Birth by cesarean section and mood disorders among adolescents of a birth cohort study in northern Brazil.

The increasing number of cesarean sections worldwide has encouraged research on the long-term effects of this birth type on the offspring's mental health. The objective of this study was to investigate whether there is an association between birth by cesarean section and the development of mood disorders (depression and bipolar disorders) in adolescents. A cohort study was carried out with 1603 adolescents from 18 to 19 years old who participated in the third phase of a birth cohort study in São Luís, MA, in 2016. Information on birth type and weight, prematurity, mother's age and schooling, parity, marital status, and smoking behavior during pregnancy, were collected at birth. The study outcomes were depression, bipolar disorder, and "mood disorder" construct. A Directed Acyclic Graph (DAG) was developed to select the variables for minimal adjustment for confounding and collision bias. Associations were estimated through propensity score weighting using a two-step estimation model, and confounders for cesarean birth were used in the predictive model. There was no significant association in the relationship between birth type and depression (95%CI: -0.037 to 0.017; P=0.47), bipolar disorder (95%CI: -0.019 to 0.045; P=0.43), and mood disorder (95%CI: -0.033 to 0.042; P=0.80) in adolescents of both sexes. Birth by cesarean section was not associated with the development of mood disorders in adolescents.

Birth by cesarean section and mood disorders among adolescents of a birth cohort study in northern Brazil

The increasing number of cesarean sections worldwide has encouraged research on the long-term effects of this birth type on the offspring's mental health. The objective of this study was to investigate whether there is an association between birth by cesarean section and the development of mood disorders (depression and bipolar disorders) in adolescents. A cohort study was carried out with 1603 adolescents from 18 to 19 years old who participated in the third phase of a birth cohort study in São Luís, MA, in 2016. Information on birth type and weight, prematurity, mother's age and schooling, parity, marital status, and smoking behavior during pregnancy, were collected at birth. The study outcomes were depression, bipolar disorder, and "mood disorder" construct. A Directed Acyclic Graph (DAG) was developed to select the variables for minimal adjustment for confounding and collision bias. Associations were estimated through propensity score weighting using a two-step estimation model, and confounders for cesarean birth were used in the predictive model. There was no significant association in the relationship between birth type and depression (95%CI: -0.037 to 0.017; P=0.47), bipolar disorder (95%CI: -0.019 to 0.045; P=0.43), and mood disorder (95%CI: -0.033 to 0.042; P=0.80) in adolescents of both sexes. Birth by cesarean section was not associated with the development of mood disorders in adolescents.

Determinants of the introduction of early complementary feeding before and after the third month of life: a multinomial analysis

The introduction of early complementary feeding (ECF) is determined by different factors depending on when it occurs. The objective of this study was to analyze factors associated with the introduction of ECF in two different moments of the infant's life: from zero to three and from four to five months of age. A cohort with 3,306 dyads studied in the BRISA survey in São Luis/MA in 2010 was used. Questionnaires were applied at birth and at follow-up when the infants were 15 to 36 months of age of women with more than 20 weeks of gestational age, residing in this municipality. A multivariate model of multinomial logistic regression was used to verify associations between independent variables and ECF at 0 to 3 months and at 4 to 5 months of age. A hierarchical analysis model was used to select variables for confounding adjustment. Variables with a P-value <0.05 were considered significant. For ECF introduced between 0-3 months, the variables "use of pacifier", "maternal paid activity", "smoking", and "postpartum pregnancy" were identified as risk factors. The variables "use of pacifier" and "maternal paid activity" remained associated as a risk for ECF introduced from 4-5 months. The variable 'mother without partner' (RR=1.26 and P=0.04) represented a risk factor for ECF only for the 4-5 months period. Although each period presented specific risk factors, the use of pacifier and maternal professional activity were associated in the two periods studied, indicating their importance for the introduction of ECF.

