Clinical Predictors of Severe Exacerbations in Pediatric Patients With Recurrent Wheezing.

Introduction Wheezing is common in preschool-aged children, affecting about half of all children within their first six years of life. Children who have recurrent wheezing experience disease-related morbidity, including increased emergency visits and hospitalizations. Early-life lower respiratory tract viral infections are linked to recurrent wheezing and eventual asthma onset. Identifying high-risk children is crucial, with the frequency and severity of wheezing episodes being good predictors of long-term outcomes. Aim To identify predictors of severe exacerbations in children with recurrent wheezing. Methods We conducted a retrospective cohort study involving 168 pediatric patients with recurrent wheezing followed up at our outpatient clinic. The outcome of interest was the occurrence of a severe exacerbation, defined as any exacerbation requiring hospitalization and the need for supplemental oxygenation or ventilatory support. Results The median age of the first wheezing exacerbation was five months, with a predominance of the male gender. Approximately two-thirds of the patients had a family history of atopy. Comorbid allergic rhinitis and atopic dermatitis were present in 15.4% and 16.7% of patients, respectively. Twenty percent of patients had a severe wheezing exacerbation as the first form of presentation, and 30% presented at least one severe exacerbation from the first presentation to the last follow-up. Patients with severe exacerbations were younger at the first episode (median age 4 months, IQR 2-7, versus 7 months, IQR 4-12, p=0.027) and more frequently had a family history of atopy (71.7% versus 55.6%, p=0.050). In this cohort, patients who initially presented with a severe episode are at increased risk of incident severe exacerbations during follow-up, HR 2.24 (95%CI 1.01-4.95). Conclusions We know that the severity of exacerbations in children with recurrent wheezing correlates with the long-term outcomes of the disease. Therefore, preventing severe exacerbations can positively impact the prognosis of these patients. In this analysis, we found independent predictors of severe exacerbations to be the first clinical episode before the age of three months and a family history of atopy. We also found that patients whose initial presentation was severe have a higher risk of new severe exacerbations. Therefore, these subgroups of patients should be closely monitored by pediatricians.

Evolution of household availability of regional foods in Amazonas.

OBJECTIVE: To evaluate the evolution of household availability of regional foods in the state of Amazonas, their distribution according to sociodemographic characteristics, and potential differences when compared to the remaining areas of Brazil. METHODS: Data on food acquisition for home consumption from the 2002-2003, 2008-2009, and 2017-2018 Pesquisa de Orçamentos Familiares (POFs - Consumer Expenditure Surveys) were analyzed, covering, respectively, 48,470, 55,970, and 57,920 households in Brazil, of which 1,075, 1,344, and 1,833 are in Amazonas. Foods were categorized into three groups: cassava and its derivatives, freshwater fish, and regional fruits. The study analyzed the amount of regional food purchased, expressed in relative household caloric share, for the entire area of Amazonas. Additionally, the data was stratified and analyzed according to sociodemographic variables, with differences assessed through the overlapping of 95% confidence intervals. FINDINGS: The household caloric share of the total regional foods in Amazonas was 22.54% in 2002-2003, 18.18% in 2008-2009, and 6.49% in 2017-2018. Across Brazil, those percentages were much lower in the same period: 3.67%, 3.34%, and 1.82%, respectively. Changes in Amazonas were primarily attributed to the steep drop in the cassava and derivatives group, which decreased from 14.30% in 2002-2003 to 12.74% in 2008-2009 and further declined to 3.09% in 2017-2018. Additionally, there was a gradual decline in household availability of freshwater fish, decreasing from 7.30% in 2002-2003 to 4.85% in 2008-2009 and reaching 2.90% in 2017-2018. Households in rural areas and with lower per capita income presented a higher proportion of calories from total regional foods; this particular stratum also experienced the most significant reductions in their consumption. CONCLUSION: During the study period, there was a significant decrease in the consumption of regional foods in Amazonas, particularly in lower income households in rural areas. Among them, the family reference person was typically a younger male with a lower educational background.

Kikuchi-Fujimoto Disease: A Case of SARS-CoV-2 Infection Triggering the Rare Disease.

Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, is a rare, benign, and self-limited disease caused by subacute necrotizing regional lymphadenopathy. The etiology is unknown, although virus and autoimmune mechanisms have been proposed. Patients develop enlarged lymph nodes, fever, and, less frequently, extranodal signs. No specific laboratory test contributes to the diagnosis, and lymph node biopsy is the gold standard to define the diagnosis. The treatment is generally with supportive therapy and usually is spontaneously resolved within six months.  In this article, the authors present the case of a 41-year-old female with mild SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection 10 weeks before she was admitted to the emergency department (ED) due to cervical lymphadenopathies and fever lasting over three weeks. Physical examination revealed multiple lymphadenopathies on the submandibular and jugular regions, cutaneous rash, and hepatosplenomegaly. Blood tests showed elevated acute phase proteins, thrombocytopenia, and increased transaminases and lactate dehydrogenase (LDH). Computed tomography (CT) of the neck showed multiple adenopathies at levels I, II, III, and IV according to the Classification for Lymph Nodes from the American Head and Neck Society and American Academy of Otolaryngology on the right side. Excision biopsy was performed and histopathological examination confirmed KFD. A comprehensive analysis performed was unrevealing of an infectious or autoimmune cause and was assumed to be most likely triggered by SARS-CoV-2 infection given the timeframe correlation. KFD diagnosis is challenging and there are few reported cases of association with SARS-CoV-2 in the literature. Although further investigation is still needed to better understand the relation between them, it is important that physicians take SARS-CoV-2 infection and vaccination into consideration in KFD's differential diagnosis.

Does digital media use contribute to decreased expressive language skills of pre-school-aged children? An exploratory study in Portuguese children.

PURPOSE/AIM OF THE STUDY: The purpose of this study was to analyse the relationship between digital media use and expressive language skills in the semantic and morphosyntactic domains, of pre-school-aged children (3 years-and-0 months to 5 years-and-11 months). MATERIALS AND METHODS: Verbal oral expression (VOE) tasks of the Pre-school Assessment of Language Test (Teste de Linguagem-Avaliação da Linguagem Pré-Escolar) were administered to 237 pre-school children with no previous identified neurological or developmental conditions associated with language disorders to assess expressive language skills in the semantic and morphosyntactic domains. Parents completed a questionnaire about their children's medical conditions, development (using the milestones of the Survey of Well-being of Young Children and the Pre-school Paediatric Symptom Checklist), and exposure to screens (using ScreenQ). Correlations between VOE and continuous variables such as ScreenQ were computed and a regression model incorporating all variables significantly associated with total language verbal expression was created. RESULTS: ScreenQ revealed a negative and significant correlation with children's verbal oral expression as well as significance in the regression model. Parents' education was the most significant predictor in this regression model. CONCLUSIONS: This study emphasizes the importance of parents establishing limits for digital media use and promote good practices such as co-viewing.

Expansion of ventral foregut is linked to changes in the enhancer landscape for organ-specific differentiation.

Cell proliferation is fundamental for almost all stages of development and differentiation that require an increase in cell number. Although cell cycle phase has been associated with differentiation, the actual process of proliferation has not been considered as having a specific role. Here we exploit human embryonic stem cell-derived endodermal progenitors that we find are an in vitro model for the ventral foregut. These cells exhibit expansion-dependent increases in differentiation efficiency to pancreatic progenitors that are linked to organ-specific enhancer priming at the level of chromatin accessibility and the decommissioning of lineage-inappropriate enhancers. Our findings suggest that cell proliferation in embryonic development is about more than tissue expansion; it is required to ensure equilibration of gene regulatory networks allowing cells to become primed for future differentiation. Expansion of lineage-specific intermediates may therefore be an important step in achieving high-fidelity in vitro differentiation.

Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes.

