Associações de curto e longo prazo de adversidade na infância com desfechos desenvolvimentais em crianças e jovens

Childhood adversity has been consistently associated with detrimental consequences on childhood development. Such experiences might take on different forms leading to differential influences across development. Also, their impact might remain for many years after those experiences occurred. It is unclear whether associations of childhood adversity and negative developmental outcomes vary across different forms of adversity and for how many years those experiences continue to impact development. The articles that comprise this thesis aim to investigate short-term and long-term associations of childhood adversity measured as threat and deprivation with psychopathology, emotional processing, and distinct aspects of cognition. In order to do that, data is drawn from three-time points assessments of the Brazilian High-risk Cohort (BHRC), a large school-based community cohort that takes place in the cities of São Paulo and Porto Alegre. Article #1investigate the latent constructs of threat and deprivation, following a dimensional model of adversity, while investigating their crosssectional and longitudinal associations with psychopathology, emotional processing through attention bias towards angry faces, and executive functions (EF) during a three-year time frame. Article #2 expands findings from article #1 in the sense that it investigates associations of threat and deprivation with psychopathology and EF in a six-year time frame, at the same time it adjusts these associations for other forms of environmental inputs in the form of stressful life events (SLE). Findings support theoretical models that show threat and deprivation differentially influence development, with threat being more strongly associated with psychopathology, and deprivation with worse performance on EF tasks. Influences of threat and deprivation on the outcomes were persistent across time, and were independent of other exposure to stressful life events, suggesting its important lasting influence on mental health 12 across the lifespan. Such results contribute to previous knowledge on the importance of identifying developmental dimensions that are disrupted by specific early adversity events to develop better intervention strategies aimed to prevent the onset of mental disorders, as well as treat problems and difficulties of children and adolescents exposed to childhood adverse events.Adversidade na infância tem sido consistentemente associada a consequências prejudiciais ao desenvolvimento infantil. Tais experiências podem assumir diferentes formas, levando a influências diferentes em aspectos distintos do desenvolvimento. Não é claro se as associações de adversidade na infância e desfechos negativos no desenvolvimento variam conforme as diferentes formas e tipos de eventos adversos. Os artigos que compõem esta tese têm como objetivo investigar associações transversais e longitudinais da adversidade na infância, medida como ameaça e privação, com psicopatologia, processamento emocional e aspectos distintos da cognição. Para isso, os dados são extraídos de avaliações realizadas em três momentos da Coorte Brasileira de Alto Risco (BHRC), uma grande coorte comunitária de base escolar que ocorre nas cidades de São Paulo e Porto Alegre. O artigo #1 investiga os construtos latentes de ameaça e privação, seguindo um modelo dimensional de adversidade, enquanto investiga suas associações transversais e longitudinais com psicopatologia, processamento emocional medido como viés de atenção para faces com raiva e funções executivas (FE) durante um período de três anos. O artigo nº 2 expande as descobertas do artigo nº 1 no sentido de que investiga associações de ameaça e privação com psicopatologia e FE em um período de seis anos, ao mesmo tempo em que ajusta essas associações para outras formas de experiências ambientais medidas como eventos estressores de vida (SLE). Os resultados apoiam a ideia já presente na literatura de que a ameaça e a privação influenciam diferencialmente o desenvolvimento, com a ameaça sendo mais fortemente associada à psicopatologia e a privação com pior desempenho em tarefas de FE. As influências de ameaça e privação nos resultados foram persistentes ao longo do tempo e independentes de outras exposições a eventos estressores de vida, 14 sugerindo sua influência persistente na saúde mental ao longo da vida. Tais resultados contribuem para o conhecimento prévio sobre a importância de identificar dimensões do desenvolvimento que são prejudicadas por eventos específicos de adversidade na infância na direção de desenvolver melhores estratégias de intervenção visando prevenir o aparecimento de transtornos mentais, bem como tratar de forma direcionada os problemas e dificuldades de crianças e adolescentes expostos a eventos adversos na infância

Kinetic Temperature and Electron Density Measurement in an Inductively Coupled Plasma Torch using Degenerate Four-Wave Mixing