Association between tobacco and/or alcohol consumption during pregnancy and infant development: BRISA Cohort

Fetuses exposed to alcohol and/or tobacco are at risk for perinatal adversities. However, little is currently known about the association of the separate or concomitant use of alcohol and tobacco with infant motor and cognitive development. Thus, the objective of the present study was to investigate the association between maternal consumption of alcohol and/or tobacco during pregnancy and the motor and cognitive development of children starting from the second year of life. The study included 1006 children of a cohort started during the prenatal period (22-25 weeks of pregnancy), evaluated at birth and reevaluated during the second year of life in 2011/2013. The children were divided into four groups according to the alcohol and/or tobacco consumption reported by their mothers at childbirth: no consumption (NC), separate alcohol consumption (AC), separate tobacco consumption (TC), and concomitant use of both (ACTC). The Bayley Scale of Infant and Toddler Development Third Edition screening tool was used for the assessment of motor and cognitive development. Adjusted Poisson regression models were used to determine the association between groups and delayed development. The results indicated that only the ACTC group showed a higher risk of motor delay, specifically regarding fine motor skills, compared to the NC group (RR=2.81; 95%CI: 1.65; 4.77). Separate alcohol or tobacco consumption was not associated with delayed gross motor or cognitive development. However, the concomitant use of the two substances increased the risk of delayed acquisition of fine motor skills.

Psychological distress and mother-child relationship: influence of life context on a population sample (BRISA) through the use of directed acyclic graphs (DAG)

This study aimed to investigate the association between maternal psychological distress and impairment in mother-child relationship in a sample from a Northeast capital city in Brazil with a low Human Development Index, using directed acyclic graphs (DAG). A total of 3,215 women were evaluated for the presence of psychological distress through the Self Reporting Questionnaire instrument and for the mother-child relationship by the first factor of Postpartum Bonding Questionnaire, considered the most appropriate in the literature. Demographic and socioeconomic variables were used to construct a theoretical model and, after this, multivariate logistic regression was performed using variables suggested by Directed Acyclic Graphs (DAG). Psychological distress was present in 22.7% of the women and 12.6% of them presented impaired mother-child relationships. After adjustment, the variable 'maternal mental distress' remained associated with impaired mother-child relationship (RR=3.03), and among the explanatory variables only 'primary school level' (RR=1.48) was associated as a risk factor to this outcome. The results indicated that, in this population, women with psychological distress and lower schooling are more likely to present impaired mother-child relationships.

Socio-environmental determinants of the delay in the first dental visit: results of two population-based cohort studies in Brazil

The objective of this study was to describe the timing of the first dental visit and investigate the association of socioeconomic and behavioral factors with dental visit delay among 10/11-year-old children from two live-birth population cohorts with extremely contrasting socioeconomic profiles. Follow-up data (2004-2005) from cohorts of Ribeirão Preto (RP) (n=790) and São Luís (SL) (n=673) were evaluated. Delay in dental visit was defined as not visiting a dentist before the age of 7. Covariates included family socioeconomic characteristics, mother-related health behavior, and child-related characteristics. Prevalence ratios with robust standard errors were estimated. In both cohorts, less than 5% of children had visited a dentist before the age of two and about 35% of them had not visited a dentist before the age of seven. Lower mother's schooling and lack of private health insurance were associated with the delay in first dental visit for both cohorts. A small number of mother's prenatal care visits and being from a single-father family or a family without parents were only associated in the RP cohort, while having ≥4 siblings and lifetime dental pain were associated in the SL cohort. The association with dental pain probably reveals a preventive care-seeking behavior. Therefore, the percentage of delayed first dental visit of children was very high even among those with the most educated mothers. Further studies are necessary to analyze recent changes and underlying factors related to access to first dental visit after the implementation of the National Oral Health Policy in 2006.

Association between tobacco and/or alcohol consumption during pregnancy and infant development: BRISA Cohort.