BACKGROUND: Truncating pathogenic or likely pathogenic variants of CDH1 cause hereditary diffuse gastric cancer (HDGC), a tumour risk syndrome that predisposes carrier individuals to diffuse gastric and lobular breast cancer. Rare CDH1 missense variants are often classified as variants of unknown significance. We conducted a genotype-phenotype analysis in families carrying rare CDH1 variants, comparing cancer spectrum in carriers of pathogenic or likely pathogenic variants (PV/LPV; analysed jointly) or missense variants of unknown significance, assessing the frequency of families with lobular breast cancer among PV/LPV carrier families, and testing the performance of lobular breast cancer-expanded criteria for CDH1 testing. METHODS: This genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 rare CDH1 variants and 1021 relatives, irrespective of HDGC clinical criteria, from 29 institutions in ten member-countries of the European Reference Network on Tumour Risk Syndromes (ERN GENTURIS). Data were collected from Oct 1, 2018, to Sept 20, 2022. Variants were classified by molecular type and clinical actionability with the American College of Medical Genetics and Association for Molecular Pathology CDH1 guidelines (version 2). Families were categorised by whether they fulfilled the 2015 and 2020 HDGC clinical criteria. Genotype-phenotype associations were analysed by Student's t test, Kruskal-Wallis, χ2, and multivariable logistic regression models. Performance of HDGC clinical criteria sets were assessed with an equivalence test and Youden index, and the areas under the receiver operating characteristic curves were compared by Z test. FINDINGS: From 1971 phenotypes (contributed by 854 probands and 1021 relatives aged 1-93 years), 460 had gastric and breast cancer histology available. CDH1 truncating PV/LPVs occurred in 176 (21%) of 854 families and missense variants of unknown significance in 169 (20%) families. Multivariable logistic regression comparing phenotypes occurring in families carrying PV/LPVs or missense variants of unknown significance showed that lobular breast cancer had the greatest positive association with the presence of PV/LPVs (odds ratio 12·39 [95% CI 2·66-57·74], p=0·0014), followed by diffuse gastric cancer (8·00 [2·18-29·39], p=0·0017) and gastric cancer (7·81 [2·03-29·96], p=0·0027). 136 (77%) of 176 families carrying PV/LPVs fulfilled the 2015 HDGC criteria. Of the remaining 40 (23%) families, who did not fulfil the 2015 criteria, 11 fulfilled the 2020 HDGC criteria, and 18 had lobular breast cancer only or lobular breast cancer and gastric cancer, but did not meet the 2020 criteria. No specific CDH1 variant was found to predispose individuals specifically to lobular breast cancer, although 12 (7%) of 176 PV/LPV carrier families had lobular breast cancer only. Addition of three new lobular breast cancer-centred criteria improved testing sensitivity while retaining high specificity. The probability of finding CDH1 PV/LPVs in patients fulfilling the lobular breast cancer-expanded criteria, compared with the 2020 criteria, increased significantly (AUC 0·92 vs 0·88; Z score 3·54; p=0·0004). INTERPRETATION: CDH1 PV/LPVs were positively associated with HDGC-related phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), and no evidence for a positive association with these phenotypes was found for CDH1 missense variants of unknown significance. CDH1 PV/LPVs occurred often in families with lobular breast cancer who did not fulfil the 2020 HDGC criteria, supporting the expansion of lobular breast cancer-centred criteria. FUNDING: European Reference Network on Genetic Tumour Risk Syndromes, European Regional Development Fund, Fundação para a Ciência e a Tecnologia (Portugal), Cancer Research UK, and European Union's Horizon 2020 research and innovation programme.

Evolution of household availability of regional foods in Amazonas / Evolução da disponibilidade domiciliar de alimentos regionais no Amazonas