Laser wave mixing is presented as an effective technique for spatially resolved kinetic temperature measurements in an atmospheric-pressure radio-frequency inductively-coupled plasma. Measurements are performed in a 1 kW, 27 MHz RF plasma using a continuous-wave, tunable 811.5-nm diode laser to excite the 4s(sup 3)P2 approaches 4p(sup 3)D3 argon transition. Kinetic temperature measurements are made at five radial steps from the center of the torch and at four different torch heights. The kinetic temperature is determined by measuring simultaneously the line shape of the sub-Doppler backward phase-conjugate degenerate four-wave mixing and the Doppler-broadened forward-scattering degenerate four-wave mixing. The temperature measurements result in a range of 3,500 to 14,000 K+/-150 K. Electron densities measured range from 6.1 (+/-0.3) x 10(exp 15)/cu cm to 10.1 (+/-0.3) x 10(exp 15)/cu cm. The experimental spectra are analyzed using a perturbative treatment of the backward phase-conjugate and forward-geometry wave-mixing theory. Stark width is determined from the collisional broadening measured in the phase-conjugate geometry. Electron density measurements are made based on the Stark width. The kinetic temperature of the plasma was found to be more than halved by adding deionized water through the nebulizer

A perspective on polo-like kinase-1 inhibition for the treatment of rhabdomyosarcoma

Rhabdomyosarcomas are the most common pediatric soft tissue sarcoma and are a major cause of death from cancer in young patients requiring new treatment options to improve outcomes. High-risk patients include those with metastatic or relapsed disease and tumors with PAX3-FOXO1 fusion genes that encode a potent transcription factor that drives tumourigenesis through transcriptional reprogramming. Polo-Like Kinase-1 (PLK1) is a serine/threonine kinase that phosphorylates a wide range of target substrates and alters their activity. PLK1 functions as a pleiotropic master regulator of mitosis and regulates DNA replication after stress. Taken together with high levels of expression that correlate with poor outcomes in many cancers, including rhabdomyosarcomas, it is an attractive therapeutic target. This is supported in rhabdomyosarcoma models by characterization of molecular and phenotypic effects of reducing and inhibiting PLK1, including changes to the PAX3-FOXO1 fusion protein. However, as tumor re-growth has been observed, combination strategies are required. Here we review preclinical evidence and consider biological rationale for PLK1 inhibition in combination with drugs that promote apoptosis, interfere with activity of PAX3-FOXO1 and are synergistic with microtubule-destabilizing drugs such as vincristine. The preclinical effects of low doses of the PLK1 inhibitor volasertib in combination with vincristine, which is widely used in rhabdomyosarcoma treatment, show particular promise in light of recent clinical data in the pediatric setting that support achievable volasertib doses predicted to be effective. Further development of novel therapeutic strategies including PLK1 inhibition may ultimately benefit young patients with rhabdomyosarcoma and other cancers

A perspective on polo-like kinase-1 inhibition for the treatment of rhabdomyosarcoma

Rhabdomyosarcomas are the most common pediatric soft tissue sarcoma and are a major cause of death from cancer in young patients requiring new treatment options to improve outcomes. High-risk patients include those with metastatic or relapsed disease and tumors with PAX3-FOXO1 fusion genes that encode a potent transcription factor that drives tumourigenesis through transcriptional reprogramming. Polo-Like Kinase-1 (PLK1) is a serine/threonine kinase that phosphorylates a wide range of target substrates and alters their activity. PLK1 functions as a pleiotropic master regulator of mitosis and regulates DNA replication after stress. Taken together with high levels of expression that correlate with poor outcomes in many cancers, including rhabdomyosarcomas, it is an attractive therapeutic target. This is supported in rhabdomyosarcoma models by characterization of molecular and phenotypic effects of reducing and inhibiting PLK1, including changes to the PAX3-FOXO1 fusion protein. However, as tumor re-growth has been observed, combination strategies are required. Here we review preclinical evidence and consider biological rationale for PLK1 inhibition in combination with drugs that promote apoptosis, interfere with activity of PAX3-FOXO1 and are synergistic with microtubule-destabilizing drugs such as vincristine. The preclinical effects of low doses of the PLK1 inhibitor volasertib in combination with vincristine, which is widely used in rhabdomyosarcoma treatment, show particular promise in light of recent clinical data in the pediatric setting that support achievable volasertib doses predicted to be effective. Further development of novel therapeutic strategies including PLK1 inhibition may ultimately benefit young patients with rhabdomyosarcoma and other cancers