Fetuses exposed to alcohol and/or tobacco are at risk for perinatal adversities. However, little is currently known about the association of the separate or concomitant use of alcohol and tobacco with infant motor and cognitive development. Thus, the objective of the present study was to investigate the association between maternal consumption of alcohol and/or tobacco during pregnancy and the motor and cognitive development of children starting from the second year of life. The study included 1006 children of a cohort started during the prenatal period (22-25 weeks of pregnancy), evaluated at birth and reevaluated during the second year of life in 2011/2013. The children were divided into four groups according to the alcohol and/or tobacco consumption reported by their mothers at childbirth: no consumption (NC), separate alcohol consumption (AC), separate tobacco consumption (TC), and concomitant use of both (ACTC). The Bayley Scale of Infant and Toddler Development Third Edition screening tool was used for the assessment of motor and cognitive development. Adjusted Poisson regression models were used to determine the association between groups and delayed development. The results indicated that only the ACTC group showed a higher risk of motor delay, specifically regarding fine motor skills, compared to the NC group (RR=2.81; 95%CI: 1.65; 4.77). Separate alcohol or tobacco consumption was not associated with delayed gross motor or cognitive development. However, the concomitant use of the two substances increased the risk of delayed acquisition of fine motor skills.

Determinants of the introduction of early complementary feeding before and after the third month of life: a multinomial analysis.

The introduction of early complementary feeding (ECF) is determined by different factors depending on when it occurs. The objective of this study was to analyze factors associated with the introduction of ECF in two different moments of the infant's life: from zero to three and from four to five months of age. A cohort with 3,306 dyads studied in the BRISA survey in São Luis/MA in 2010 was used. Questionnaires were applied at birth and at follow-up when the infants were 15 to 36 months of age of women with more than 20 weeks of gestational age, residing in this municipality. A multivariate model of multinomial logistic regression was used to verify associations between independent variables and ECF at 0 to 3 months and at 4 to 5 months of age. A hierarchical analysis model was used to select variables for confounding adjustment. Variables with a P-value <0.05 were considered significant. For ECF introduced between 0-3 months, the variables "use of pacifier", "maternal paid activity", "smoking", and "postpartum pregnancy" were identified as risk factors. The variables "use of pacifier" and "maternal paid activity" remained associated as a risk for ECF introduced from 4-5 months. The variable 'mother without partner' (RR=1.26 and P=0.04) represented a risk factor for ECF only for the 4-5 months period. Although each period presented specific risk factors, the use of pacifier and maternal professional activity were associated in the two periods studied, indicating their importance for the introduction of ECF.

Therapeutic efficiency of platelet gel for the treatment of oral ulcers related to chronic graft versus host disease after allogeneic haematopoietic stem cell transplantation.

BACKGROUND: Platelet (PLT) gel has been successfully used in tissue regeneration of diabetic and surgical wounds through the releasing of growth factors such as basic fibroblast and PLT-derived growth factors. Based on this background, our previous clinical trial have assessed the feasibility and efficacy of PLT gel for the treatment of muco-cutaneous lesions related to graft versus host disease (GvHD) after allogeneic haematopoietic stem cell transplantion (HSCT). The promising results reported in a small series of 6 patients, of whom 1 with oral ulcers, represent the rationale of the present study. MATERIALS AND METHODS: The aim of this study was to verify the efficacy and safety of PLT gel for treating oral ulcers due to chronic GvHD. Allogeneic hemocomponents were used to obtain PLT gel with an automated system for the on-site preparation and application of patient (autologous) or healthy blood donor (allogeneic)-derived fibrin sealant or PLT-rich fibrin (Vivostat system, Vivostat A/S). Ten patients with multiple oral lesions related to chronic GvHD underwent allogeneic PLT gel as local therapy alone or in combination with systemic therapy in half of the cases. RESULTS: After the second PLT gel application, all patients resumed the feeding and a significant improvement of the oral pain was observed. After a median of five PLT gel applications (range, 2-15), 7 out of 10 patients showed a complete response. No side effects were documented. CONCLUSION: These data confirm that the PLT gel may be used as a safe and effective tool, alone or in combination with systemic therapy, for the treatment of mucosal lesions of mouth related to cGvHD.

