible decays of the Higgs boson produced via vector boson fusion in proton-proton collisions at s\sqrt{s} = 13 TeV

A search for invisible decays of the Higgs boson produced via vector boson fusion (VBF) has been performed with 101  fb$^{-1}$ of proton-proton collisions delivered by the LHC at $\sqrt{s}$ =13  TeV and collected by the CMS detector in 2017 and 2018. The sensitivity to the VBF production mechanism is enhanced by constructing two analysis categories, one based on missing transverse momentum and a second based on the properties of jets. In addition to control regions with Z and W boson candidate events, a highly populated control region, based on the production of a photon in association with jets, is used to constrain the dominant irreducible background from the invisible decay of a Z boson produced in association with jets. The results of this search are combined with all previous measurements in the VBF topology, based on data collected in 2012 (at $\sqrt{s}$ =8  TeV), 2015, and 2016, corresponding to integrated luminosities of 19.7, 2.3, and 36.3  fb$^{-1}$, respectively. The observed (expected) upper limit on the invisible branching fraction of the Higgs boson is found to be 0.18 (0.10) at the 95% confidence level, assuming the standard model production cross section. The results are also interpreted in the context of Higgs-portal models

Observation of the Bc+_\mathrm{c}^+ Meson in Pb-Pb and pp Collisions at sNN\sqrt{s_{\mathrm{NN}}} = 5.02 TeV and Measurement of its Nuclear Modification Factor

The B$_\mathrm{c}^+$ meson is observed for the first time in heavy ion collisions. Data from the CMS detector are used to study the production of the B$_\mathrm{c}^+$ meson in lead-lead (Pb-Pb) and proton-proton (pp) collisions at a center-of-mass energy per nucleon pair of $\sqrt{s_{\mathrm{NN}}}$ = 5.02 TeV , via the B$_\mathrm{c}^+$ → (J/ψ → μ$^+$μ$^−$)μ$^+$ν$_μ$ decay. The B$_\mathrm{c}^+$ nuclear modification factor, derived from the PbPb-to-pp ratio of production cross sections, is measured in two bins of the trimuon transverse momentum and of the PbPb collision centrality. The B$_\mathrm{c}^+$meson is shown to be less suppressed than quarkonia and most of the open heavy-flavor mesons, suggesting that effects of the hot and dense nuclear matter created in heavy ion collisions contribute to its production. This measurement sets forth a promising new probe of the interplay of suppression and enhancement mechanisms in the production of heavy-flavor mesons in the quark-gluon plasma