Overall and sex-specific associations between fetal adversity and child development at age 1 year : evidence from Brazil

A growing body of epigenetic research suggests that in-utero adaptations to environmental changes display important sex-specific variation. We tested this heterogeneous adaptation hypothesis using data from 900 children born at the University Hospital in São Paulo, Brazil, between October 2013 and April 2014. Crude and adjusting linear models were used to quantify the associations between prematurity, being small for gestational age, and children's physical and mental development at 12 months of age. Prematurity was negatively associated with neuropsychological development in final models (z score difference, -0.42, 95% confidence intervals: -0.71, -0.14), but associations did not vary significantly by sex. For being small for gestational age, associations with height-for-age, weight-for-age, and neuropsychological development were also negative, but they were systematically larger for male than for female infants (P < 0.05 for all). These results suggest that male fetuses may be more vulnerable to intrauterine adversity than female fetuses. Further research will be needed to better understand the mechanisms underlying these sex-specific associations

Influence of lithium in neuron-glia interaction in hippocampal neurons: preliminary study

Recentemente, especial atenção foi dada aos possíveis efeitos neuroprotetores do lítio, especialmente pela descoberta de seus efeitos regulatórios sobre proteínas pró e anti-apoptóticas. O lítio aumenta substancialmente a expressão de proteínas citoprotetoras no sistema nervoso central, tanto no córtex de ratos quanto em células humanas de origem neuronal. Além de ações neuroprotetoras, auxilia na regeneração de axônios no sistema nervoso central de mamíferos. O lítio regula negativamente a expressão e a atividade de enzimas que exercem funções importantes na homeostase cerebral: plasticidade sináptica, neurogênese e fosforilação da proteína tau. Microglia é conhecida por sua importância na neuropatologia. No entanto, sob condições fisiológicas, tais células imunes interagem ativamente com os neurônios, sendo capazes de modular o destino e as funções das sinapses. Essa capacidade das células microgliais sugere as conseqüências de mudanças no fenótipo microglial sob condições patológicas, o que torna relevante o entendimento da interação entre micróglia e outras células cerebrais em desenvolvimento e sua influência na formação de redes neuronais e sinápticas. O presente trabalho tem como objetivo identificar a principal via de integração neurônio-glia ativada pelo tratamento crônico com lítio em neurônios, explorando o uso de ferramentas de bioinformática em dados de microarray. O tratamento de neurônios hipocampais com lítio alterou os genes relacionados a diferentes vias de neuroproteção na dose terapêutica mais alta. Houve dissociação entre a dose terapêutica e sub-terapêutica de lítio na neuroproteção. Portanto, o tratamento em doses terapêuticas (2mM) modificou diferentes vias de sinalização quando comparado com as doses sub-terapêuticas (0,02 e 0,2mM).Recently, special attention has been given to the possible neuroprotective effects of lithium, especially by the discovery of its regulatory effects on pro and anti-apoptotic proteins. Lithium substantially increases the cytoprotective proteins expression in the central nervous system, both in rat cortex and in human cells of neuronal origin. In addition to neuroprotective actions, it aids in the regeneration of axons in the central nervous system of mammals. Lithium negatively regulates the expression and activity of enzymes that exert important functions in cerebral homeostasis: synaptic plasticity, neurogenesis, and phosphorylation of tau protein. Microglia is known for its importance in neuropathology. However, under physiological conditions, such immune cells interact actively with neurons, being able to modulate the fate and functions of the synapses. Such ability of microglial cells suggests the consequences of changes in microglial phenotype under pathological conditions, which makes it relevant to understand the interaction between microglial and other developing brain cells and their influence on the formation of neuronal and synaptic networks. The current work aims to identify the main pathway of neuronal-glia integration activated by chronic treatment with lithium in neurons, exploring the use of bioinformatics tools in microarray data. Treatment of primary hippocampal neurons with lithium changed the genes related to different neuroprotection pathways at the highest therapeutic dose. There was dissociation between the therapeutic and sub-therapeutic dose of lithium in neuroprotection. Therefore, treatment at therapeutic doses (2mM) modified different signaling pathways when compared to the sub-therapeutic dose (0.02 and 0.2mM)

Identification of protein expression signatures in gastric carcinomas using clustering analysis