Identification of the G protein-coupled estrogen receptor (GPER) in human prostate: expression site of the estrogen receptor in the benign and neoplastic gland.

Estrogens are involved in growth, differentiation and pathogenesis of human prostate through the mediation of the classical estrogen receptors ERα and ERß. The G protein-coupled estrogen receptor (GPER) is a 'novel' mediator of estrogen signaling which has been recently recognized in some human reproductive tissues, but its expression in the prostate gland is still unknown. Here, we investigated GPER in benign (from 5 patients) and neoplastic prostatic tissues (from 50 patients) by immunohistochemical analysis and Western blotting. Normal areas of benign prostates revealed a strong GPER immunoreactivity in the basal epithelial cells while luminal epithelial cells were unreactive and stromal cells were weakly immunostained. GPER was also immunolocalized in adenocarcinoma samples but the immunoreactivity of tumoral areas decreased from Gleason pattern 2 to Gleason pattern 4. Furthermore, a strong GPER immunostaining was also revealed in cells of pre-neoplastic lesions (high-grade prostatic intra-epithelial neoplasia). Western blot analysis of benign and tumor protein extracts showed the presence of a ~42 kDa band, consistent with the GPER molecular weight. An increase in both pAkt and p cAMP-response-binding protein (pCREB) levels was also observed in poorly differentiated PCa samples. Finally, this work identified GPER in the epithelial basal cells of benign human prostate, with a different localization with respect to the classical estrogen receptors. Furthermore, the expression of GPER in prostatic adenocarcinoma cells was also observed but with a modulation of the immunoreactivity according to tumor cell arrangements.

Purinergic signaling modulates human visceral adipose inflammatory responses: implications in metabolically unhealthy obesity.

Obesity is accompanied by chronic inflammation of VAT, which promotes metabolic changes, and purinergic signaling has a key role in a wide range of inflammatory diseases. Therefore, we addressed whether fat inflammation could be differentially modulated by this signaling pathway in the MUO and in individuals who remain MHO. Our results show that the necrotized VAT of both groups released greater levels of ATP compared with lean donors. Interestingly, MUO tissue SVCs showed up-regulation and engagement of the purinergic P2X7R. The extracellular ATP concentration is regulated by an enzymatic process, in which CD39 converts ATP and ADP into AMP, and CD73 converts AMP into adenosine. In VAT, the CD73 ectoenzyme was widely distributed in immune and nonimmune cells, whereas CD39 expression was restricted to immune CD45PAN+ SVCs. Although the MUO group expressed the highest levels of both ectoenzymes, no difference in ATP hydrolysis capacity was found between the groups. As expected, MUO exhibited the highest NLRP3 inflammasome expression and IL-1ß production. MUO SVCs also displayed up-regulation of the A2AR, allowing extracellular adenosine to increase IL-1ß local secretion. Additionally, we demonstrate that metabolic parameters and BMI are positively correlated with purinergic components in VAT. These findings indicate that purinergic signaling is a novel mechanism involved in the chronic inflammation of VAT underlying the metabolic changes in obesity. Finally, our study reveals a proinflammatory role for adenosine in sustaining IL-1ß production in this tissue.

Sirolimus-based graft-versus-host disease prophylaxis promotes the in vivo expansion of regulatory T cells and permits peripheral blood stem cell transplantation from haploidentical donors.

Hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA) haploidentical family donors is a promising therapeutic option for high-risk hematologic malignancies. Here we explored in 121 patients, mostly with advanced stage diseases, a sirolimus-based, calcineurin-inhibitor-free prophylaxis of graft-versus-host disease (GvHD) to allow the infusion of unmanipulated peripheral blood stem cell (PBSC) grafts from partially HLA-matched family donors (TrRaMM study, Eudract 2007-5477-54). Conditioning regimen was based on treosulfan and fludarabine, and GvHD prophylaxis on antithymocyte globulin Fresenius (ATG-F), rituximab and oral administration of sirolimus and mycophenolate. Neutrophil and platelet engraftment occurred in median at 17 and 19 days after HSCT, respectively, and full donor chimerism was documented in patients' bone marrow since the first post-transplant evaluation. T-cell immune reconstitution was rapid, and high frequencies of circulating functional T-regulatory cells (Treg) were documented during sirolimus prophylaxis. Incidence of acute GvHD grade II-IV was 35%, and occurrence and severity correlated negatively with Treg frequency. Chronic GvHD incidence was 47%. At 3 years after HSCT, transpant-related mortality was 31%, relapse incidence 48% and overall survival 25%. In conclusion, GvHD prophylaxis with sirolimus-mycophenolate-ATG-F-rituximab promotes a rapid immune reconstitution skewed toward Tregs, allowing the infusion of unmanipulated haploidentical PBSC grafts.

Quality of surgery and neoadjuvant combined therapy in the ISG-GEIS trial on soft tissue sarcomas of limbs and trunk wall.

BACKGROUND: To explore correlation between the quality of surgery and outcome in high-risk soft tissue sarcoma (STS) patients treated within a phase III randomized trial. PATIENTS AND METHODS: In the trial, all patients received three cycles of preoperative chemotherapy (CT) with epirubicin 120 mg/m(2) and ifosfamide 9 g/m(2) and were randomly assigned to receive two further postoperative cycles. Radiotherapy (RT) could be delivered in the preoperative or postoperative setting. The association between surgical margins and overall survival (OS) was studied in a univariate and multivariate fashion. RESULTS: Two hundred and fifty-two patients completed the whole treatment and were operated conservatively. At a median follow-up of 60 months (IQR, 45-74 months), the 5-year OS was 0.73, even in patients with positive and negative margins. The 5-year cumulative incidence (CI) of local recurrence (LR) in patients with positive and negative microscopic margins was 0.17 (standard error, SE, 0.08) and 0.03 (SE, 0.01), respectively. In the subgroup of patients receiving combined preoperative CT-RT and with positive surgical margins, the CI of LR was 0. CONCLUSIONS: In this setting of high-risk STS treated by preoperative CT or CT-RT, the negative impact of positive margins on the outcome was limited. When close margins can be anticipated preoperative CT-RT may be a reasonable option to maximize the chance of cure.

Wnt4 inhibits cell motility induced by oncogenic Ras.

Aberrant motility and invasive ability are relevant hallmarks of malignant tumor cells. Pathways regulating the movement of cancer cells from the site of primary tumor toward adjacent and/or distant tissues are not entirely defined. By using a model of malignant transformation induced by Ras, we identified Wnt4 as an early target of Ras oncogenic signaling. Here we show that Wnt4 is repressed by Ras and that forced Wnt4 expression inhibits Ras-induced cell motility. Accordingly, we found that Wnt4 is downregulated in human anaplastic thyroid carcinomas, the most malignant and metastatic thyroid cancer histotype. Wnt4 interferes with Ras-induced actin cytoskeleton reorganization through non-canonical pathways, by altering the balance between the activation of different Rho-family small guanosine triphosphatases (GTPases). Finally, we demonstrate that Wnt4 is post-transcriptionally repressed by miR-24, a Ras-induced micro RNA (miRNA) targeting the 3'-untranslated region (UTR) of Wnt4. Taken together our data highlight a novel Ras-regulated miRNA-dependent circuitry regulating the motile phenotype of cancer cells.

[Study on the efficacy of personal protective equipment for skin against nicotine absorption through the skin route in tobacco workers]. / Verifica dell'efficacia protettiva dei dispositivi di protezione individuale per la cute, nei confronti dell'esposizione per via cutanea a nicotina, in operatori addetti alla lavorazione del tabacco.

