Macrophage TNF-α mediates parathion-induced airway hyperreactivity in guinea pigs.

Organophosphorus pesticides (OPs) are implicated in human asthma. We previously demonstrated that, at concentrations that do not inhibit acetylcholinesterase activity, the OP parathion causes airway hyperreactivity in guinea pigs as a result of functional loss of inhibitory M2 muscarinic receptors on parasympathetic nerves. Because macrophages are associated with asthma, we investigated whether macrophages mediate parathion-induced M2 receptor dysfunction and airway hyperreactivity. Airway physiology was measured in guinea pigs 24 h after a subcutaneous injection of parathion. Pretreatment with liposome-encapsulated clodronate induced alveolar macrophage apoptosis and prevented parathion-induced airway hyperreactivity in response to electrical stimulation of the vagus nerves. As determined by qPCR, TNF-α and IL-1β mRNA levels were increased in alveolar macrophages isolated from parathion-treated guinea pigs. Parathion treatment of alveolar macrophages ex vivo did not significantly increase IL-1β and TNF-α mRNA but did significantly increase TNF-α protein release. Consistent with these data, pretreatment with the TNF-α inhibitor etanercept but not the IL-1β receptor inhibitor anakinra prevented parathion-induced airway hyperreactivity and protected M2 receptor function. These data suggest a novel mechanism of OP-induced airway hyperreactivity in which low-level parathion activates macrophages to release TNF-α-causing M2 receptor dysfunction and airway hyperreactivity. These observations have important implications regarding therapeutic approaches for treating respiratory disease associated with OP exposures

Ganho de peso, dislipidemia e parâmetros alterados para síndrome metabólica em pacientes de primeiro episódio psicótico após seguimento de seis meses

OBJECTIVES: Obesity and metabolic abnormalities are frequent in psychotic patients, including first-episode psychosis. We evaluated weight and metabolic parameters in first-episode psychotic outpatients from the First Episode Psychosis Program, Universidade Federal de São Paulo (UNIFESP). METHOD: Weight, height, waist and hip circumferences, glucose and lipid levels were measured at baseline and after a six-month period. RESULTS: Fifty-seven patients were included and 44 (77.2%) of them finished the study. Patients had a median age of 26.3 years, 60% were men and 43% had a diagnosis of schizophrenia at the endpoint. Weight and BMI values increased significantly during the follow-up (p < 0.01). The average weight gain at the follow-up was 10.1% of the baseline weight (SD = 11.9). Only women presented significant waist abnormalities: at the first assessment the waist mean was 79.12 cm (SD = 10.68) and 6 months later it had increased to 89.65 cm (SD = 11.19, z = -3.182, p = 0.001). After 6 months, the total cholesterol (p = 0.004), and triglyceride levels (p = 0.016) increased, while HDL-cholesterol levels decreased (p = 0.025). During the follow-up period one patient (2.3%) developed diabetes mellitus, one (2.3%) presented altered fasting glucose, 12 (27.2%) patients developed at least two altered parameters for metabolic syndrome and 3 (6.8%) patients developed metabolic syndrome (p = 0.001). DISCUSSION: The results of this study showed that in a short period of time individuals under antipsychotic treatment had their weight increased significantly and developed important metabolic abnormalities. CONCLUSIONS: Clinicians should be aware of these risks, choose an antipsychotic that causes less weight gain and should monitor these patients carefully, and recommend prophylactic measures as diet restriction and physical activities.OBJETIVOS: Obesidade e alterações metabólicas são freqüentes em pacientes psicóticos, inclusive no primeiro episódio psicótico. Foram avaliados peso e parâmetros metabólicos em pacientes em tratamento no Programa de Episódio Psicótico da Universidade Federal de São Paulo (UNIFESP). MÉTODO: Peso, altura, medida de cintura e quadril, glicemia e perfil lipídico foram avaliados no início do tratamento e após seis meses. RESULTADOS: Cinqüenta e sete pacientes foram incluídos no estudo e 44 (72%) concluíram o estudo. Os pacientes apresentavam em média 26,3 anos, 60% eram do sexo masculino e, ao final do estudo, 43% apresentavam diagnóstico de esquizofrenia. Houve aumento significativo do peso e índice de massa corporal durante o estudo (p < 0,01). Em média, o peso aumentou 10,1% do peso inicial (SD = 11,9). Apenas mulheres apresentaram alterações na medida da cintura: no início, a média da cintura era de 79,12 cm (SD = 10,68) e, após seis meses, houve um aumento para 89,65 cm (SD = 11,19, z = -3,182, p = 0,001). Após seis meses, houve aumento do colesterol total (p = 0,004) e triglicérides (p = 0,016), e diminuição dos níveis de colesterol HDL (p = 0,025). No período, um paciente (2,3%) desenvolveu diabetes mellitus, um paciente (2,3%) apresentou glicemia de jejum alterada, 12 (27,2%) desenvolveram pelo menos dois parâmetros alterados para síndrome metabólica, e 3 (6,8%) apresentaram síndrome metabólica (p = 0,001). DISCUSSÃO: Os resultados deste estudo mostram que em um curto período de tempo pacientes em tratamento com antipsicóticos aumentaram substancialmente o peso e desenvolveram importantes alterações metabólicas. CONCLUSÃO: Os clínicos devem estar atentos a esses riscos, escolher medicações que causem menor ganho de peso, devendo monitorar esses pacientes cuidadosamente e recomendar medidas profiláticas como restrição dietética e atividade física.Universidade Federal de São Paulo (UNIFESP) Department of Psychiatry First-episode Psychosis ProgramUNIFESP, Department of Psychiatry First-episode Psychosis ProgramSciEL