Gene expression changes associated with trajectories of psychopathology in a longitudinal cohort of children and adolescents

We aimed to identify blood gene expression patterns associated to psychopathological trajectories retrieved from a large community, focusing on the emergence and remission of general psychiatric symptoms. Hundred and three individuals from the Brazilian High-Risk Cohort Study (BHRCS) for mental disorders were classified in four groups according to Child Behavior Checklist (CBCL) total score at the baseline (w0) and after 3 years (w1): low–high (L–H) (N = 27), high–low (H–L) (N = 12), high–high (H–H) (N = 34) and low–low (L–L) groups (N = 30). Blood gene expression profile was measured using Illumina HT-12 Beadchips, and paired analyses comparing w0 and w1 were performed for each group. Results: 98 transcripts were differentially expressed comparing w0 and w1 in the L-H, 33 in the H–L, 177 in the H–H and 273 in the L–L. Of these, 66 transcripts were differentially expressed exclusively in the L–H; and 6 only in the H–L. Cross-Lagged Panel Models analyses revealed that RPRD2 gene expression at w1 might be influenced by the CBCL score at w0. Moreover, COX5B, SEC62, and NDUFA2 were validated with another technique and were also differentially regulated in postmortem brain of subjects with mental disorders, indicating that they might be important not only to specific disorders, but also to general psychopathology and symptoms trajectories. Whereas genes related to metabolic pathways seem to be associated with the emergence of psychiatric symptoms, mitochondrial inner membrane genes might be important over the course of normal development. These results suggest that changes in gene expression can be detected in blood in different psychopathological trajectories

Apremilast, a novel PDE4 inhibitor, inhibits spontaneous production of tumour necrosis factor-alpha from human rheumatoid synovial cells and ameliorates experimental arthritis

Introduction: Type 4 phosphodiesterases (PDE4) play an important role in immune cells through the hydrolysis of the second messenger, cAMP. Inhibition of PDE4 has previously been shown to suppress immune and inflammatory responses, demonstrating PDE4 to be a valid therapeutic target for immune-mediated pathologies. We assessed the anti-inflammatory effects of a novel PDE4 inhibitor, apremilast, in human synovial cells from rheumatoid arthritis (RA) patients, as well as two murine models of arthritis

Cinnamomum zeylanicum Essential Oil Reduces Infestation by Alphitobius diaperinus in Poultry Litter

Background: Even though insecticides are managed and the period of sanitary emptiness in poultry is respected, the elimination of Alphitobius diaperinus may not be successful. The use of essential oils of plant origin presents as a good alternative in the substitution of insecticides with synthetic molecules, since they are easy to obtain, with rapid degradationand without risk of residues for non-target organisms. The main objective of the present study was to examine whether Cinnamomum zeylanicum oil reduces Alphitobius diaperinus (Panzer) (Coleoptera: Tenebrionidae) infestations under experimental conditions, without causing toxicity to broilers chicks exposed to treated litter.Materials, Methods & Results: The experimental design was completely randomized, with four replications per treatment. The treatments were as follows: solvent control using the diluent Dimethyl Sulfoxide 5% (oil diluent); chemical control using 5 g/m² cypermethrin; one spray of C. zeylanicum 5% oil; and two sprays of C. zeylanicum 5% oil. Each experimental unit was infested with 150 lesser mealworm adults. At 15 days of the broiler chick’s life, blood was collected for biochemical analysis (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total protein, albumin, globulin, triglycerides and uric acid), and liver fragments were isolated for histopathological analysis. Using TupeTrap devices, we counted lesser mealworm 40 days after treatment. The treatments did not alter biochemical variables, and did not causehistopathological lesions in liver. The treatments with C. zeylanicum 5% oil with one and two sprays efficiently reduced lesser mealworm infestation compared with solvent control. Cypermethrin treatment had no effect.Discussion: Many of the commercial products present low effectiveness in the control of A. diaperinus, since the target organisms develop resistance to the product. In the present study, we used a higher cypermethrin dose than that recommended by the manufacturer, in order to increase efficacy in the face of possible resistance. Even so, cypermethrin did not efficiently control the organism. The effectiveness of the essential oil of C. zeylanicum tested can be attributed to the compounds found in greater quantity in the oil composition, such as cinnamaldehyde (41.27%), linalool (13.05%) and methyl eugenol (10.87%), characterized as responsible for the action of oil repellency. Monoterpenoid compounds found in essential oils extracted from plants have insecticidal action acting on the central nervous system of insects, which impairs their development, being characterized as neurotoxic compounds. The results found with the essential oil of C. zeylanicum are of great importance, since the control of A. diaperinus is not efficient because this organism has behavior that favors reinfestation in the poultry houses, such as shelter in cracks, in the draperies, below the feeders and in the soil. The biochemical analyzes of the blood can as important tools to assist in the monitoring of broilers health, in the diagnosis and treatment of diseases, and therefore the results presented are of great importance since they assist in the search for alternative methods for the control of A. diaperinus, where we can affirm that the essential oil of C. zeylanicum does not cause toxicity to broilers. Based on these results we can affirm that essential oil of Cinnamomum zeylanicum, 5%, is an effective substitute for existing commercially-available insecticides.Keywords: alternative control, cinnamon oil, insecticide, lesser mealworm