ABSTRACT OBJECTIVE To evaluate the evolution of household availability of regional foods in the state of Amazonas, their distribution according to sociodemographic characteristics, and potential differences when compared to the remaining areas of Brazil. METHODS Data on food acquisition for home consumption from the 2002-2003, 2008-2009, and 2017-2018 Pesquisa de Orçamentos Familiares (POFs - Consumer Expenditure Surveys) were analyzed, covering, respectively, 48,470, 55,970, and 57,920 households in Brazil, of which 1,075, 1,344, and 1,833 are in Amazonas. Foods were categorized into three groups: cassava and its derivatives, freshwater fish, and regional fruits. The study analyzed the amount of regional food purchased, expressed in relative household caloric share, for the entire area of Amazonas. Additionally, the data was stratified and analyzed according to sociodemographic variables, with differences assessed through the overlapping of 95% confidence intervals. FINDINGS The household caloric share of the total regional foods in Amazonas was 22.54% in 2002-2003, 18.18% in 2008-2009, and 6.49% in 2017-2018. Across Brazil, those percentages were much lower in the same period: 3.67%, 3.34%, and 1.82%, respectively. Changes in Amazonas were primarily attributed to the steep drop in the cassava and derivatives group, which decreased from 14.30% in 2002-2003 to 12.74% in 2008-2009 and further declined to 3.09% in 2017-2018. Additionally, there was a gradual decline in household availability of freshwater fish, decreasing from 7.30% in 2002-2003 to 4.85% in 2008-2009 and reaching 2.90% in 2017-2018. Households in rural areas and with lower per capita income presented a higher proportion of calories from total regional foods; this particular stratum also experienced the most significant reductions in their consumption. CONCLUSION During the study period, there was a significant decrease in the consumption of regional foods in Amazonas, particularly in lower income households in rural areas. Among them, the family reference person was typically a younger male with a lower educational background.

RESUMO OBJETIVO Avaliar a evolução da disponibilidade domiciliar de alimentos regionais no Amazonas, sua distribuição segundo características sociodemográficas e potenciais diferenças em relação ao restante do Brasil. MÉTODOS Foram analisados dados de aquisição de alimentos para consumo domiciliar das Pesquisas de Orçamentos Familiares (POFs) de 2002-2003, 2008-2009 e 2017-2018, que estudaram, respectivamente, 48.470, 55.970 e 57.920 domicílios no Brasil, dos quais 1,075, 1.344 e 1.833 estão no Amazonas. Os alimentos foram reunidos em três grupos: macaxeira e derivados, peixes de água doce, e frutos regionais. A quantidade de alimento regional adquirido, expressa em participação calórica relativa domiciliar, foi analisada para o Amazonas como um todo e segundo variáveis sociodemográficas (diferenças avaliadas pela sobreposição dos intervalos de confiança de 95%). RESULTADOS A participação calórica domiciliar do total de alimentos regionais no Amazonas foi de 22,54% em 2002-2003, 18,18% em 2008-2009 e 6,49% em 2017-2018. No Brasil, estes percentuais foram bem menores no mesmo período: 3,67%, 3,34% e 1,82%, respectivamente. As mudanças no Amazonas ocorreram, principalmente, pela drástica redução do grupo de macaxeira e derivados (de 14,30% em 2002-2003 para 12,74% em 2008-2009 e 3,09% em 2017-2018) e pelo declínio gradativo da disponibilidade domiciliar de peixes de água doce (de 7,30% em 2002-2003 para 4,85% 2008-2009 e 2,90% em 2017-2018). Domicílios do meio rural e com menor renda per capita tiveram maior participação calórica do total de alimentos regionais, estratos que também tiveram as maiores reduções. CONCLUSÃO Houve redução significativa da presença de alimentos regionais no Amazonas no período estudado, atingindo principalmente os domicílios da zona rural e com menor renda, cuja pessoa de referência da família era do sexo masculino, mais jovem e com menor escolaridade.

IgA Vasculitis involving four systems / Vasculitis IgA que afecta a cuatro sistemas

Henoch-Schonlein Purpura (HSP) is a systemic vasculitis now called IgA vasculitis, that infrequently occurs in adults. While rheumatological andgastrointestinal complications are common, lung involvement is a rare complication. We report the case of a 70 year-old female that presented tothe hospital with purpuric lesions on her legs and ileitis. During her hospital stay she developed respiratory distress, and the computed tomography (CT scan) showed evidence of Diffuse Alveolar Hemorrhage (DAH). She also had renal dysfunction, and the renal biopsy confirmed the presence of leukocytoclastic vasculitis on histology, consistent with HSP. The patient was initiated on corticosteroid therapy and cyclophosphamide,in addition to supportive management, leading to the resolution of her symptoms.This case is unique, as it presents a rare complication of HSP, with pulmonary disease, causing DAH. Furthermore, adult onset HSP is also anuncommon occurrence.It is very important to recognize DAH early in HSP, as it holds a high mortality rate. (AU)

Transcriptional heterogeneity and cell cycle regulation as central determinants of Primitive Endoderm priming.