DIANNEXIN DOWN-MODULATES TNF-INDUCED ENDOTHELIAL MICROPARTICLE RELEASE BY BLOCKING MEMBRANE BUDDING PROCESS.

BACKGROUND: Microparticles are now recognised as true biological effectors with a role in immunopathology through their ability to disseminate functional properties. Diannexin, a homodimer of annexin V, binds to PS with a higher affinity and longer blood half-life than the monomer, inhibits prothrombinase complex activity thereby diminishing coagulation and reperfusion injury mediators and prevent microvesicle-mediated material transfer. Our aim was to determine if Diannexin could modulate microparticle production by endothelial cells by interacting with the phosphatidylserine exposure occurring during the release of these vesicles. RESULTS: In this study we showed that fluorescently labelled Diannexin binds to calcimycin-activated endothelial cells but not to resting cells. After overnight incubation, Diannexin enters cells and their released MP carry Diannexin. Some Diannexin seems to be processed via early endosomes and later is found in lysosomes. Both unlabelled Diannexin and fluorescent Diannexin inhibit MP release from TNF-activated endothelial cells. However, Diannexin treatment does not prevent endothelial activation by TNF. In addition, the inhibitory effect of Diannexin on MP release could be observed when cells were pre-, concomitantly or post-treated with cytokines. Scanning electron microscopy showed differences in the numbers and types of protuberances at the cell surface when cells were treated or not with Diannexin. Finally, there is no apparent congruency between fluorescent Diannexin labelling and surface protuberances as shown by correlative microscopy. CONCLUSIONS: Altogether these data suggest that Diannexin can inhibit endothelial vesiculation by binding PS present either at the cell surface or at the level of the inner leaflet of the plasma membrane

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis

Search for direct pair production of the top squark in all-hadronic final states in proton-proton collisions at s√=8 TeV with the ATLAS detector

The results of a search for direct pair production of the scalar partner to the top quark using an integrated luminosity of 20.1fb−1 of proton–proton collision data at √s = 8 TeV recorded with the ATLAS detector at the LHC are reported. The top squark is assumed to decay via t˜→tχ˜01 or t˜→ bχ˜±1 →bW(∗)χ˜01 , where χ˜01 (χ˜±1 ) denotes the lightest neutralino (chargino) in supersymmetric models. The search targets a fully-hadronic final state in events with four or more jets and large missing transverse momentum. No significant excess over the Standard Model background prediction is observed, and exclusion limits are reported in terms of the top squark and neutralino masses and as a function of the branching fraction of t˜ → tχ˜01 . For a branching fraction of 100%, top squark masses in the range 270–645 GeV are excluded for χ˜01 masses below 30 GeV. For a branching fraction of 50% to either t˜ → tχ˜01 or t˜ → bχ˜±1 , and assuming the χ˜±1 mass to be twice the χ˜01 mass, top squark masses in the range 250–550 GeV are excluded for χ˜01 masses below 60 GeV