Repellent Effects of Andiroba and Copaiba Oils against Musca domestica (Common House Fly) and Ecotoxicological Effects on the Environment

Background: The main challenge in raising cattle in Brazil is related to ectoparasites, that cause negative effects on milk and meat production, and in severe cases, animal death. Sheds known as crèches attracts large number insects mainly due to milk residues in the environment. The housefly is a major problem due to act as vectors of many other diseases, and so there is the possibility of control of infestations with natural products. Andiroba and copaiba oils may act as natural biocides, there are only a few studies on their effect on biological soil parameters. Therefore, this study aimed to evaluate the repellent effect of andiroba and copaiba oils against flies and on biological soil parameters.Materials, Methods & Results: The repellency effect of oils of andiroba and copaiba was tested at a concentration of 5% in lambs shed maternity, containing 64 bays (1.8 m2). It was sprayed 30 mL per pen, where they were housed five lambs each. Pre-treatment counts were taken before the treatment (mean 46 per pen after Musca domestica), and post-treatment count was made on 2, 24 and 48 h. The data collected at 2 and 24 h was evaluated and the number of flies was reduced significantly (P 0.05). Ecotoxicological test using increasing concentrations in the soil (0, 1, 5, 10, 25, 50, and 100 mg/kg) regarding changes in basal respiration (C-CO2), and survival and reproduction of springtails (Folsomia candida). It was observed an increased amount of mineralized C-CO2 until the day 10 of incubation for both oils without inhibition of the microbial respiratory process in any dose. The copaiba oil showed higher amounts of accumulated C-CO2 compared to andiroba oil in all studied concentrations (P 0.05), the same was observed for the reproduction results, where there was no reduction in the number of juveniles (P > 0.05).Discussion: According literature, andiroba and copaiba oils have repellent effect against domestic fly when sprayed onto infected cow’s horn fly, similar results also were reported in vitro tests against M. domestica larvae using andiroba oil and noted 80% larval mortality. The use of natural products in disease control is growing, but its impacts on the environment are not known, so in addition to suggesting therapies it is important to be concerned with ecotoxicological tests. Researchers showed an effect of Eucalyptus globulus essential oil on F. candida and reported 76% reduction in its survival rate at concentration of 60 mg/kg soil.  Basal soil respiration is a sensitive indicator that quickly reveals changes in the environmental conditions that affect microbial activity, and the data presented herein reveal an increase in the respiration of microorganisms depending on the amount of oil added to the soil.  The essential oils of copaiba and andiroba have repellent effect against Musca domestica, and did not show any toxicity to inhibit microbial activity in the soil. In addition, the presence of the oils in the soil did not affect the survival and reproduction of springtails Folsomia candida

Geometric Configurations, Regular Subalgebras of E10 and M-Theory Cosmology

We re-examine previously found cosmological solutions to eleven-dimensional supergravity in the light of the E_{10}-approach to M-theory. We focus on the solutions with non zero electric field determined by geometric configurations (n_m, g_3), n\leq 10. We show that these solutions are associated with rank $g$ regular subalgebras of E_{10}, the Dynkin diagrams of which are the (line) incidence diagrams of the geometric configurations. Our analysis provides as a byproduct an interesting class of rank-10 Coxeter subgroups of the Weyl group of E_{10}.Comment: 48 pages, 27 figures, 5 tables, references added, typos correcte