During embryonic development cells acquire identity as they proliferate, implying that an intrinsic facet of cell fate choice requires coupling lineage decisions to cell division. How is the cell cycle regulated to promote or suppress heterogeneity and differentiation? We explore this question combining time lapse imaging with single-cell RNA-seq in the contexts of self-renewal, priming, and differentiation of mouse embryonic stem cells (ESCs) towards the Primitive Endoderm (PrE) lineage. Since ESCs are derived from the inner cell mass (ICM) of the mammalian blastocyst, ESCs in standard culture conditions are transcriptionally heterogeneous containing dynamically interconverting subfractions primed for either of the two ICM lineages, Epiblast and PrE. Here, we find that differential regulation of cell cycle can tip the balance between these primed populations, such that naïve ESC culture promotes Epiblast-like expansion and PrE differentiation stimulates the selective survival and proliferation of PrE-primed cells. In endoderm differentiation, this change is accompanied by a counter-intuitive increase in G1 length, also observed in vivo. While fibroblast growth factor/extracellular signal-regulated kinase (FGF/ERK) signalling is a key regulator of ESC differentiation and PrE specification, we find it is not just responsible for ESCs heterogeneity, but also the inheritance of similar cell cycles between sisters and cousins. Taken together, our results indicate a tight relationship between transcriptional heterogeneity and cell cycle regulation in lineage specification, with primed cell populations providing a pool of flexible cell types that can be expanded in a lineage-specific fashion while allowing plasticity during early determination.

Psychometric properties of the ScreenQ for measuring digital media use in Portuguese young children.

AIM: Digital media use is prevalent among children and linked to potential developmental and health risks, but validated measures of children's digital media use are lacking. The aim of this study was to validate the Portuguese version of the ScreenQ with three distinct children's age groups. METHODS: Parents of children living in Portugal completed an online survey including the 16-item version of the ScreenQ and items related to home activities and digital media use. A combination of classical and modern theory (Rasch) methods was used for analysis. RESULTS: A total of 549 mothers and 51 fathers of 325 girls and 322 boys from 6 months to 9 years and 11 months old responded to the survey. Point-measure correlations were all positive and endorsement of item values were within acceptable ranges. Cronbach's coefficient α was acceptable for a new measure, and test-retest reliability was high. Statistically significant correlations were found between ScreenQ total scores and relevant demographic, play-related, parenting and digital media use items. CONCLUSION: The Portuguese version of the ScreenQ exhibited sound psychometric properties, including internal consistency and concurrent validity referenced to external items. Higher ScreenQ scores were correlated with higher digital media multitasking, lower parent-child interaction, and higher concerns regarding child's learning and behaviour.

Screening Health-Promoting Compounds for Their Capacity to Induce the Activity of FOXO3.

Several chemical compounds including natural products have been suggested as being effective against age-related diseases or as beneficial for a healthy life. On the other hand, forkhead box O (FOXO) proteins are emerging as key cellular components associated with extreme human longevity. FOXO proteins are mainly regulated by posttranslational modifications and as these modifications are reversible, activation and inactivation of FOXO are attainable through pharmacological treatment. Here, we questioned whether a panel of compounds with known health-beneficial properties has the capacity to induce the activity of FOXO factors. We show that resveratrol, a phytoalexin present in grapes and other food products, the amide alkaloid piperlongumine found in the fruit of the long pepper, and the plant-derived ß-carboline compound harmine induced nuclear translocation of FOXO3. We also show that piperlongumine and harmine but not resveratrol activate FOXO-dependent transcription. We determined the half maximal effective concentration (EC50) values for resveratrol, piperlongumine, and harmine for FOXO translocation, and analyzed their inhibitory impact on chromosomal maintenance 1 (CRM1)-mediated nuclear export and the production of reactive oxygen species (ROS). We also used chemical biology approach and Western blot analysis to explore the underlying molecular mechanisms. We show that harmine, piperlongumine, and resveratrol activate FOXO3 independently of phosphoinositide 3-kinase (PI3K)/AKT signaling and the CRM1-mediated nuclear export. The effect of harmine on FOXO3 activity is at least partially mediated through the inhibition of dual-specificity tyrosine (Y) phosphorylationregulated kinase 1A (DYRK1A) and can be reverted by the inhibition of sirtuins (SIRTs).