During a previous assessment on the efficacy of some recently installed general dust extraction systems in a tuscan cigar manufacture line, both environmental and biologic monitoring were performed. Although the analysis of environmental samples supported the efficacy of the new general protection implant, these data did not parallel the results from the biologic monitoring, suggesting that nicotine skin absorption needed to be further investigated. We, therefore, carried out a study aimed at evaluating the efficacy of three different kind of PPE for skin (two nitrile gloves of different thickness and one latex glove), to be used by tobacco workers. The results of this study showed that the performance of these three materials in stopping nicotine transfer through the gloves was significantly different. The 0.22 mm thick nicotine gloves resulted, by far, the best gloves in protecting the workers' skin against nicotine exposure.

Downregulation of HMGA-targeting microRNAs has a critical role in human pituitary tumorigenesis.

Previous studies have demonstrated that high mobility group A proteins have a critical role on the onset of human pituitary adenomas. Indeed, both high mobility group A (HMGA) genes are overexpressed in pituitary adenomas, and consistently transgenic mice overexpressing either the Hmga1 or the Hmga2 gene develop mixed growth hormone/prolactin (GH-PRL)-secreting pituitary adenomas. Trisomy of chromosome 12, where HMGA2 is located, and/or amplification of the HMGA2 gene locus account for the HMGA2 overexpression in most human prolactinomas. Conversely, HMGA1 overexpression is not associated to any rearrangement or amplification of the HMGA1 locus. We have first identified micro RNAs (miRNAs) able to target both HMGA1 and HMGA2 messenger RNAs. Then, all of these miRNAs have been found downregulated in pituitary adenomas of different histotypes, compared with normal pituitary. Interestingly, their downregulation was also observed in nonfunctioning pituitary adenomas where HMGA2 overexpression is not associated to any alteration of the HMGA2 locus. Functional studies show that all these HMGA-targeting miRNAs inhibit the proliferation of the rat pituitary adenoma cell line GH3. Therefore, these results indicate that the downregulation of the miRNAs able to target the HMGA genes could contribute to increase HMGA protein levels in human pituitary adenomas, and then to pituitary tumorigenesis.

Upregulation of miR-21 by Ras in vivo and its role in tumor growth.

miR-21 is a microRNA (miRNA) frequently overexpressed in human cancers. Here we show that miR-21 is upregulated both in vitro and in vivo by oncogenic Ras, thus linking this miRNA to one of the most frequently activated oncogenes in human cancers. Ras regulation of miR-21 occurs with a delayed kinetic and requires at least two Ras downstream pathways. A screen of human thyroid cancers and non-small-cell lung cancers for the expression of miR-21 reveals that it is overexpressed mainly in anaplastic thyroid carcinomas, the most aggressive form of thyroid cancer, whereas in lung its overexpression appears to be inversely correlated with tumor progression. We also show that a LNA directed against miR-21 slows down tumor growth in mice. Consistently, a search for mRNAs downregulated by miR-21 shows an enrichment for mRNAs encoding cell cycle checkpoints regulators, suggesting an important role for miR-21 in oncogenic Ras-induced cell proliferation.

[Assessment of urinary cotinine in a group occupationally exposed to nicotine]. / Valutazione della cotinina urinaria in un gruppo di esposti professionalmente alla nicotina.

In a Tobacco processing company, located in central Italy, both air nicotine and, one of its metabolites, the urinary cotinine were assessed, as part of the evaluation of the effectiveness of recently implemented technical preventive controls. Urinary cotinine measurements ranged from 9,63 to 234,09 microg/gr creat. in non-smokers and from 178,79 to 2476,19 microg/gr creat. in smokers. Urinary cotinine proved useful as an exposure biological index especially in terms of population monitoring. On the contrary, the meaning of the measured values were less clear in single workers, because of significant both intra- and inter-individual variability.