Background and Aim: The identification of gastric carcinomas (GC) has traditionally been based on histomorphology. Recently, DNA microarrays have successfully been used to identify tumors through clustering of the expression profiles. Random forest clustering is widely used for tissue microarrays and other immunohistochemical data, because it handles highly-skewed tumor marker expressions well, and weighs the contribution of each marker according to its relatedness with other tumor markers. In the present study, we e identified biologically- and clinically-meaningful groups of GC by hierarchical clustering analysis of immunohistochemical protein expression. Methods: We selected 28 proteins (p16, p27, p21, cyclin D1, cyclin A, cyclin B1, pRb, p53, c-met, c-erbB-2, vascular endothelial growth factor, transforming growth factor [TGF]-beta I, TGF-beta II, MutS homolog-2, bcl-2, bax, bak, bcl-x, adenomatous polyposis coli, clathrin, E-cadherin, beta-catenin, mucin (MUC) 1, MUC2, MUC5AC, MUC6, matrix metalloproteinase [ MMP]-2, and MMP-9) to be investigated by immunohistochemistry in 482 GC. The analyses of the data were done using a random forest-clustering method. Results: Proteins related to cell cycle, growth factor, cell motility, cell adhesion, apoptosis, and matrix remodeling were highly expressed in GC. We identified protein expressions associated with poor survival in diffuse-type GC. Conclusions: Based on the expression analysis of 28 proteins, we identified two groups of GC that could not be explained by any clinicopathological variables, and a subgroup of long-surviving diffuse-type GC patients with a distinct molecular profile. These results provide not only a new molecular basis for understanding the biological properties of GC, but also better prediction of survival than the classic pathological grouping.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [98/14335-2

An Inherited Small Microdeletion at 15q13.3 in a Patient\ud with Early- Onset Obsessive-Compulsive Disorder

Copy number variations (CNVs) have been previously associated with several different neurodevelopmental psychiatric\ud disorders, such as autism, schizophrenia, and attention deficit hyperactivity disorder (ADHD). The present study consisted of\ud a pilot genome-wide screen for CNVs in a cohort of 16 patients with early-onset obsessive-compulsive disorder (OCD) and\ud 12 mentally healthy individuals, using array-based comparative genomic hybridization (aCGH) on 44K arrays. A small rare\ud paternal inherited microdeletion (,64 kb) was identified in chromosome 15q13.3 of one male patient with very early onset\ud OCD. The father did not have OCD. The deletion encompassed part of the FMN1 gene, which is involved with the\ud glutamatergic system. This finding supports the hypothesis of a complex network of several genes expressed in the brain\ud contributing for the genetic risk of OCD, and also supports the glutamatergic involvement in OCD, which has been\ud previously reported in the literature.We wish to thank the patients and heathy controls who volunteered to participate in this study.This study was supported by grants to Dras Cappi and Brentani from the Foundation for Research Support of the State of São Paulo (FAPESP); grant number: 2008/11537-7, and from the Brazilian National Council for Scientific and Technological Development (CNPq; protocol number MCT/CNPq 14/2008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

HOXB7 mRNA is overexpressed in pancreatic ductal adenocarcinomas and its knockdown induces cell cycle arrest and apoptosis

Background\ud Human homeobox genes encode nuclear proteins that act as transcription factors involved in the control of differentiation and proliferation. Currently, the role of these genes in development and tumor progression has been extensively studied. Recently, increased expression of HOXB7 homeobox gene (HOXB7) in pancreatic ductal adenocarcinomas (PDAC) was shown to correlate with an invasive phenotype, lymph node metastasis and worse survival outcomes, but no influence on cell proliferation or viability was detected. In the present study, the effects arising from the knockdown of HOXB7 in PDAC cell lines was investigated.\ud \ud Methods\ud Real time quantitative PCR (qRT-PCR) (Taqman) was employed to assess HOXB7 mRNA expression in 29 PDAC, 6 metastatic tissues, 24 peritumoral tissues and two PDAC cell lines. siRNA was used to knockdown HOXB7 mRNA in the cell lines and its consequences on apoptosis rate and cell proliferation were measured by flow cytometry and MTT assay respectively.\ud \ud Results\ud Overexpression of HOXB7 mRNA was observed in the tumoral tissues and in the cell lines MIA PaCa-2 and Capan-1. HOXB7 knockdown elicited (1) an increase in the expression of the pro-apoptotic proteins BAX and BAD in both cell lines; (2) a decrease in the expression of the anti-apoptotic protein BCL-2 and in cyclin D1 and an increase in the number of apoptotic cells in the MIA PaCa-2 cell line; (3) accumulation of cell in sub-G1 phase in both cell lines; (4) the modulation of several biological processes, especially in MIA PaCa-2, such as proteasomal ubiquitin-dependent catabolic process and cell cycle.\ud \ud Conclusion\ud The present study confirms the overexpression of HOXB7 mRNA expression in PDAC and demonstrates that decreasing its protein level by siRNA could significantly increase apoptosis and modulate several biological processes. HOXB7 might be a promising target for future therapies.This study was supported in part by a FAPESP grant 2010/01421-1