Drug-Induced Liver Injury Due To Losartan.

Drug-induced liver injury (DILI) is a challenging diagnosis since a wide variety of medicines can cause adverse reactions. Losartan is an angiotensin II receptor antagonist (ARA-II) approved for the treatment of arterial hypertension. The most common adverse effects are fatigue, anaemia, weakness and cough. An increase in transaminases has been reported with less frequency (<2% of cases). Although the mechanism is not fully understood, DILI onset is usually within 1-8 weeks of therapy, and hepatic enzymology usually normalizes 2-4 months after drug suspension. The authors present the case of a 66-year-old male patient with a medical history of arterial hypertension and a prior hospitalization (4 years previously) for drug-induced hepatitis, which, at the time, was attributed to a dietary supplement. Four years later, because of new onset of hypertension, losartan was reintroduced. After 3 weeks, the patient was admitted to the emergency department with complaints of acute abdominal pain associated with asthenia, nausea and increased abdominal volume that had first developed 8 days previously. After exclusion of other causes, DILI associated with losartan was assumed. This is a very rare adverse effect since only seven cases have been described in the literature. LEARNING POINTS: Toxic hepatitis due to losartan is very rare, despite widespread use of the drug.A high index of suspicion for drug-induced liver injury (DILI) should be maintained while other diagnoses are carefully excluded.Monitoring the use of the offending drug is crucial, since DILI recurrence is associated with worse prognosis.

Q Fever: An Emerging Reality in Portugal.

Q fever is a zoonosis caused by Coxiella burnetii with worldwide distribution at the increasing expression in Europe and endemic in Portugal. It is transmitted by inhalation of aerosols containing spores, main reservoir being cattle, goats and sheep as by ingesting cottage cheese or unpasteurized milk. The majority of patients are asymptomatic; however, they may present with fever, atypical pneumonia, acute hepatitis, cutaneous manifestations and rarely with cardiac or neurological involvement. Although most cases are self-limited, focal persistent or chronic Q fever can manifest years after the onset, wherefore follow-up is essential. The clinical heterogeneity may be so variable that the disease is often diagnosed only if it has been systematically considered. It should be especially taken into account in the presence of risk factors as valvular or joint prostheses, immunocompromised patients, pregnant women and epidemiological setting. The authors present a rare case of Coxiella burnetii pneumonia with cutaneous and hepatic manifestations without any risk factor. This case aims to emphasize the importance of Q fever in the differential diagnosis of fever or atypical pneumonia, even in the absence of known risk factors. The diagnosis is often challenging for clinicians and it is necessary to maintain a high index of suspicion. In Europe and specifically in Portugal is mandatory to report the cases to establish the real impact of this disease.

Are Emotional and Behavioral Problems of Infants and Children Aged Younger Than 7 Years Related to Screen Time Exposure During the Coronavirus Disease 2019 Confinement? An Exploratory Study in Portugal.

The coronavirus disease 2019 outbreak forced most of the world's population to be confined at home to prevent contagion. Research reveals that one of the consequences of this confinement for children is an increased amount of time spent using screens (television, computers, and mobile devices, etc.) at home. This exploratory study aims to analyze the association between screen time exposure and emotional/behavioral problems of infants and children aged under 7 years, as manifested during the lockdown period in Portugal due to the coronavirus disease 2019 outbreak. The study was controlled for sociodemographic and confinement variables. A sample of 193 parents of children aged from 6 months to 6 years and 12 months, residing in Portugal, completed a survey about the time and manner of use of screen time exposure of their children. Data were derived on circumstances both before and after the confinement; the survey also explored the child's behavioral and emotional adjustment. The findings revealed a modest relationship between children's exposure time to screens and behavioral and emotional problems on children studied. It was also found that parents may play an important role in children's behavioral and emotional adjustment during the confinement period.

Naïve human pluripotent stem cells respond to Wnt, Nodal and LIF signalling to produce expandable naïve extra-embryonic endoderm.

Embryonic stem cells (ESCs) exist in at least two states that transcriptionally resemble different stages of embryonic development. Naïve ESCs resemble peri-implantation stages and primed ESCs the pre-gastrulation epiblast. In mouse, primed ESCs give rise to definitive endoderm in response to the pathways downstream of Nodal and Wnt signalling. However, when these pathways are activated in naïve ESCs, they differentiate to a cell type resembling early primitive endoderm (PrE), the blastocyst-stage progenitor of the extra-embryonic endoderm. Here, we apply this context dependency to human ESCs, showing that activation of Nodal and Wnt signalling drives the differentiation of naïve pluripotent cells toward extra-embryonic PrE, or hypoblast, and these can be expanded as an in vitro model for naïve extra-embryonic endoderm (nEnd). Consistent with observations made in mouse, human PrE differentiation is dependent on FGF signalling in vitro, and we show that, by inhibiting FGF receptor signalling, we can simplify naïve pluripotent culture conditions, such that the inhibitor requirements closer resemble those used in mouse. The expandable nEnd cultures reported here represent stable extra-embryonic endoderm, or human hypoblast, cell lines.This article has an associated 'The people behind the papers' interview.

Dynamic lineage priming is driven via direct enhancer regulation by ERK.

Central to understanding cellular behaviour in multi-cellular organisms is the question of how a cell exits one transcriptional state to adopt and eventually become committed to another. Fibroblast growth factor-extracellular signal-regulated kinase (FGF -ERK) signalling drives differentiation of mouse embryonic stem cells (ES cells) and pre-implantation embryos towards primitive endoderm, and inhibiting ERK supports ES cell self-renewal1. Paracrine FGF-ERK signalling induces heterogeneity, whereby cells reversibly progress from pluripotency towards primitive endoderm while retaining their capacity to re-enter self-renewal2. Here we find that ERK reversibly regulates transcription in ES cells by directly affecting enhancer activity without requiring a change in transcription factor binding. ERK triggers the reversible association and disassociation of RNA polymerase II and associated co-factors from genes and enhancers with the mediator component MED24 having an essential role in ERK-dependent transcriptional regulation. Though the binding of mediator components responds directly to signalling, the persistent binding of pluripotency factors to both induced and repressed genes marks them for activation and/or reactivation in response to fluctuations in ERK activity. Among the repressed genes are several core components of the pluripotency network that act to drive their own expression and maintain the ES cell state; if their binding is lost, the ability to reactivate transcription is compromised. Thus, as long as transcription factor occupancy is maintained, so is plasticity, enabling cells to distinguish between transient and sustained signals. If ERK signalling persists, pluripotency transcription factor levels are reduced by protein turnover and irreversible gene silencing and commitment can occur.

Prenatal sonographic diagnosis of isolated fetal ascites in cri-du-chat (5p-) syndrome: A case report.

Isolated fetal ascites and cri-du-chat syndrome (CdCS; OMIM #123450) are two very rare conditions that, to our best knowledge, have never been reported together. Here, we describe a case of isolated fetal ascites detected in the first trimester ultrasound, with no other remarkable signs. After an extensive work-up (fetal ultrasound, serologies, Coombs test, and NIPT), an amniocentesis was performed and revealed an abnormal karyotype of 46,XX,del(5)(p15.2), characteristic of CdCS. We hypothesize that isolated fetal ascites has to be considered an antenatal ultrasonographic marker for CdCS, a finding that should be confirmed in further cases.

Alimentação no Amazonas: evolução da participação dos alimentos regionais e percepção da satisfação com o consumo no domicílio / Feeding in Amazonas: evolution of regional food participation and perception of satisfaction with consumption at home