Schedule for affective disorders and schizophrenia for school-age children - present and lifetime version (K-SADS-PL), DSM-5 update : translation into Brazilian Portuguese

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Influence of the interaction between nodal fibroblast and breast cancer cells on gene expression

Our aim was to evaluate the interaction between breast cancer cells and nodal fibroblasts, by means of their gene expression profile. Fibroblast primary cultures were established from negative and positive lymph nodes from breast cancer patients and a similar gene expression pattern was identified, following cell culture. Fibroblasts and breast cancer cells (MDA-MB231, MDA-MB435, and MCF7) were cultured alone or co-cultured separated by a porous membrane (which allows passage of soluble factors) for comparison. Each breast cancer lineage exerted a particular effect on fibroblasts viability and transcriptional profile. However, fibroblasts from positive and negative nodes had a parallel transcriptional behavior when co-cultured with a specific breast cancer cell line. The effects of nodal fibroblasts on breast cancer cells were also investigated. MDA MB-231 cells viability and migration were enhanced by the presence of fibroblasts and accordingly, MDA-MB435 and MCF7 cells viability followed a similar pattern. MDA-MB231 gene expression profile, as evaluated by cDNA microarray, was influenced by the fibroblasts presence, and HNMT, COMT, FN3K, and SOD2 were confirmed downregulated in MDA-MB231 co-cultured cells with fibroblasts from both negative and positive nodes, in a new series of RT-PCR assays. In summary, transcriptional changes induced in breast cancer cells by fibroblasts from positive as well as negative nodes are very much alike in a specific lineage. However, fibroblasts effects are distinct in each one of the breast cancer lineages, suggesting that the inter-relationships between stromal and malignant cells are dependent on the intrinsic subtype of the tumor

Differences in children and adolescents with SARS-CoV-2 infection: a cohort study in a Brazilian tertiary referral hospital

OBJECTIVES: To compare demographic/clinical/laboratory/treatments and outcomes among children and adolescents with laboratory-confirmed coronavirus disease 2019 (COVID-19). METHODS: This was a cross-sectional study that included patients diagnosed with pediatric COVID-19 (aged <18 years) between April 11, 2020 and April 22, 2021. During this period, 102/5,951 (1.7%) of all admissions occurred in neonates, children, and adolescents. Furthermore, 3,962 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection samples were processed in patients aged <18 years, and laboratory-confirmed COVID-19 occurred in 155 (4%) inpatients and outpatients. Six/155 pediatric patients were excluded from the study. Therefore, the final group included 149 children and adolescents (n=97 inpatients and 52 outpatients) with positive SARS-CoV-2 results. RESULTS: The frequencies of sore throat, anosmia, dysgeusia, headache, myalgia, nausea, lymphopenia, pre-existing chronic conditions, immunosuppressive conditions, and autoimmune diseases were significantly reduced in children and adolescents (p<0.05). Likewise, the frequencies of enoxaparin use (p=0.037), current immunosuppressant use (p=0.008), vasoactive agents (p=0.045), arterial hypotension (p<0.001), and shock (p=0.024) were significantly lower in children than in adolescents. Logistic regression analysis showed that adolescents with laboratory-confirmed COVID-19 had increased odds ratios (ORs) for sore throat (OR 13.054; 95% confidence interval [CI] 2.750-61.977; p=0.001), nausea (OR 8.875; 95% CI 1.660-47.446; p=0.011), and lymphopenia (OR 3.575; 95% CI 1.355-9.430; p=0.010), but also had less hospitalizations (OR 0.355; 95% CI 0.138-0.916; p=0.032). The additional logistic regression analysis on patients with preexisting chronic conditions (n=108) showed that death as an outcome was significantly associated with pediatric severe acute respiratory syndrome (SARS) (OR 22.300; 95% CI 2.341-212.421; p=0.007) and multisystem inflammatory syndrome in children (MIS-C) (OR 11.261; 95% CI 1.189-106. 581; p=0.035). CONCLUSIONS: Half of the laboratory-confirmed COVID-19 cases occurred in adolescents. Individuals belonging to this age group had an acute systemic involvement of SARS-CoV-2 infection. Pediatric SARS and MIS-C were the most important factors associated with the mortality rate in pediatric chronic conditions with COVID-19