A adoção de uma abordagem sistêmica da alimentação que respeite a diversidade e a sustentabilidade vem corroborar os preceitos da Segurança Alimentar e Nutricional. A alimentação vem sofrendo forte influência do fenômeno da globalização, originando um comportamento alimentar padronizado. A transição alimentar no Amazonas ainda não está claramente identificada. Nesse cenário de mudanças, a presença dos alimentos regionais precisa ser entendida. Assim, esse estudo, teve como objetivo, analisar a alimentação no Amazonas por meio da disponibilidade domiciliar de alimentos, avaliando a evolução da participação dos alimentos regionais e identificando a relação entre a percepção da satisfação com o consumo domiciliar com padrões de aquisição de alimentos. No primeiro manuscrito foram utilizados dados de aquisição alimentar da Pesquisa de Orçamento Familiar (POF) 2002-2003 e 2008- 2009. Os alimentos regionais do Amazonas foram reunidos em sete grupos : farinha de mandioca, goma de tapioca e produtos, raízes e tubérculos, peixes de água doce, carnes de caça, frutas regionais e oleaginosas. A quantidade de alimento regional adquirido expressa em participação calórica relativa (%) per capita foi analisada segundo as variáveis sociodemográficas por comparação das médias, utilizando intervalos de confiança de 95%. No segundo manuscrito foram utilizados dados de aquisição alimentar referentes aos domicílios do Amazonas urbano da edição da POF 2008-2009, a partir dos quais foram identificados padrões alimentares por meio da análise fatorial exploratória, utilizando a extração por componentes principais. A percepção da satisfação com o consumo domiciliar foi avaliada por comparação das médias dos scores dos padrões alimentares e as categorias das variáveis, utilizando intervalos de confiança de 95%. Foram identificadas importantes informações sobre a alimentação no Amazonas. Houve redução significativa da presença de alimentos regionais no Amazonas no referido período, atingindo principalmente os domicílios da zona rural e com menor renda, bem como, as famílias cuja pessoa de referência era do sexo masculino, mais jovem e com menor escolaridade. Foram identificados quatro padrões alimentares: tradicional misto, regional e fast food. A maior satisfação com a quantidade e a qualidade do alimento consumido no domicílio ocorreu entre as famílias com adesão ao padrão misto. Famílias com maior adesão ao padrão tradicional estavam insatisfeitas com a quantidade. Assim como, aquelas aderidas ao padrão regional apresentaram insatisfação com a qualidade. O estudo revelou que a alimentação no Amazonas possui peculiaridades, sugerindo que a transição alimentar em nível local pode não estar ocorrendo da mesma forma que no cenário nacional. Ações que visem promover alimentação saudável devem considerar os perfis de comportamento alimentar existentes e a percepção em relação aos alimentos consumidos, para que as boas práticas sejam de fato aceitas e incorporadas pela população

The adoption of a systemic approach to food that respects diversity and sustainability corroborates the precepts of Food and Nutrition Security. Food has been strongly influenced by the phenomenon of globalization, resulting in a standardized food behavior. The food transition in Amazonas has not yet been clearly identified. In this scenario of changes, the presence of regional foods needs to be understood. The purpose of this study was to analyze food in Amazonas through household availability of food, assessing the evolution of regional food participation and identifying the relationship between the perception of satisfaction with household consumption and patterns of food acquisition. In the first manuscript, food acquisition data from the Family Budget Survey (POF) 2002-2003 and 2008-2009 were used. The regional foods of Amazonas were grouped into seven groups: cassava flour, tapioca gum and products, roots and tubers, freshwater fish, game meat, regional fruits and oilseeds. The amount of regional food purchased expressed as relative (%) per capita caloric intake was analyzed according to sociodemographic variables by comparison of means, using 95% confidence intervals. In the second manuscript, food acquisition data referring to the households of the urban Amazonas of the edition of POF 2008-2009 were used, from which food patterns were identified through exploratory factorial analysis, using main component extraction. The perception of satisfaction with home consumption was evaluated by comparing the means of the scores of the food standards and the categories of the variables, using 95% confidence intervals. Important information on feeding in Amazonas was identified. There was a significant reduction in the presence of regional foods in Amazonas in the period, reaching mainly the rural households with lower income, as well as the families whose reference person was male, younger and with less schooling. Four food standards were identified: traditional mixed, regional and fast food. The greatest satisfaction with the quantity and quality of food consumed at home occurred among families with adherence to the mixed pattern. Families with greater adherence to the traditional pattern were dissatisfied with the quantity. Likewise, those adhering to the regional standard showed dissatisfaction with quality. The study revealed that food in Amazonas has peculiarities, suggesting that the food transition at the local level may not be occurring in the same way as in the national scenario. Actions aimed at promoting healthy eating should consider existing eating behavior patterns and perceptions of food consumption, so that good practices are actually accepted and incorporated by the population